Erratum to: Fibrinogen production is enhanced in an in-vitro model of non-alcoholic fatty liver disease: an isolated risk factor for cardiovascular events?
Emily YeungPhilipp TreskesSarah F. MartinJonathan ManningDonald R. DunbarSophie M. RogersThierry Le BihanK. A. LockmanSteven D. MorleyPeter C. HayesLeonard J. NelsonJohn Plevris
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Cardiovascular disease (CVD) remains the major cause of excess mortality in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the individual contribution of NAFLD to CVD risk factors in the absence of pathogenic influences from other comorbidities often found in NAFLD patients, by using an established in-vitro model of hepatic steatosis.Histopathological events in non-alcoholic fatty liver disease were recapitulated by focused metabolic nutrient overload of hepatoblastoma C3A cells, using oleate-treated-cells and untreated controls for comparison. Microarray and proteomic data from cell culture experiments were integrated into a custom-built systems biology database and proteogenomics analysis performed. Candidate genes with significant dysregulation and concomitant changes in protein abundance were identified and STRING association and enrichment analysis performed to identify putative pathogenic pathways.The search strategy yielded 3 candidate genes that were specifically and significantly up-regulated in nutrient-overloaded cells compared to untreated controls: fibrinogen alpha chain (2.2 fold), fibrinogen beta chain (2.3 fold) and fibrinogen gamma chain (2.1 fold) (all rank products pfp <0.05). Fibrinogen alpha and gamma chain also demonstrated significant concomitant increases in protein abundance (3.8-fold and 2.0-fold, respectively, p <0.05).In-vitro modelling of NAFLD and reactive oxygen species formation in nutrient overloaded C3A cells, in the absence of pathogenic influences from other comorbidities, suggests that NAFLD is an isolated determinant of CVD. Nutrient overload-induced up-regulation of all three fibrinogen component subunits of the coagulation cascade provides a possible mechanism to explain the excess CVD mortality observed in NAFLD patients.Keywords:
Steatosis
Introduction: Liver grafts with limited steatosis are currently used for liver transplantation, but the natural history of graft steatosis is not well known. Project Aims or Questions: This program evaluation aimed at assessing changes of steatosis after liver transplantation. Design: A retrospective chart review was performed assessing presence and severity of steatosis in the liver explant and in time zero donor graft biopsies carried out at the time-point of liver transplantation on histopathology and on imaging one year thereafter in 30 well characterized patients. Results: Ten patients (33%) showed steatosis on explant. Time zero biopsy revealed steatosis in 18 grafts (60%) and no steatosis in 12 (40%). One year after transplantation, 8 patients (27%) had steatosis and 22 patients (63%) had none. Fourteen patients (47%) showed changes in steatosis: 12 showed resolution and 2 showed de novo steatosis. Explant macrovesicular steatosis was associated with presence of steatosis 1 year after transplantation (binary logistic regression model, p = 0.014), but not macrovesicular steatosis in the donor graft at time-point of transplantation. Conclusion: Resolution of graft steatosis was frequent. Presence of steatosis in the recipient's liver, but not graft steatosis, was a risk factor for steatosis 1 year after transplantation. Factors related to the recipient seem to prevail over donor-related factors in determining the persistence or de novo appearance of steatosis after liver transplantation.
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Liver steatosis
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Abstract Background: Steatosis is diagnosed on the basis of the macroscopic aspect of the liver evaluated by the surgeon at the time of organ extraction or by means of a frozen biopsy. Aim: In the present study, the applicability of laser‐induced fluorescence (LIF) spectroscopy was investigated as a method for the diagnosis of different degrees of steatosis experimentally induced in rats. Material and methods: Rats received a high‐lipid diet for different periods of time. The animals were divided into groups according to the degree of induced steatosis diagnosis by histology. The concentration of fat in the liver was correlated with LIF by means of the steatosis fluorescence factor (SFF). Results: The histology classification, according to liver fat concentration was, Severe Steatosis, Moderate Steatosis, Mild Steatosis and Control (no liver steatosis). Fluorescence intensity could be directly correlated with fat content. It was possible to estimate an average of fluorescence intensity variable by means of different confidence intervals ( P =95%) for each steatosis group. SFF was significantly higher in the Severe Steatosis group ( P <0.001) compared with the Moderate Steatosis, Mild Steatosis and Control groups. Conclusion: The various degrees of steatosis could be directly correlated with SFF. LIF spectroscopy proved to be a method capable of identifying the degree of hepatic steatosis in this animal model, and has the potential of clinical application for non‐invasive evaluation of the degree of steatosis.
