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Sonia Gandoura,
Emmanuel Weiss,
Pierre-Emmanuel Rautou,
Magali Fasseu,
Thierry Gustot,
Frédéric Lemoine,
Margarita Hurtado-Nedelec,
Caroline Hego,
Nathalie Vadrot,
Laure Elkrief,
Philippe Lettéron,
Zéra Tellier,
Marie-Anne Pocidalo,
Dominique Valla, Didier Lebrec,
André Groyer,
Renato C Monteiro,
Pierre de la Grange,
Richard Moreau
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ABSTRACT: BACKGROUND & AIMS: Lipopolysaccharide (LPS)-expressing bacteria cause severe inflammation in cirrhotic patients. The global gene response to LPS is unknown in cirrhotic immune cells. METHODS: Gene-expression profiling using Affymetrix Human Exon Array analyzed the expression of 14,851 genes in LPS-stimulated peripheral blood mononuclear cells (PBMCs) from 4 patients with cirrhosis and 4 healthy subjects. We performed validation studies using RT-qPCR in LPS-simulated PBMCs from 57 patients and 9 healthy subjects and investigated the association of gene induction with mortality in 26 patients. RESULTS: Gene-expression profiling of LPS-stimulated cirrhotic cells showed 509 upregulated genes and 1,588 downregulated genes. In LPS-stimulated "healthy" cells, 952 genes were upregulated and 838 genes downregulated. The 741 LPS-regulated genes shared by cirrhotic and "healthy" cells were involved in cytokine production/activity and the induction of "immune paralysis". Comparison of functions associated with the 1,356 genes that were specifically regulated by LPS in cirrhotic cells to functions of the 1,049 genes specifically regulated in "healthy "cells allowed to define a cirrhosis-specific phenotype. Unlike in "healthy" cells, LPS failed to induce an interferon-mediated program in cirrhotic cells. In cirrhotic PBMCs, LPS specifically induced certain molecules involved in apoptosis and downregulated molecules involved in endocytic trafficking. RT-qPCR experiments showed that LPS-stimulated cirrhotic PBMCs had an enhanced induction of certain proinflammatory cytokines and chemokines. In the prognosis study, higher ex-vivo LPS-induction of inflammatory genes IL6 and CXCL5 were significant predictors of mortality. CONCLUSIONS: Our results show that LPS-stimulated cirrhotic PBMCs exhibit an extensive and often unexpected transcriptional response.
Journal of Hepatology 01/2013; · 9.26 Impact Factor
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ABSTRACT: The MELDNa score was developed to improve the prognostic value of the MELD score in cirrhosis and was built for serum sodium concentrations numerically capped between 125 and 140 mmol/L. This model is not validated in a well-defined population of patients with cirrhosis and refractory ascites in whom severe hyponatremia (≤ 125 mmol/L) is frequent. This study assessed the prognostic value of severe hyponatremia and the MELDNa score in these patients.
A consecutive, single-centre, observational, prospective study was performed in patients with cirrhosis and refractory ascites defined according to the International Ascites Club criteria. The prevalence of low serum sodium was assessed in this population. Predictive factors of mortality were analyzed and compared.
One hundred seventy-four patients were included. Sixty-six (37.9%) had low serum sodium (< 130 mmol/L). Sixty-one (35.1%) had diuretic-intractable ascites due to severe hyponatremia (≤ 125 mmol/L). The median MELDNa score was 23 (10-33). The 1-year cumulative incidence of death was 55% (95% CI: 55-56%). The best predictive factors of mortality were the following: severe hyponatremia (≤ 125 mmol/L) as an underlying cause of refractory ascites, a higher Child-Pugh score, beta-blocker therapy, and a high frequency of large-volume paracentesis. The Child-Pugh score had a higher area under receiver operating curve to predict mortality than MELDNa.
In patients with cirrhosis and refractory ascites, severe hyponatremia and Child-Pugh score are better predictors of mortality than MELDNa.
Journal of Hepatology 04/2012; 57(2):274-80. · 9.26 Impact Factor
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Pierre-Emmanuel Rautou,
Julie Bresson,
Yannis Sainte-Marie,
Anne-Clemence Vion,
Valerie Paradis,
Jean-Marie Renard,
Cecile Devue,
Christophe Heymes,
Philippe Letteron,
Laure Elkrief, Didier Lebrec,
Dominique Valla,
Alain Tedgui,
Richard Moreau,
Chantal M Boulanger
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ABSTRACT: Circulating membrane-shed microparticles (MPs) participate in regulation of vascular tone. We investigated the cellular origins of MPs in plasma from patients with cirrhosis and assessed the contribution of MPs to arterial vasodilation, a mechanism that contributes to portal hypertension.
