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Jean-François Cadranel,
Jean-Baptiste Nousbaum,
Christophe Bessaguet,
Pierre Nahon,
Eric Nguyen-Khac, Richard Moreau,
Thierry Thévenot,
Christine Silvain,
Christophe Bureau,
Olivier Nouel,
Christophe Pilette,
Thierry Paupard,
Arnaud Pauwels,
Thierry Sapey,
Jean-Didier Grangé,
Albert Tran
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ABSTRACT: To compare the incidence of spontaneous bacterial peritonitis in cirrhotic outpatients and inpatients undergoing therapeutic paracentesis
From January 1 to May 31, 2004, 1041 patients from 70 different hospitals underwent 2123 therapeutic abdominal paracentesis (AP) performed as a outpatient procedure in 355 and as inpatient procedure in 686 cases respectively. The following parameters were compared prospectively between outpatients and inpatients: spontaneous bacterial peritonitis (SBP) prevalence, age, gender, cause of cirrhosis, symptoms, score and grade according to Child-Pugh classification, cirrhosis complications, antibiotics treatment, serum creatinine, platelet count and ascitic protein concentration.
SBP was observed in 91 patients. In the whole population the SBP prevalence was 8.7% (95%CI: 7.2-10.6) it was 11.7% (95%CI: 9.5-14.3) in inpatients and 3.1% (95%CI: 1.7-5.5) in outpatients (P < 0.00001). SBP prevalence was 8.3% (95%CI: 4.3-15.6) in symptomatic outpatients vs 1.2% (95%CI: 0.4-3.4) in asymptomatic outpatients (P < 0.002). Patients undergoing outpatient AP were significantly different from those undergoing inpatient AP; they were older (61.1 ± 11.1 years vs 59.4 ± 11.7 years; P = 0.028), cause of cirrhosis was less often alcohol (83 .7 vs 88.2%; P < 0.001), Child-Pugh score was lower (8.9 vs 10.1; P < 0.001) and more often B than C (63.7% vs 38%; P < 0.001). In addition, in outpatients the platelet count was higher (161 ± 93 Giga/L vs 143 ± 89 Giga/L; P = 0.003), serum total bilirubin concentration was lower (38.2 ± 60.7 μmol/L vs 96.3 ± 143.3 μmol/L; P < 0.0001), and ascitic protein concentration higher (17.9 ± 10.7 g/L vs 14.5 ± 10.9 g/L; P < 0.001) than in inpatients.
In asymptomatic cirrhotic outpatients, the incidence of spontaneous bacterial peritonitis is low thus exploratory paracentesis could be avoided in these patients without significant risk.
World journal of hepatology. 03/2013; 5(3):104-8.
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Richard Moreau,
Rajiv Jalan,
Pere Gines,
Marco Pavesi,
Paolo Angeli,
Juan Cordoba,
Francois Durand,
Thierry Gustot,
Faouzi Saliba,
Marco Domenicali,
Alexander Gerbes,
Julia Wendon,
Carlo Alessandria,
Wim Laleman,
Stefan Zeuzem,
Jonel Trebicka,
Mauro Bernardi,
Vicente Arroyo
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ABSTRACT: BACKGROUND & AIMS: Patients with cirrhosis hospitalized for an acute decompensation (AD) and organ failure are at risk for imminent death and considered to have acute-on-chronic liver failure (ACLF). However, there are no established diagnostic criteria for ACLF, so little is known about its development and progression. We aimed to identify diagnostic criteria of ACLF and describe the development of this syndrome in European patients with AD. METHODS: We collected data from 1343 hospitalized patients with cirrhosis and AD, from February through September 2011, in 29 Liver Units in 8 European countries. We used the organ failure and mortality data to define ACLF grades, assess mortality, and identify differences between ACLF and AD. We established diagnostic criteria for ACLF based on analyses of patients with organ failure (defined by the chronic liver failure [CLIF]-SOFA score) and high 28-day mortality (>15%). RESULTS: Of the patients assessed, 303 had ACLF when the study began, 112 developed ACLF, and 928 did not have ACLF. Twenty-eight day mortality among patients who had ACLF when the study began was 33.9%, among those who developed ACLF was 29.7%, and among those who did not have ACLF was 1.9%. Patients with ACLF were younger and more frequently alcoholics, had more associated bacterial infections, and had higher numbers of leukocytes and plasma levels of C-reactive protein than patients without ACLF (P <.001). Higher CLIF-SOFA scores and leukocyte counts were independent predictors of mortality in patients with ACLF. In patients without a prior history of AD, ACLF was unexpectedly characterized by higher numbers of organ failures, leukocyte count, and mortality, compared to ACLF in patients with prior history of AD. CONCLUSIONS: We analyzed data from patients with cirrhosis and AD to establish diagnostic criteria for ACLF, and show that it is distinct from AD, based not only on the presence of organ failure(s) and high mortality, but also on age, precipitating events, and systemic inflammation. ACLF mortality is associated with loss of organ function and high leukocyte counts. ACLF is especially severe in patients with no prior history of AD.
