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Le Touquet – Paris-Plage, France

Kantari-Mimoun C.,French Institute of Health and Medical Research | Castells M.,French Institute of Health and Medical Research | Klose R.,French Institute of Health and Medical Research | Meinecke A.-K.,University of Duisburg - Essen | And 9 more authors.
Hepatology | Year: 2015

Angiogenesis is a key feature of liver fibrosis. Although sinusoidal remodeling is believed to contribute to fibrogenesis, the impact of sinusoidal angiogenesis on the resolution of liver fibrosis remains undefined. Myeloid cells, particularly macrophages, constantly infiltrate the fibrotic liver and can profoundly contribute to remodeling of liver sinusoids. We observe that the development of fibrosis is associated with decreased hepatic vascular endothelial growth factor (VEGF) expression as well as sinusoidal rarefication of the fibrotic scar. In contrast, the resolution of fibrosis is characterized by a rise in hepatic VEGF levels and revascularization of the fibrotic tissue. Genetic ablation of VEGF in myeloid cells or pharmacological inhibition of VEGF receptor 2 signaling prevents this angiogenic response and the resolution of liver fibrosis. We observe increased expression of matrix metalloproteases as well as decreased expression of tissue inhibitor of metalloproteases confined to sinusoidal endothelial cells in response to myeloid cell VEGF. Remarkably, reintroduction of myeloid cell-derived VEGF upon recovery restores collagenolytic acitivity and the resolution of fibrosis. Conclusion: We identify myeloid cell-derived VEGF as a critical regulator of extracellular matrix degradation by liver endothelial cells, thereby unmasking an unanticipated link between angiogenesis and the resolution of fibrosis. © 2014 by the American Association for the Study of Liver Diseases.

Moreau R.,French Institute of Health and Medical Research | Moreau R.,University Paris Diderot | Moreau R.,DHU Unity | Moreau R.,University of Paris Pantheon Sorbonne | And 5 more authors.
Journal of Hepatology | Year: 2015

SELECTION OF THE MONTH Daily drinking and consuming more than 14 units of alcohol per week increases risk of alcoholic cirrhosis Deaths from liver disease have increased dramatically over the past 30 years and one of the culprits for this increase is excessive alcohol consumption. Using the Danish Cancer, Diet, and Health study, which included 55,917 participants over an 8-year period, Askgaard and colleagues showed that daily drinking was worse than drinking 3-4 days per week and the risk of liver cirrhosis started at 14 units consumption per week. This is important given that the current recommendation regarding safe limits of alcohol is 21 units per week. Clearly, current recommendations will need to be revisited. Also the study provided novel data showing that compared to beer and liquor, wine might be associated with a lower risk of alcoholic cirrhosis. Display Omitted. © 2015 European Association for the Study of the Liver.

Zeuzem S.,Goethe University Frankfurt | Soriano V.,Charles III University of Madrid | Asselah T.,DHU Unity | Gane E.J.,Auckland Clinical Studies | And 15 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n = 362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-timesdaily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28WNR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.) Copyright © 2015 American Society for Microbiology. All Rights Reserved.

Nery F.,Centro Hospitalar do Porto | Nery F.,Abel Salazar Biomedical Sciences Institute | Valla D.,DHU Unity | Valla D.,University Paris Diderot
Current Hepatitis Reports | Year: 2014

Venous thromboembolism (deep vein thrombosis and pulmonary embolism) and portal vein thrombosis (PVT) occur in up to 6.3 % and 15.9 % of patients with cirrhosis, respectively. There is recent evidence that a procoagulable prothrombotic state is related to cirrhosis despite the reduced levels of many coagulation factors, and decreased platelet counts. Indeed, (i) the combination of high levels of factor VIII, with low levels of protein C and antithrombin induces a procoagulant state in vitro; while (ii) increased levels of von Willebrand factor and decreased ADAMTS 13 activity can compensate for decreased platelet counts. PVT is partial in a majority of patients in whom it develops and may spontaneously resolve in some of them. Although PVT is associated with features of more severe liver disease, it is uncertain whether it plays a causal role in the decompensation of cirrhosis. In patients listed for liver transplantation, PVT may make the procedure difficult or impossible. Pretransplant PVT is associated with increased post-transplant mortality rates. Studies evaluating clinical outcome of anticoagulation therapy for splanchnic or extrasplanchnic venous thrombosis are scarce. Anticoagulation therapy, given to patients with cirrhosis of intermediate severity before PVT occurrence, in prophylactic doses, appears to decrease decompensation and mortality rate. Interestingly, this improvement is out of proportion of the prophylaxis of extrahepatic portal vein thrombosis. The risk of bleeding does not seem to be increased in patients with cirrhosis receiving anticoagulation therapy, once prophylaxis for bleeding related to portal hypertension has been implemented. Overall, the room for anticoagulation therapy is probably larger than previously recognized, and may be of particular benefit in patients without portal vein thrombosis. However, clinical trials remain to be done before the benefit risk ratio of anticoagulation therapy is properly evaluated. © Springer Science+Business Media New York 2014.

Moreau R.,French Institute of Health and Medical Research | Moreau R.,University Paris Diderot | Moreau R.,DHU Unity | Moreau R.,University of Paris Pantheon Sorbonne | And 5 more authors.
Journal of Hepatology | Year: 2016

Selection of the monthUrgent need to increase awareness and screening programs for HCV infection Reliable data about the population-based prevalence of hepatitis C virus (HCV)-induced cirrhosis are unavailable for most countries. Udompap et al. addressed this question by determining the cirrhosis prevalence using the National Health and Nutrition Examination Survey (NHANES), which contains a population generalizable to the entire United States households. The authors also raised the important question of whether awareness of the infection impacts cirrhosis prevalence. While the overall prevalence of HCV infection has decreased over time from 1.5% in 1988-94 (Era 1), to 1.2% in 1999-2006 (Era 2), and then to 1.0 in 2007-12 (Era 3), the proportion of HCV patients with cirrhosis has more than doubled during the study period reaching 17% in the latest era. Most importantly, cirrhosis prevalence in patients unaware of their infection was as high as in those with established HCV diagnosis. The study emphasizes the need for implementing HCV awareness and screening programs for primary prevention of cirrhosis and its complication.

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