We analyzed MPs from blood samples of 91 patients with cirrhosis and 30 healthy individuals (controls) using flow cytometry; their effects on the vascular response to vasoconstrictors were examined in vitro and in vivo.
Circulating levels of leuko-endothelial (CD31(+)/41(-)), pan-leukocyte (CD11a(+)), lymphocyte (CD4(+)), and erythrocyte (CD235a(+)) MPs were higher in patients with cirrhosis than in controls. Plasma of patients with cirrhosis contained hepatocyte-derived MPs (cytokeratin-18(+)), whereas plasma from controls did not. The severity of cirrhosis and systemic inflammation were major determinants of the levels of leuko-endothelial and hepatocyte MPs. MPs from patients with advanced cirrhosis significantly impaired contraction of vessels in response to phenylephrine, whereas MPs from healthy controls or from patients of Child-Pugh class A did not. This effect depended on cyclooxygenase type 1 and required phosphatidylserine on the surface of MPs. Intravenous injection of MPs from patients with cirrhosis into BALB/C mice decreased mean arterial blood pressure.
Cirrhosis is associated with increases in circulating subpopulations of MPs, likely resulting from systemic inflammation and liver cell damage. The overall pool of circulating MPs from patients with advanced cirrhosis impairs vasoconstrictor responses and decreases blood pressure, contributing to the arterial vasodilation associated with portal hypertension.
Gastroenterology 03/2012; 143(1):166-76.e6. · 11.68 Impact Factor
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Didier Lebrec,
Jaime Bosch,
Rajiv Jalan,
Francis J Dudley,
Rada Jessic,
Richard Moreau,
Juan Carlos Garcia-Pagan,
Rajeshwar P Mookerjee,
Eleonora Chiossi,
Paul L M Van Giersbergen,
Andjela Kusic-Pajic,
Jasper Dingemanse
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ABSTRACT: To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated.
The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2-3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein.
Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration (r = 0.82). There was a strong correlation (r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group.
In patients with cirrhosis, a 2- to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF.
European Journal of Clinical Pharmacology 11/2011; 68(5):533-41. · 2.85 Impact Factor
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Emilie Tissandié,
Willy Morelle,
Laureline Berthelot,
François Vrtovsnik,
Eric Daugas,
Francine Walker, Didier Lebrec,
Jean-Marie Trawalé,
Claire Francoz,
François Durand,
Ivan C Moura,
Valérie Paradis,
Richard Moreau,
Renato C Monteiro
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ABSTRACT: Abnormalities of IgA arise in alcoholic cirrhosis, including mesangial IgA deposits with possible development of secondary IgA nephropathy (IgAN). Since little is known about circulating immune complexes in cases of secondary IgAN, we analyzed IgA-associated parameters in the serum of 32 patients with compensated or advanced alcoholic cirrhosis. Galactose deficiency and decreased sialylation of IgA1, as well as increased amounts of abnormally glycosylated polymeric IgA1, were detected in the serum of patients with advanced alcoholic cirrhosis. Moreover, aberrant IgA1 formed complexes with IgG and soluble CD89 in serum of patients with advanced alcoholic cirrhosis, similar to those found in primary IgAN. The IgA1 of alcoholic cirrhosis, however, had a modified N-glycosylation, not found in primary IgAN. In patients with alcoholic cirrhosis and IgAN, IgA deposits were associated with CD71 overexpression in mesangial areas, suggesting that CD71 might be involved in deposit formation. Although the IgA1 found in alcoholic cirrhosis bound more extensively to human mesangial cells than control IgA1, they differ from primary IgAN by not inducing mesangial cell proliferation. Thus, abnormally glycosylated IgA1 and soluble CD89-IgA and IgA-IgG complexes, features of primary IgAN, are also present in alcoholic cirrhosis. Hence, common mechanisms appear to be shared by diseases of distinct origins, indicating that common environmental factors may influence the development of IgAN.