Gastroenterology 03/2013; · 11.68 Impact Factor
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ABSTRACT: Patients with cirrhosis frequently develop renal dysfunction, a proportion of who do not fulfill criteria for hepatorenal syndrome (HRS). We hypothesized that the kidneys in these patients would exhibit histological and biomarker evidence of kidney injury. We looked specifically for TLR expression as they may mediate kidney injury.
Sixty seven subjects (6); alcoholic cirrhosis: compensated (9), acute deterioration of alcoholic cirrhosis (52)] were included. Renal dysfunction was defined as a creatinine of >133 μmol/L and/or according to the AKI network criteria. Urinary biomarkers, KIM-1, πGST, αGST and a novel biomarker, urinary TLR4 were measured. Renal biopsies were also available from eight other alcoholic cirrhosis patients (three non-HRS renal dysfunction; five HRS) that were stained for TLR4 and caspase-3.
Fourteen patients developed renal dysfunction, amongst these three had type 2 HRS. KIM-1, πGST and αGST were higher in patients with acute deterioration of cirrhosis compared with patients with compensated cirrhosis, but did not differ between those with and without renal dysfunction. Urinary TLR4 was significantly higher in patients with renal dysfunction associated with infection/inflammation. Kidney biopsies from non-HRS renal dysfunction patients showed tubular damage with evidence of increased tubular expression of TLR4, and caspase-3. Minor changes were observed in HRS patients.
The data provide proof of concept that renal dysfunction in patients with cirrhosis with superimposed inflammation is associated with significant tubular injury and apoptosis and with increased renal expression and urinary excretion of the TLR4, suggesting a potential role of TLR4 as mediator of renal injury.
Liver international: official journal of the International Association for the Study of the Liver 03/2013; 33(3):398-409. · 3.82 Impact Factor
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Journal of Hepatology 02/2013; · 9.26 Impact Factor
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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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Thierry Thevenot,
Thibault Degand,
Natacha Grelat,
Laure Elkrief,
Camille Christol, Richard Moreau,
Jean Henrion,
Jean-François Cadranel,
Frances Sheppard,
Christophe Bureau,
Vincent di Martino,
Arnaud Pauwels
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ABSTRACT: BACKGROUND: Guidelines recommend antibiotic prophylaxis (AP) in well-selected groups of cirrhotic patients, but the impact of these recommendations has not been assessed in France. AIM: To evaluate AP prescription tendencies for gastrointestinal bleeding, and primary and secondary prophylaxis of spontaneous bacterial peritonitis (SBP). METHODS: Practitioners (n = 1,159) working in general hospitals (GH) or in university hospitals (UH) received a self-administered questionnaire. RESULTS: Three hundred and eighty-nine (33.6%; GH 35% and UH 30.4%) practitioners responded. AP was prescribed by 97.7%, 72.3% and 94.8% of practitioners, without significant differences between UH and GH, respectively, for gastrointestinal bleeding (quinolones 48.2%, third-generation cephalosporins 27.7% and amoxicillin-clavulanic acid 22.2%), primary (quinolones 97.2%) and secondary prophylaxis of SBP (quinolones 99%). For gastrointestinal bleeding, ofloxacin (47.6%) and norfloxacin (37.4%) were the main quinolones prescribed, and ceftriaxone (77%) was the main third-generation cephalosporin prescribed. The principal reasons for prescribing AP were a decrease in bacterial infection (88.9% for gastrointestinal bleeding, 91.3% for primary and 94.3% for secondary prophylaxis of SBP), a recommendation by a consensus conference (83%, 38% and 74.4% respectively) and an improvement in survival (72.8%, 41.3% and 57.7% respectively). Only 31.7% of practitioners (39.6% for UH vs. 28.6% for GH; P = 0.038) believed that AP may reduce the risk of bleeding recurrence. Reported side effects (28%) of AP mainly concerned the risk of quinolone resistance (62% of cases). CONCLUSION: Antibiotic prophylaxis is well-recognized by French practitioners, but its routine use depends on the expertise of practitioners. Quinolones remain the main antibiotic class prescribed irrespective of the type of prophylaxis.