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In 12 patients treated with 100 mg rt-PA/3 h for acute myocardial infarction (AMI), serial fibrinogen levels were measured with the Clauss clotting rate assay ("functional fibrinogen") and with a new enzyme immunoassay for immunologically intact fibrinogen ("intact fibrinogen"). Levels of functional and "intact fibrinogen" were strikingly different: functional levels were higher at baseline; showed a more pronounced breakdown during rt-PA therapy; and a rebound phenomenon which was not seen for "intact fibrinogen". The ratio of functional to "intact fibrinogen" was calculated for each individual patient and each time point. The mean ratio (n = 12) was 1.6 at baseline, 1.0 at 90 min, and increased markedly between 8 and 24 h to a maximum of 2.1 (p < 0.01), indicating that functionality of circulating fibrinogen changes during AMI and subsequent thrombolytic therapy. The increased ratio of functional to "intact fibrinogen" seems to reflect a more functional fibrinogen at baseline and following rt-PA infusion. This is in keeping with data that the relative amount of fast clotting "intact HMW fibrinogen" of total fibrinogen is increased in initial phase of AMI. The data suggest that about 20% of HMW fibrinogen are converted to partly degraded fibrinogen during rt-PA infusion. The rebound phenomenon exhibited by functional fibrinogen may result from newly synthesized fibrinogen with a high proportion of HMW fibrinogen with its known higher degree of phosphorylation. Fibrinogen- and fibrin degradation products were within normal range at baseline. Upon infusion of the thrombolytic agent, maximum median levels of 5.88 micrograms/ml and 5.28 micrograms/ml, respectively, were measured at 90 min.(ABSTRACT TRUNCATED AT 250 WORDS)
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Introduction Steatotic liver grafts represent the most common type of extended criteria of liver grafts organ that have been introduced in the last decade due to the disparity between liver transplant candidates and the number of available organs. The aim of this study was to determine the effect of donor graft steatosis on the outcomes of liver transplantation (LT). Material and Methods We performed a retrospective study during the period between 2006-2016. Excluding HIV positive recipients, split grafts, simultaneos liver-kidney transplantation, donors eldier than 70 years, we analyzed 172 patients. The sample divided into 3 groups: normal histology (steatosis<10%), mild steatosis (10-30%), and moderate steatosis (30-60%). Factors such as mortality, overall survival, graft surgical complications, graft rejection were analyzed following the degrees of steatosis. Results Among the existing pathology reports of the 172 cases we found 94 (54%) with normal pathology (steatosis less than 10%), 74 (43%) with mild steatosis (10-30%) and 4 (3%) patients with moderate steatosis (30-60%). If we compare the MELD score before transplantation or the transfusional requierements using the McCluskey index, no differences were seen among the three groups. Mean ICU stay were also similar: 6.7 days in the non steatosis group, 7.6 days in mild steatosis and 3,5 in moderate steatosis (p=0.6). No difference was observed between the three groups for the incidence of complications such as acute graft rejection (p=0,1), ischemic cholangiopathy (p=0,1), hepatic artery thrombosis or chronic rejection (p=0,2). Regarding the early allograft disfunction (EAD) and primary non function (PNF), no differences were observed: 8 EAD (8,5%) in no steatosis group and 6 (8,1%) in the mild steatosis. No difference was found on the actuarial survival (AS) at 1,3 and 5 years, being for each group: steatosis<10%, the AS was 87%, 82% and respectively 81%. In mild steatosis group the AS was 85%, 83% and respectively 82% (p=0,5). If we take a look to the early mortality, during the hospitalization stay, 3 (3%) died in the non steatosis group and 6 (8%) in the mild steatosis. Conclusion Though we need a larger sample size, we did not find differences in terms of overall survival or complications after LT using grafts with middle to moderate steatosis (<60%).