Kidney International 08/2011; 80(12):1352-63. · 6.61 Impact Factor
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Emilie Tissandi|[eacute,
Willy Morelle,
Laureline Berthelot,
Fran|[ccedil]|ois Vrtovsnik,
Eric Daugas,
Francine Walker, Didier Lebrec,
Jean-Marie Trawal|[eacute,
Claire Francoz,
Fran|[ccedil]|ois Durand,
Ivan C Moura,
Val|[eacute]|rie Paradis,
Richard Moreau,
Renato C Monteiro
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[hide abstract]
ABSTRACT: Abnormalities of IgA arise in alcoholic cirrhosis, including mesangial IgA deposits with possible development of secondary IgA nephropathy (IgAN). Since little is known about circulating immune complexes in cases of secondary IgAN, we analyzed IgA-associated parameters in the serum of 32 patients with compensated or advanced alcoholic cirrhosis. Galactose deficiency and decreased sialylation of IgA1, as well as increased amounts of abnormally glycosylated polymeric IgA1, were detected in the serum of patients with advanced alcoholic cirrhosis. Moreover, aberrant IgA1 formed complexes with IgG and soluble CD89 in serum of patients with advanced alcoholic cirrhosis, similar to those found in primary IgAN. The IgA1 of alcoholic cirrhosis, however, had a modified N-glycosylation, not found in primary IgAN. In patients with alcoholic cirrhosis and IgAN, IgA deposits were associated with CD71 overexpression in mesangial areas, suggesting that CD71 might be involved in deposit formation. Although the IgA1 found in alcoholic cirrhosis bound more extensively to human mesangial cells than control IgA1, they differ from primary IgAN by not inducing mesangial cell proliferation. Thus, abnormally glycosylated IgA1 and soluble CD89–IgA and IgA–IgG complexes, features of primary IgAN, are also present in alcoholic cirrhosis. Hence, common mechanisms appear to be shared by diseases of distinct origins, indicating that common environmental factors may influence the development of IgAN.Keywords: alcoholic cirrhosis; glycosylation; IgA; nephropathy; receptors
Kidney International 08/2011; 80(12):1352-1363. · 6.61 Impact Factor
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ABSTRACT: Patients with cirrhosis in Child-Pugh class C or those in class B who have persistent bleeding at endoscopy are at high risk for treatment failure and a poor prognosis, even if they have undergone rescue treatment with a transjugular intrahepatic portosystemic shunt (TIPS). This study evaluated the earlier use of TIPS in such patients.
We randomly assigned, within 24h after admission, a total of 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy to treatment with a polytetrafluoroethylene-covered stent within 72 h after randomization (early-TIPS group, 32 patients) or continuation of vasoactive-drug therapy, followed after 3-5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapy-EBL group, 31 patients).
During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapy-EBL group as compared with 1 patient in the early-TIPS group (P = 0.001). The 1-year actuarial probability of remaining free of this composite end point was 50% in the pharmacotherapy-EBL group versus 97% in the early-TIPS group (P < 0.001). Sixteen patients died (12 in the pharmacotherapy-EBL group and 4 in the early-TIPS group, P = 0.01). The 1-year actuarial survival was 61% in the pharmacotherapy-EBL group versus 86% in the early-TIPS group (P < 0.001). Seven patients in the pharmacotherapy-EBL group received TIPS as rescue therapy, but four died. The number of days in the intensive care unit and the percentage of time in the hospital during follow-up were significantly higher in the pharmacotherapy-EBL group than in the early-TIPS group. No significant differences were observed between the two treatment groups with respect to serious adverse events.
In these patients with cirrhosis who were hospitalized for acute variceal bleeding and at high risk for treatment failure, the early use of TIPS was associated with significant reductions in treatment failure and in mortality.