Liver international: official journal of the International Association for the Study of the Liver 12/2012; · 3.82 Impact Factor
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Marie-Hélène Nicolas-Chanoine,
Coraline Gruson,
Suzanne Bialek-Davenet,
Xavier Bertrand,
Frédérique Thomas-Jean,
Frédéric Bert,
Mati Moyat,
Elodie Meiller,
Estelle Marcon,
Nicolas Danchin,
Latifa Noussair, Richard Moreau,
Véronique Leflon-Guibout
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ABSTRACT: OBJECTIVES: In 2006, 0.6% of healthy subjects living in the Paris area had extended-spectrum β-lactamase (ESBL)-producing Escherichia coli in their gut. To assess the evolution of this rate, a study identical to that of 2006 was conducted in 2011. PARTICIPANTS AND METHODS: Healthy adults who visited the IPC check-up centre in February-March 2011 and agreed to participate, provided stools and answered a questionnaire on the visit day. Stools were analysed to detect ESBL producers and to isolate the dominant E. coli population. ESBLs were molecularly characterized. For the subjects harbouring ESBL-producing E. coli, the phylogenetic group and sequence type (ST) were determined for both ESBL-producing and dominant E. coli isolates. PFGE profiles were also determined when two types of isolates had the same ST. RESULTS: Among the 345 subjects included, 21 (6%) had ESBL-producing E. coli faecal carriage. None of the previously published risk factors was identified. CTX-M accounted for 86% and SHV-12 for 14%. Dominant and ESBL-producing E. coli were similarly distributed into phylogenetic groups (A, 52%-48%; B1, 5%; B2, 24%-14%; and D, 19%-33%). Dominant and ESBL-producing E. coli displayed a polyclonal structure (18 STs each). However, ST10 and ST131 were identified in dominant and ESBL-producing E. coli isolates from different subjects. Most (20/21) ESBL producers were subdominant and belonged (16/21) to STs different from that of the corresponding dominant E. coli. CONCLUSIONS: The 10-fold increase in the rate of healthy subjects with ESBL-producing E. coli faecal carriage over a 5 year period suggests wide dissemination of these isolates in the Parisian community.
