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Bruno S.,A.O. Fatebenefratelli e Oftalmico | Crosignani A.,University of Sao Paulo | Facciotto C.,A.O. Fatebenefratelli e Oftalmico | Rossi S.,A.O. Fatebenefratelli e Oftalmico | And 5 more authors.
Hepatology | Year: 2010

The incidence of de novo development of esophageal varices (EV) in patients with compensated liver cirrhosis has been determined by few studies in the short term and never in the long term. The aims of the present study were to determine the incidence and the risk factors associated with the development of EV and to assess whether antiviral treatment and achievement of sustained virologic response (SVR) may prevent de novo EV development in patients with HCV-induced cirrhosis. We studied 218 patients with compensated EV-free, HCV-induced cirrhosis consecutively enrolled between 1989 and 1992 at three referral centers in Milan, Italy. Endoscopic surveillance was performed at 3-year intervals according to international guidelines. SVR was defined as undetectable serum HCV-RNA 24 weeks after treatment discontinuation. During a median follow-up of 11.4 years, 149/218 (68%) patients received antiviral treatment and 34 (22.8%) achieved SVR. None of the SVR patients developed EV compared with 22 (31.8%) of the 69 untreated subjects (P < 0.0001) and 45 (39.1%) of the 115 non-SVR patients (P < 0.0001). On multivariate analysis, HCV genotype 1b (hazard ratio [HR] 2.40; 95% confidence interval [CI] 1.17-4.90) and baseline model for end-stage liver disease (MELD) score (HR 1.20; 95% CI 1.07-1.35 for 1 point increase) were independent predictors of EV. Conclusion: In the long term, the achievement of SVR prevents the development of EV in patients with compensated HCV-induced cirrhosis. Therefore, in these patients, endoscopic surveillance can be safely delayed or avoided. Genotype 1b infection and MELD score identify the subset of patients at higher risk of EV development who need tailored endoscopic surveillance. Copyright © 2010 by the American Association for the Study of Liver Diseases. Source


Talens S.,Erasmus University Rotterdam | Hoekstra J.,Erasmus University Rotterdam | Dirkx S.P.G.,Erasmus University Rotterdam | Murad S.D.,Erasmus University Rotterdam | And 8 more authors.
Journal of Hepatology | Year: 2011

Background & Aims: Budd-Chiari syndrome (BCS) is a rare vascular liver disorder caused by thrombosis of the hepatic veins. In some patients, no known thrombophilic factor can be identified. This study aimed to identify novel factors that might play a role in thrombosis in BCS-patients by using a proteomic approach. Methods: The abundance of plasma clot-bound proteins was compared between nine BCS-patients and nine controls by using two-dimensional difference gel electrophoresis. The protein with the most significant decrease in patients was identified by mass spectrometry. Plasma levels of this protein were measured and the results were validated in a large cohort of BCS-patients. Results: A total of 26 protein spots significantly differed (p <0.001). The spot that decreased with the highest statistical significance in patients was identified by mass spectrometry as apolipoprotein A1 (apo A1). The mean level of apo A1 in the plasma of these BCS-patients (0.74 g/L) was also significantly lower than in controls (1.45 g/L, p = 0.002). This finding was validated in a large cohort of 101 BCS-patients and 101 controls (0.97 g/L vs. 1.32 g/L, p <0.0001). There was no major correlation between plasma levels of apo A1 and various liver function tests. Conclusions: BCS-patients show decreased clot-bound protein abundance and plasma levels of apo A1. Decreased levels of apo A1 may play a role in the etiology of thrombosis in BCS-patients and possibly in other patients with venous thrombosis. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source


Smalberg J.H.,Erasmus University Rotterdam | Koehler E.,Erasmus University Rotterdam | Murad S.D.,Erasmus University Rotterdam | Plessier A.,University Paris Diderot | And 9 more authors.
Blood | Year: 2011