Journal of Hepatology 06/2011; 55(5):1148-9. · 9.26 Impact Factor
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Pierre-Emmanuel Rautou,
Dominique Cazals-Hatem,
Gérard Feldmann,
Abdellah Mansouri,
Alain Grodet,
Sandrine Barge,
Michèle Martinot-Peignoux,
Aurélie Duces,
Ivan Bièche, Didier Lebrec,
Pierre Bedossa,
Valérie Paradis,
Patrick Marcellin,
Dominique Valla,
Tarik Asselah,
Richard Moreau
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ABSTRACT: Autophagy is a regulated process that can be involved in the elimination of intracellular microorganisms and in antigen presentation. Some in vitro studies have shown an altered autophagic response in hepatitis C virus infected hepatocytes. The present study aimed at evaluating the autophagic process in the liver of chronic hepatitis C (CHC) patients. Fifty-six CHC patients and 47 control patients (8 with nonalcoholic steatohepatitis or alcoholic liver disease, 18 with chronic heptatitis B virus infection, and 21 with no or mild liver abnormalities at histological examination) were included. Autophagy was assessed by means of electron microscopy and microtubule-associated protein light chain 3 immunoblotting. Using light chain 3 immunoblotting, the form present on autophagic vesicle (light chain 3-II) was significantly higher in CHC patients than in controls (P < 0.05). Using quantitative electron microscopy analysis, the median number of autophagic vesicles observed in hepatocytes from CHC patients was sixfold higher than in overall controls (P < 0.001). In contrast, there was no difference between CHC patients and controls in the number of mature lysosomes with electron-dense contents arguing in favor of a lack of fusion between autophagosome and lysosome. Neither genotype nor viral load influenced the autophagy level. In conclusion, autophagy is altered in hepatocytes from CHC patients, likely due to a blockade of the last step of the autophagic process.
American Journal Of Pathology 06/2011; 178(6):2708-15. · 4.89 Impact Factor
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Thomas Sersté,
Frédéric Bert,
Véronique Leflon-Guibout,
Chantal Chauvet,
Estelle Marcon,
Tarik Asselah,
Claire Francoz,
François Durand, Didier Lebrec,
Dominique Valla,
Richard Moreau,
Marie-Hélène Nicolas-Chanoine
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ABSTRACT: Bacterial DNA (bactDNA) has been found in serum and ascitic fluid (AF) of 30-40% of hospitalized patients with cirrhosis and non-neutrocytic ascites, but its prevalence in outpatients is unknown. The aim of this prospective study was to investigate the presence of bactDNA in AF and serum among cirrhotic outpatients with non-neutrocytic ascites.
Thirty-one consecutive patients with cirrhosis and non-neutrocytic ascites, who underwent therapeutic paracentesis in our outpatient clinic, were enrolled over a 13-week period. Of these patients, 13 had a single paracentesis and 18 patients had several consecutive paracenteses (2-10) over the study period. Overall, 98 serum and non-neutrocytic AF specimens were obtained and tested for the presence of bactDNA by polymerase chain reaction amplification of the 16S ribosomal RNA gene.
The main causes of cirrhosis were alcohol (53.5%) and hepatitis C (30%). The median MELD score was 16 and there were 54.8% Child-Pugh C patients. BactDNA was negative in all samples from 28 of the 31 patients, including 15 patients with several paracentesis. One patient had a single AF sample culture positive and bactDNA positive for Streptococcus mitis, whereas the simultaneous blood sample was negative. For each of the last two patients, DNA from Lactococcus lactis was detected in a single blood sample but not in the simultaneous AF sample.
In contrast to that reported previously in hospitalized patients, bactDNA is rarely detected in serum and AF of outpatients with cirrhosis and non-neutrocytic ascites.
Liver international: official journal of the International Association for the Study of the Liver 04/2011; 31(4):494-8. · 3.82 Impact Factor
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ABSTRACT: Severe portal hypertension is responsible for complications and death. Although measurement of the hepatic venous pressure gradient is the most accurate method for evaluating the presence and severity of portal hypertension, this technique is considered invasive and is not routinely performed in all centers. Several noninvasive techniques have been proposed to measure portal hypertension. Certain methods evaluate elements related to the pathogenesis of portal hypertension through the measurement of hyperkinetic syndrome, for example, or they investigate the development of hepatic fibrosis through the measurement of increased intrahepatic vascular resistance. Other methods evaluate the clinical consequences of portal hypertension, such as the presence of esophageal varices or the development of portosystemic shunts. Methods evaluating increased hepatic vascular resistance are fairly accurate and mainly involve the detection of hepatic fibrosis by serum markers and transient elastography. The radiological assessment of hyperkinetic syndrome probably has value but is still under investigation. The assessment of severe portal hypertension by the presence of varices may be performed with simple tools such as biological assays, computed tomography, and esophageal capsules. More sophisticated procedures seem promising but are still under development. Screening tools for large populations must be simple, whereas more complicated procedures could help in the follow-up of already diagnosed patients. Although most of these noninvasive methods effectively identify severe portal hypertension, methods for diagnosing moderate portal hypertension need to be developed; this shows that further investigation is needed in this field.