Journal of Antimicrobial Chemotherapy 11/2012; · 5.07 Impact Factor
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ABSTRACT: In Klebsiella pneumoniae, overexpression of non-specific efflux pumps causes low-level cross-resistance to β-lactams (mainly cefoxitin) and to antibiotics belonging to other families, such as quinolones, chloramphenicol and tetracycline (11, 12).…
Antimicrobial Agents and Chemotherapy 10/2012; · 4.84 Impact Factor
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Erwan Guyot,
Angela Sutton,
Pierre Rufat,
Christelle Laguillier,
Abdellah Mansouri, Richard Moreau,
Nathalie Ganne-Carrié,
Michel Beaugrand,
Nathalie Charnaux,
Jean-Claude Trinchet,
Pierre Nahon
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ABSTRACT: BACKGROUND & AIMS: Several studies have reported an association between the genetic variant rs738409 (G) in the PNPLA3 gene and the risk of cirrhosis in various liver diseases. Our purpose was to assess the influence of this polymorphism on the risk of hepatocellular carcinoma (HCC) occurrence in two distinct longitudinal cohorts of patients with cirrhosis as well as its possible usefulness in HCC-risk model prediction. METHODS: PNPLA3 rs738409 genotypes were assessed in 279 patients with alcoholic- and 253 patients with HCV-related cirrhosis. These patients were followed-up and screened for the risk of HCC and the influence of rs738409 on the occurrence of liver cancer was assessed using the Kaplan-Meier method then according to multivariate Cox model. RESULTS: In patients with HCV-related cirrhosis, rs738409 genotypes did not influence the risk of HCC development (log-rank=0.7) or death (log-rank=0.2). Conversely, in patients with alcoholic cirrhosis, the rs738409 (GG) genotype was an independent risk factor for HCC occurrence (HR=1.72 [1.21-2.45], log-rank=0.002) as well as older age, male gender, and higher BMI. Combining these features enabled HCC-risk stratification of this population into three groups with 6-year cumulative incidence ranging from 3.4% (low risk, n=58), 12.2% (intermediate risk, n=163), and 51.7% (high risk, n=58), respectively (HR=4.3 [2.7-6.4]; log-rank<0.0001). CONCLUSIONS: This study provides key data that affirm the influence of the rs738409 (GG) genotype on the occurrence of HCC in patients with alcoholic cirrhosis. Its combination with clinical features refines the selection of patients at higher risk of liver cancer development.
Journal of Hepatology 10/2012; · 9.26 Impact Factor
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ABSTRACT: Acute-on-chronic liver failure (ACLF) is an increasingly recognised entity encompassing an acute deterioration of liver function in patients with cirrhosis, which is usually associated with a precipitating event and results in the failure of one or more organs and high short term mortality. Prospective data to define this is lacking but there is a large body of circumstantial evidence suggesting that this condition is a distinct clinical entity. From the pathophysiologic perspective, altered host response to injury and infection play important roles in its development. This review focuses upon the current understanding of this syndrome from the clinical, prognostic and pathophysiologic perspectives and indicates potential biomarkers and therapeutic targets for intervention.
Journal of Hepatology 06/2012; · 9.26 Impact Factor
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ABSTRACT: Extended-spectrum β-lactamase-producing Enterobacteriaceae isolates (ESBLE) are emerging pathogens that confer resistance to antimicrobial drugs. We conducted a 10-year study in France (January 2001-April 2010) to investigate the incidence of and risk factors for ESBLE infections after liver transplant. Of 710 transplant patients screened preoperatively for ESBLE fecal carriage, 5.5% had ESBLE infection develop within 4 months after surgery; patients with pretransplant ESBLE fecal carriage were more likely to have infection develop than were noncarriers. Typing showed extensive genetic diversity, with a large predominance of CTX-M enzymes. Independent predictors of ESBLE infection were pretransplant fecal carriage, Model for End Stage Liver Disease score >25, and return to surgery. Our results indicate that the influx of preoperatively acquired ESBLE isolates into the hospital outweighs cross-transmission in the epidemiology of ESBLE infections after liver transplant. Transplant candidates should be systematically screened for carriage, and posttransplant infection in carriers should be treated with carbapenems.