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AIMS To evaluate the frequency and the severity of hepatic steatosis in chronic hepatitis C patients, to identify the associated factors with the presence of steatosis and to determine the relationship between the presence of steatosis and severity of hepatic fibrosis. METHODS Lecture of hepatic biopsies was performed blindly by the same histopathologist, using the METAVIR grading. Hepatic steatosis was graded as macrovacuolar or microvesicular. Steatosis was considered as mild, moderate and severe if involving less than 10%, between 10 and 30% and more than 30% of hepatocytes respectively. RESULTS One hundred and nine patients were studied. Determination of the virus genotype was performed in 59 patients, with 93% of genotype 1. Significant fibrosis was noted in 72 patients (66%). Hepatic steatosis was detected in 53 cases (49%): Mild in 32 cases (30%), moderate in 9 cases (8%) and severe in 12 cases (11%). In univariate analysis, associated factors with steatosis are age more than 50 years, weight more than 65 kg, body mass index more than 25 kg/m2, ASAT levels more than 80 UI/l and ALAT levels more than 100 UI/l. In multivariate analysis, only body mass index more than 25 kg/m2 is associated with the presence of steatosis (p=0.02 OR [95%CI]: 3.37 [1.19-9.53]). Significant fibrosis was more frequently detected in patients with steatosis compared to patients without steatosis (42/53: 80% vs 30/56: 54%; p=0.004). CONCLUSION Hepatic steatosis is frequent in chronic viral hepatitis C. In our Tunisian population, steatosis is associated with body mass index and not with virological factors.
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Objective:To evaluate the accuracy of determinating fibrinogen with Prithrombin time derived.Methods:The plasma fibrinogen of 113 patienss were determined by PT and recorded the derived fibrinogen,compared with the fibrinogen results of CLAUSS methed.Results:The within cv of PT derived fibrinogen was 3 5%.When the fibrinogen determination of PT derived was 1 50~2 99g/L,P0 05;when the fibrinogen was 3 00g/L, P 0 01,the results of PT derived fibrinogen were higher than the results of CLAUSS method.Conclusion:Plasma fibrinogen determination of PT derived is simple,economical,but not suitable for clinical application if the fibrinogen of PT derived result was over 3 00g/L.
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The relationship between steatosis and angiogenesis in chronic hepatitis C (CHC) is unclear.The aim was to explain whether liver steatosis presence and its extent are associated with the number of new-formed blood vessels in lobules and portal tracts in CHC. 72 CHC patients infected with viral genotype 1b, 35 of whom had steatosis were evaluated. Monoclonal antibody anti-CD34 was used to identify new-formed blood vessels.Patients with steatosis had a significantly more advanced stage of fibrosis (p = 0.002) and higher inflammatory activity grade (p = 0.062). CD34 expression in portal tracts (CD34pt), lobules and fibrous septa (CD34lfs) and total (CD34) were significantly higher in patients with steatosis (p = 0.034; p = 0.021; p = 0.023, respectively). CD34, CD34pt and CD34lfs differed significantly between patients with various steatosis grade (p = 0.006; p = 0.009; p = 0.013, respectively). CD34 and CD34pt differed significantly between each steatosis grade whereas CD34lfs between grade 1 and 3. Fibrosis stage and inflammatory grade were positively associated with steatosis extent (p = 0.015; p = 0.003, respectively).Our observations suggest that extensive steatosis of liver parenchyma in CHC patients is associated with formation of new blood vessels in lobules and portal tracts. Understanding the relationship between steatosis, fibrosis and angiogenesis is therefore of great importance for the introduction of new therapeutic approaches and in the evaluation of CHC progression.
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Hepatic steatosis is a common histological feature of chronic hepatitis C. Various factors are associated with hepatic steatosis, including obesity, high alcohol consumption, diabetes type II, and hyperlipidaemia. These factors may contribute to steatosis in patients with chronic hepatitis C. In humans, hepatitis C virus (HCV) genotype 3 is more commonly associated with steatosis. In vitro studies and the transgenic mouse model have suggested that the HCV core protein (genotype 1) can induce lipid accumulation within hepatocytes. However, what is the relevance of steatosis in chronic hepatitis C? It seems that in certain populations, steatosis may be associated with fibrosis progression and this may be genotype specific. The mechanisms underlying this association are unknown; neither is it clear whether this holds true for all patients or only a subgroup. Indeed, after antiviral treatment, virus related steatosis disappears whereas the host associated steatosis remains unaffected. This review describes and discusses the basic and clinical aspects of the relationship between steatosis and progression of fibrosis, and response to treatment in patients with chronic hepatitis C.
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