Hepatology 02/2011; 53(2):683-94. · 11.66 Impact Factor
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Nicolas Coant,
Marika Simon-Rudler,
Thierry Gustot,
Magali Fasseu,
Sonia Gandoura,
Kévin Ragot,
Waël Abdel-Razek,
Dominique Thabut,
Philippe Lettéron,
Eric Ogier-Denis,
Romy Ouziel,
Jacques Devière,
Gérard Lizard,
Zéra Tellier, Didier Lebrec,
Richard Moreau
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ABSTRACT: In decompensated cirrhosis, the early innate immune response to the Toll-like receptor 4 (TLR4) agonist, lipopolysaccharides (LPS), is characterized by a hyper-production of pro-inflammatory cytokines and hypo-production of the anti-inflammatory cytokine IL-10. In LPS-stimulated non-cirrhotic immune cells, the constitutively active glycogen synthase kinase (GSK) 3 favors pro- vs. anti-inflammatory cytokines, by acting on gene induction. However, in these cells, TLR4 dampens its own pro-inflammatory response by inducing early (within minutes) AKT-mediated phosphorylation of GSK3β (one of two GSK3 isoforms) on Ser9. Phosphorylation of GSK3β (Ser9) inhibits its activity, decreases pro-inflammatory cytokines, and increases IL-10. Thus, we investigated the role of GSK3 in LPS-induced cytokine production by peripheral blood mononuclear cells (PBMCs) or monocytes from patients with advanced cirrhosis and normal subjects.
Cells were pre-incubated with or without GSK3 inhibitor (SB216763 or lithium chloride) for 1h and then stimulated with LPS. Cytokine production was assessed at mRNA and secreted proteins levels, by real-time RT-PCR at 1h and ELISA at 20 h, respectively. GSK3β phosphorylation was assessed using Western blotting.
In cirrhotic and normal PBMCs pretreated with GSK3 inhibitors, LPS-induced production of pro-inflammatory proteins TNF-α and IL-12p40 was significantly decreased while that of IL-10 was increased. LPS-induced, AKT-mediated phosphorylation of GSK3β on Ser9 found in normal monocytes, was abolished in cirrhotic cells.
GSK3 is involved in the early TLR4-mediated pro-inflammatory response in patients with decompensated cirrhosis. This was associated with a defect in AKT-mediated GSK3β phosphorylation resulting in unrestricted 'pro-inflammatory' activity of the enzyme.
Journal of Hepatology 02/2011; 55(4):784-93. · 9.26 Impact Factor
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ABSTRACT: In patients with cirrhosis and refractory ascites the role of beta-blockers in the development of paracentesis-induced circulatory dysfunction (PICD) is unknown. The aim of this study was to investigate the incidence of PICD before and after discontinuation of beta-blockers in patients with cirrhosis and refractory ascites. A self control cross-over study was performed.
Patients with cirrhosis and refractory ascites treated with beta-blockers were selected. Heart rate, arterial pressure, and plasma renin concentrations (PRC) were collected before, immediately after and 1 week after large-volume paracentesis associated with intravenous albumin administration. Beta-blocker therapy was progressively discontinued after complete endoscopic eradication of varices. The clinical and biological evaluation was then repeated. The presence of PICD was defined as an increase in PRC of at least 50% above baseline 1 week after paracentesis.
Ten patients were included (nine men, mean age 59.1 ± 10.7 years old). The MELD score was 17.7 ± 4.4 and eight patients were Child-Pugh C. When patients were given beta-blockers, the heart rate did not change immediately after paracentesis while mean arterial pressure significantly decreased; PICD developed in eight patients. After beta-blockers were discontinued, the heart rate significantly increased immediately after paracentesis and mean arterial pressure significantly decreased; PICD only developed in one patient; the difference in the incidence of PICD was significant when these same patients were treated with beta-blockers.
The use of beta-blockers may be associated with a high risk of PICD in patients with cirrhosis and refractory ascites.