The germline JAK2 46/1 haplotype has been associated with the development of JAK2 V617F-positive as well as JAK2 V617F-negative myeloproliferative neoplasms (MPNs). In this study we examined the role of the 46/1 haplotype in the etiology and clinical presentation of patients with splanchnic vein thrombosis (SVT), in which MPNs are the most prominent underlying etiological factor. The singlenucleotide polymorphism rs12343867, which tags 46/1, was genotyped in 199 SVT patients. The 46/1 haplotype was overrepresented in JAK2 V617F-positive SVT patients compared with controls (P<.01). Prevalence of the 46/1 haplotype in JAK2 V617F-negative SVT patients did not differ from prevalence in the controls. However, JAK2 V617F-negative SVT patients with a proven MPN also exhibited an increased frequency of the 46/1 haplotype (P =.06). Interestingly, 46/1 was associated with increased erythropoiesis in JAK2 V617F-negative SVT patients. We conclude that the 46/1 haplotype is associated with the development of JAK2 V617F-positive SVT. In addition, our findings in JAK2 V617F-negative SVT patients indicate an important role for the 46/1 haplotype in the etiology and diagnosis of SVT-related MPNs, independent of JAK2 V617F, that requires further exploration. © 2011 by The American Society of Hematology. Source


Hoekstra J.,Erasmus University Rotterdam | Guimaraes A.H.C.,Erasmus Medical Center | Leebeek F.W.G.,Erasmus Medical Center | Murad S.D.,Erasmus University Rotterdam | And 11 more authors.
Blood | Year: 2010

In Budd-Chiari syndrome (BCS), thrombosis develops in the hepatic veins or inferior vena cava. To study the relationship between hypofibrinolysis and BCS, we measured plasma levels of fibrinolysis proteins in 101 BCS patients and 101 healthy controls and performed a plasmabased clot lysis assay. In BCS patients, plasminogen activator inhibitor 1 (PAI-1) levels were significantly higher than in controls (median, 6.3 vs 1.4 IU/mL,. P < .001). Thrombin-activatable fibrinolysis inhibitor and plasmin inhibitor levels were lower than in controls (13.8 vs 16.9 μg/mL and 0.91 vs 1.02 U/L, both P < .001). Median plasma clot lysis time (CLT) was 73.9 minutes in cases and 73.0 minutes in controls (P = .329).Asubgroup of cases displayed clearly elevated CLTs. ACLT above the 90th or 95th percentile of controls was associated with an increased risk of BCS, with odds ratios of 2.4 (95% confidence interval, 1.1-5.5) and 3.4 (95% confidence interval, 1.2-9.7), respectively. In controls, only PAI-1 activity was significantly associated with CLT. Analysis of single nucleotide polymorphisms of fibrinolysis proteins revealed no significant differences between cases and controls. This case-control study provides the first evidence that an impaired fibrinolytic potential, at least partially caused by elevated PAI-1 levels, is related to the presence of BCS. © 2010 by The American Society of Hematology. Source


Pizarro T.T.,Case Western Reserve University | Pastorelli L.,Case Western Reserve University | Pastorelli L.,Gastroenterology and Gastrointestinal Endoscopy Unit | Pastorelli L.,University of Milan | And 9 more authors.
Inflammatory Bowel Diseases | Year: 2011

The SAMP1/YitFc mouse strain represents a model of Crohn's disease (CD)-like ileitis that is ideal for investigating the pathogenesis of chronic intestinal inflammation. Different from the vast majority of animal models of colitis, the ileal-specific phenotype characteristic of SAMP1/YitFc mice occurs spontaneously, without genetic, chemical, or immunological manipulation. In addition, SAMP1/YitFc mice possess remarkable similarities to the human condition with regard to disease location, histologic features, incidence of extraintestinal manifestations, and response to conventional therapies. SAMP1/YitFc mice also display a well-defined time course of a predisease state and phases of acute and chronic ileitis. As such, the SAMP1/YitFc model is particularly suitable for elucidating pathways that precede the clinical phenotype that may lead to preventive, and therefore more efficacious, intervention with the natural course of disease, or alternatively, for the development of therapeutic strategies directed against chronic, established ileitis. In this review we summarize important contributions made by our group and others that uncover potential mechanisms in the pathogenesis of CD using this unique murine model of chronic intestinal inflammation. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc. Source

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