Emerging Infectious Diseases 06/2012; 18(6):908-16. · 6.79 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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ABSTRACT: During chronic liver inflammation, up-regulated Tumor Necrosis Factor alpha (TNF-α) targets hepatocytes and induces abnormal reactive oxygen species (ROS) production responsible for mitochondrial DNA (mtDNA) alterations. The serine/threonine Glycogen Synthase Kinase 3 beta (GSK3β) plays a pivotal role during inflammation but its involvement in the maintenance of mtDNA remains unknown. The aim of this study was to investigate its involvement in TNF-α induced mtDNA depletion and its interrelationship with p53 a protein known to maintain mtDNA copy numbers. Using quantitative polymerase chain reaction (qPCR) we found that at 30 min in human hepatoma HepG2 cells TNF-α induced 0.55±0.10 mtDNA lesions per 10 Kb and a 52.4±2.8% decrease in mtDNA content dependent on TNF-R1 receptor and ROS production. Both lesions and depletion returned to baseline from 1 to 6 h after TNF-α exposure. Luminol-amplified chemiluminescence (LAC) was used to measure the rapid (10 min) and transient TNF-α induced increase in ROS production (168±15%). A transient 8-oxo-dG level of 1.4±0.3 ng/mg DNA and repair of abasic sites were also measured by ELISA assays. Translocation of p53 to mitochondria was observed by Western Blot and co-immunoprecipitations showed that TNF-α induced p53 binding to GSK3β and mitochondrial transcription factor A (TFAM). In addition, mitochondrial D-loop immunoprecipitation (mtDIP) revealed that TNF-α induced p53 binding to the regulatory D-loop region of mtDNA. The knockdown of p53 by siRNAs, inhibition by the phosphoSer(15)p53 antibody or transfection of human mutant active GSK3βS9A pcDNA3 plasmid inhibited recovery of mtDNA content while blockade of GSK3β activity by SB216763 inhibitor or knockdown by siRNAs suppressed mtDNA depletion. This study is the first to report the involvement of GSK3β in TNF-α induced mtDNA depletion. We suggest that p53 binding to GSK3β, TFAM and D-loop could induce recovery of mtDNA content through mtDNA repair.
PLoS ONE 01/2012; 7(7):e40879. · 4.09 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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Pierre Nahon,
Angela Sutton,
Pierre Rufat,
Nathalie Charnaux,
Abdellah Mansouri, Richard Moreau,
Nathalie Ganne-Carrié,
Véronique Grando-Lemaire,
Gisèle N'Kontchou,
Jean-Claude Trinchet,
Dominique Pessayre,
Michel Beaugrand
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ABSTRACT: Genetic dimorphisms modulate the activities of several pro- or antioxidant enzymes, including myeloperoxidase (MPO), catalase (CAT), manganese superoxide dismutase (SOD2), and glutathione peroxidase 1 (GPx1). We assessed the role of the G(-463)A-MPO, T(-262)C-CAT, Ala16Val-SOD2, and Pro198Leu-GPx1 variants in modulating HCC development in patients with HCV-induced cirrhosis.
Two hundred and five patients with HCV-induced, biopsy-proven cirrhosis but without detectable HCC at inclusion were prospectively followed-up for HCC development. The influence of various genotypes on HCC occurrence was assessed with the Kaplan-Meier method.
During follow-up (103.2±3.4 months), 84 patients (41%) developed HCC, and 66 died. Whereas the Ala16Val-SOD2 or Pro198Leu-GPx1 dimorphisms did not modulate the risk, HCC occurrence was increased in patients with either the homozygous GG-MPO genotype (HR=2.8 [1.7-4.4]; first quartile time to HCC occurrence: 45 vs. 96 months; LogRank <0.0001) or the homozygous CC-CAT genotype (HR=1.74 [1.06-2.82]; first quartile time to HCC occurrence: 55 vs. 96 months; LogRank=0.02). Compared to patients with neither of these two at risk factors, patients with only the CC-CAT genotype had a HR of 2.05 [0.9-4.6] (p=0.08) and patients with only the GG-MPO genotype had a HR of 3.8 [1.5-9.1] (p=0.002), while patients with both risk factors had an HR of 4.8 [2.2-10.4] (p<0.0001). However, only the GG-MPO genotype was independently associated with the HCC risk in multivariate Cox analysis.
The high activity-associated GG-MPO genotype increases the rate of HCC occurrence in patients with HCV-induced cirrhosis.