Journal of Hepatology 02/2011; 55(4):794-9. · 9.26 Impact Factor
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Hepatology 01/2011; 54(1):376. · 11.66 Impact Factor
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ABSTRACT: Autophagy, or cellular self-digestion, is a cellular pathway crucial for development, differentiation, survival, and homeostasis. Its implication in human diseases has been highlighted during the last decade. Recent data show that autophagy is involved in major fields of hepatology. In liver ischemia reperfusion injury, autophagy mainly has a prosurvival activity allowing the cell for coping with nutrient starvation and anoxia. During hepatitis B or C infection, autophagy is also increased but subverted by viruses for their own benefit. In hepatocellular carcinoma, the autophagy level is decreased. In this context, autophagy has an anti-tumor role and therapeutic strategies increasing autophagy, as rapamycin, have a beneficial effect in patients. Moreover, in hepatocellular carcinoma, Beclin-1 level, an autophagy protein, has a prognostic significance. In α-1-antitrypsin deficiency, the aggregation-prone ATZ protein accumulates in the endoplasmic reticulum. This activates the autophagic response which aims at degrading mutant ATZ. Some FDA-approved drugs which enhance autophagy and the disposal of aggregation-prone proteins may be useful in α-1-antitrypsin deficiency. Following alcohol consumption, autophagy is decreased in liver cells, likely due to a decrease in intracellular 5'-AMP-activated protein kinase (AMPk) and due to an alteration in vesicle transport in hepatocytes. This decrease in autophagy contributes to the formation of Mallory-Denk bodies and to liver cell death. Hepatic autophagy is defective in the liver in obesity and its upregulation improves insulin sensitivity.
Journal of Hepatology 12/2010; 53(6):1123-34. · 9.26 Impact Factor
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ABSTRACT: Beta-blockers may have a negative impact on survival in patients with cirrhosis and refractory ascites. The aim of this study was to evaluate the effect of the administration of beta-blockers on long-term survival in patients with cirrhosis and refractory ascites. We performed a single-center, observational, case-only, prospective study of patients with cirrhosis and refractory ascites who did or did not receive beta-blockers for the prevention of gastrointestinal bleeding; 151 patients were included. The mean Model for End-Stage Liver Disease score was 18.8 +/- 4.1. All patients regularly underwent large-volume paracentesis and intravenous albumin administration. Seventy-seven patients (51%) were treated with propranolol (113 +/- 46 mg/day). The median follow-up for the whole group was 8 months. The median survival time was 10 months [95% confidence interval (CI) = 8-12 months]. The probability of survival at 1 year was 41% (95% CI = 33%-49%). The clinical characteristics and laboratory values at enrolment were not significantly different between patients who were receiving propranolol and those who were not. The median survival time was 20.0 months (95% CI = 4.8-35.2 months) in patients not treated with propranolol and 5.0 months (95% CI = 3.5-6.5 months) in those treated with propranolol (P = 0.0001). The 1-year probability of survival was significantly lower in patients who received propranolol [19% (95% CI = 9%-29%)] versus those who did not [64% (95% CI = 52%-76%), P < 0.0001]. The independent variables of mortality were Child-Pugh class C, hyponatremia and renal failure as causes of refractory ascites, and beta-blocker therapy. CONCLUSION: The use of beta-blockers is associated with poor survival in patients with refractory ascites. These results suggest that beta-blockers should be contraindicated in these patients.
Hepatology 09/2010; 52(3):1017-22. · 11.66 Impact Factor
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Pierre-Emmanuel Rautou,
Ludivine Douarin,
Marie-Hélène Denninger,
Sylvie Escolano, Didier Lebrec,
Richard Moreau,
Michel Vidaud,
Raphaël Itzykson,
Rami Moucari,
Annie Bezeaud,
Dominique Valla,
Aurélie Plessier
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ABSTRACT: Anticoagulation therapy is recommended for patients with Budd-Chiari syndrome (BCS). This study aimed to assess the incidence, severity, and risk factors of major bleeding in patients with Budd-Chiari syndrome (BCS) receiving anticoagulation therapy.
We evaluated 94 consecutive BCS patients. Major bleeding required hospitalization, and/or transfusion of ≥ 2 red blood cell units, and/or was located intracranially, and/or retroperitoneally, and/or was fatal.
After a median follow-up of 43 months, 47 patients had 92 major bleeding episodes (22.8 per 100 patient-years). Forty episodes were related to invasive therapy for BCS. The origin of the 52 other episodes was gastrointestinal in 26 (including 15 related to portal hypertension) and genital in 10; 26 were spontaneous and 26 provoked. Excess anticoagulation was identified in 13 (27%) out of 49 documented episodes. Bleeding was managed by interrupting or reducing anticoagulation in 34 episodes, surgery in 18, endoscopy in 12, and radiological intervention in 8. The presence of esophageal varices was an independent predictor of bleeding unrelated to invasive therapy for BCS. Bleeding contributed to death in five patients and caused neurological complications in two. These poor outcomes were associated with more severe liver disease at baseline.
Major bleeding is common in BCS patients receiving anticoagulation therapy. Invasive procedures and portal hypertension are major factors, while excess anticoagulation plays a secondary role. Baseline BCS severity is the main determinant of prognosis at bleeding. Reducing anticoagulation intensity during invasive therapy and reinforced prophylaxis for portal hypertension could improve the benefit-risk ratio of anticoagulation.
Journal of Hepatology 08/2010; 54(1):56-63. · 9.26 Impact Factor
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Tarik Asselah,
Ivan Bièche,
Abdellah Mansouri,
Ingrid Laurendeau,
Dominique Cazals-Hatem,
Gérard Feldmann,
Pierre Bedossa,
Valérie Paradis,
Michelle Martinot-Peignoux, Didier Lebrec,
Cécile Guichard,
Eric Ogier-Denis,
Michel Vidaud,
Zéra Tellier,
Vassili Soumelis,
Patrick Marcellin,
Richard Moreau
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ABSTRACT: In hepatocytes, the accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and the unfolded protein response (UPR), mediated by the ER-resident stress sensors ATF-6, IRE1, and PERK. UPR-responsive genes are involved in the fate of ER-stressed cells. Cells carrying hepatitis C virus (HCV) subgenomic replicons exhibit in vitro ER stress and suggest that HCV inhibits the UPR. Since in vivo ER homeostasis is unknown in livers with chronic HCV infection, we investigated ER stress and the UPR in liver samples from untreated patients with chronic hepatitis C (CHC), in comparison with normal livers. Electron microscopy, western blotting, and real-time RT-PCR were used in liver biopsy specimens. Electron microscopy identified features showing ER stress in hepatocyte samples from patients with CHC; however, 'ER-stressed' hepatocytes were found in clusters (3-5 cells) that were scattered in the liver parenchyma. Western blot analysis confirmed the existence of hepatic ER stress by showing activation of the three ER stress sensors ATF-6, IRE1, and PERK in CHC. Real-time RT-PCR showed no significant induction of UPR-responsive genes in CHC. In contrast, genes involved in the control of diffuse processes such as liver proliferation, inflammation, and apoptosis were significantly induced in CHC. In conclusion, livers from patients with untreated CHC exhibit in vivo hepatocyte ER stress and activation of the three UPR sensors without apparent induction of UPR-responsive genes. This lack of gene induction may be explained by the inhibiting action of HCV per se (as suggested by in vitro studies) and/or by our finding of the localized nature of hepatocyte ER stress.
The Journal of Pathology 07/2010; 221(3):264-74. · 6.32 Impact Factor
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ABSTRACT: Little is known on the morphological changes in the kidneys of cirrhotic patients with abnormal urinalysis and/or high serum creatinine levels. This retrospective, one-point-in-time study aimed to report the results of the analysis of renal biopsy specimens obtained in patients with cirrhosis.
We retrieved information on 65 patients who underwent transvenous renal biopsy for proteinuria >0.5 g/day and/or microscopic haematuria and/or unexplained renal impairment (defined by serum creatinine levels >1.5 mg/dl).
Fifty-one per cent of the patients had proteinuria >0.5 g/day, 58% had haematuria and 83% had renal impairment. Renal biopsy disclosed injury to glomeruli in 77% of the patients, to vessels in 69% and to the tubulointerstitium system in 94% (chronic in 77%; acute in 75%). Fibrous endarteritis was the most common renal vascular lesion. Injuries to different structures were frequently combined. Isolated glomerular alterations were found in only two patients. Acute tubular necrosis was significantly more common in patients with fibrous endarteritis than in those without. Among 18 patients with renal impairment, proteinuria <0.5 mg/day and no haematuria, 10 had glomerular lesions, 13 had chronic tubulointerstitial lesions and 12 acute tubulointerstitial lesions.