Journal of Hepatology 09/2011; 56(2):426-32. · 9.26 Impact Factor
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ABSTRACT: A frequent mechanism for drug-induced liver injury (DILI) is the formation of reactive metabolites that trigger hepatitis through direct toxicity or immune reactions. Both events cause mitochondrial membrane disruption. Genetic or acquired factors predispose to metabolite-mediated hepatitis by increasing the formation of the reactive metabolite, decreasing its detoxification, or by the presence of critical human leukocyte antigen molecule(s). In other instances, the parent drug itself triggers mitochondrial membrane disruption or inhibits mitochondrial function through different mechanisms. Drugs can sequester coenzyme A or can inhibit mitochondrial β-oxidation enzymes, the transfer of electrons along the respiratory chain, or adenosine triphosphate (ATP) synthase. Drugs can also destroy mitochondrial DNA, inhibit its replication, decrease mitochondrial transcripts, or hamper mitochondrial protein synthesis. Quite often, a single drug has many different effects on mitochondrial function. A severe impairment of oxidative phosphorylation decreases hepatic ATP, leading to cell dysfunction or necrosis; it can also secondarily inhibit ß-oxidation, thus causing steatosis, and can also inhibit pyruvate catabolism, leading to lactic acidosis. A severe impairment of β-oxidation can cause a fatty liver; further, decreased gluconeogenesis and increased utilization of glucose to compensate for the inability to oxidize fatty acids, together with the mitochondrial toxicity of accumulated free fatty acids and lipid peroxidation products, may impair energy production, possibly leading to coma and death. Susceptibility to parent drug-mediated mitochondrial dysfunction can be increased by factors impairing the removal of the toxic parent compound or by the presence of other medical condition(s) impairing mitochondrial function. New drug molecules should be screened for possible mitochondrial effects.
Drug Metabolism Reviews 09/2011; 44(1):34-87. · 6.40 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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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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Amal Choumar,
Arige Tarhuni,
Philippe Lettéron,
Florence Reyl-Desmars,
Nismah Dauhoo,
Julie Damasse,
Nathalie Vadrot,
Pierre Nahon, Richard Moreau,
Dominique Pessayre,
Abdellah Mansouri
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ABSTRACT: Hepatic energy depletion has been described in severe sepsis, and lipopolysaccharide (LPS) has been shown to cause mitochondrial DNA (mtDNA) damage. To clarify the mechanisms of LPS-induced mtDNA damage and mitochondrial alterations, we treated wild-type (WT) or transgenic manganese superoxide dismutase-overerexpressing (MnSOD(+++)) mice with a single dose of LPS (5 mg/kg). In WT mice, LPS increased mitochondrial reactive oxygen species formation, hepatic inducible nitric oxide synthase (NOS) mRNA and protein, tumor necrosis factor-alpha, interleukin-1 beta, and high-mobility group protein B1 concentrations. Six to 48 h after LPS administration (5 mg/kg), liver mtDNA levels, respiratory complex I activity, and adenosine triphosphate (ATP) contents were decreased. In addition, LPS increased interferon-β concentration and decreased mitochondrial transcription factor A (Tfam) mRNA, Tfam protein, and mtDNA-encoded mRNAs. Morphological studies showed mild hepatic inflammation. The LPS (5 mg/kg)-induced mtDNA depletion, complex I inactivation, ATP depletion, and alanine aminotransferase increase were prevented in MnSOD(+++) mice or in WT mice cotreated with 1400W (a NOS inhibitor), (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride, monohydrate (a superoxide scavenger) or uric acid (a peroxynitrite scavenger). The MnSOD overexpression delayed death in mice challenged by a higher, lethal dose of LPS (25 mg/kg). In conclusion, LPS administration damages mtDNA and alters mitochondrial function. The protective effects of MnSOD, NOS inhibitors, and superoxide or peroxynitrite scavengers point out a role of the superoxide anion reacting with NO to form mtDNA- and protein-damaging peroxynitrite. In addition to the acute damage caused by reactive species, decreased levels of mitochondrial transcripts contribute to mitochondrial dysfunction.
Antioxidants & Redox Signaling 07/2011; 15(11):2837-54. · 8.20 Impact Factor