In patients with cirrhosis, various types of renal injuries are frequently combined. Chronic lesions (vascular or tubulointerstitial) may influence the outcome, in particular in patients who subsequently undergo liver transplantation and receive anticalcineurins. Renal vascular lesions may increase the risk of acute tubular necrosis. In patients with renal impairment, the absence of significant proteinuria and haematuria do not rule out the presence of renal lesions.
Liver international: official journal of the International Association for the Study of the Liver 05/2010; 30(5):725-32. · 3.82 Impact Factor
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Didier Lebrec,
Dominique Thabut,
Frederic Oberti,
Jean-Marc Perarnau,
Bertrand Condat,
Helene Barraud,
Faouzi Saliba,
Nicolas Carbonell,
Philippe Renard,
Marie-Jose Ramond,
Richard Moreau,
Thierry Poynard
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ABSTRACT: Pentoxifylline, an inhibitor of tumor necrosis factor-alpha, is given to patients with liver diseases, but its effects in patients with advanced cirrhosis are unknown. We performed a randomized, placebo-controlled, double-blind trial of its effects in patients with cirrhosis.
A total of 335 patients with cirrhosis (Child-Pugh class C) were assigned to groups given either pentoxifylline (400 mg, orally, 3 times daily; n = 164) or placebo (n = 171) for 6 months. The primary end point was mortality at 2 months. Secondary end points were mortality at 6 months and development of liver-related complications.
By 2 months, 28 patients in the pentoxifylline group (16.5%) and 31 in the placebo group (18.2%) had died (P = .84). At 6 months, 50 patients in the pentoxifylline group (30.0%) and 54 in the placebo group (31.5%) had died (P = .75). The proportions of patients without complications (eg, bacterial infection, renal insufficiency, hepatic encephalopathy, or gastrointestinal hemorrhage) were higher in the pentoxifylline group than in the placebo group at 2 months (78.6% vs 63.4%; P = .006) and 6 months (66.8% vs 49.7%; P = .002). The probability of survival without complications was higher in the pentoxifylline group than in the placebo group at 2 and 6 months (P = .04). In multivariate analysis, the factors associated with death were age, the Model for End-Stage Liver Disease score, and presence of early-stage carcinoma. Treatment with pentoxifylline was the only factor associated with liver-related complications.
Although pentoxifylline does not decrease short-term mortality in patients with advanced cirrhosis, it does reduce the risk of complications.
Gastroenterology 05/2010; 138(5):1755-62. · 11.68 Impact Factor
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ABSTRACT: Sepsis is physiologically viewed as a proinflammatory and procoagulant response to invading pathogens. There are three recognized stages in the inflammatory response with progressively increased risk of end-organ failure and death: sepsis, severe sepsis, and septic shock. Patients with cirrhosis are prone to develop sepsis, sepsis-induced organ failure, and death. There is evidence that in cirrhosis, sepsis is accompanied by a markedly imbalanced cytokine response ("cytokine storm"), which converts responses that are normally beneficial for fighting infections into excessive, damaging inflammation. Molecular mechanisms for this excessive proinflammatory response are poorly understood. In patients with cirrhosis and severe sepsis, high production of proinflammatory cytokines seems to play a role in the worsening of liver function and the development of organ/system failures such as shock, renal failure, acute lung injury or acute respiratory distress syndrome, coagulopathy, or hepatic encephalopathy. In addition, these patients may have sepsis-induced hyperglycemia, defective arginine-vasopressin secretion, adrenal insufficiency, or compartmental syndrome. In patients with cirrhosis and spontaneous bacterial peritonitis (SBP), early use of antibiotics and intravenous albumin administration decreases the risk for developing renal failure and improves survival. There are no randomized studies that have been specifically performed in patients with cirrhosis and severe sepsis to evaluate treatments that have been shown to improve outcome in patients without cirrhosis who have severe sepsis or septic shock. These treatments include recombinant human activated C protein and protective-ventilation strategy for respiratory failure. Other treatments should be evaluated in the cirrhotic population with severe sepsis including the early use of antibiotics in "non-SBP" infections, vasopressor therapy, hydrocortisone, renal-replacement therapy and liver support systems, and selective decontamination of the digestive tract or oropharynx.
Hepatology 08/2009; 50(6):2022-33. · 11.66 Impact Factor
