Alcoholic liver disease in humans frequently leads to cirrhosis. Experimental models of hepatic f... more Alcoholic liver disease in humans frequently leads to cirrhosis. Experimental models of hepatic fibrogenesis are available, but extrapolation of those findings to human ethanol-induced liver injury is difficult. Hepatic ethanol-induced fibrosis in humans has often been studied in relatively small patient populations. During the past decade, several animal models and human studies have attributed fibrogenesis in the liver to the role played by hepatocytes, Kupffer cells, endothelial cells, and especially stellate cells. To determine the contribution of the main liver cell types to ethanol-induced fibrogenesis. For that purpose, we studied the expression of the following immunologic parameters: smooth muscle-specific alpha actin (SMSA), CD68, CD34, transforming growth factor beta1, intercellular adhesion molecule 1, and collagen types 1 and 3. The Dako LSAB+ kit (peroxidase method) was used. We recently studied a large cohort of patients with alcoholic liver disease in France. In this...
ABSTRACT— Two cases are reported, a daughter and her mother who both have myotonic dystrophy with... more ABSTRACT— Two cases are reported, a daughter and her mother who both have myotonic dystrophy with abnormalities of liver function tests and an important perisinusoidal cell enlargement without other pathologic features. In both cases, the myotonic dystrophy was clinically obvious and confirmed by electromyography. No other causes of perisinusoidal cell enlargement were found including vitamin A intake, psoriasis, viral disease or alcoholism. These observations suggest a genetic linkage and that serum test abnormalities could be associated with a perisinusoidal cell change.
Background: Biopsy is the usual gold standard for liver steatosis assessment. The aim of this stu... more Background: Biopsy is the usual gold standard for liver steatosis assessment. The aim of this study was to identify a panel of biomarkers (SteatoTest), with sufficient predictive values, for the non-invasive diagnosis of steatosis in patients with or without chronic liver disease. Biomarkers and panels were assessed in a training group of consecutive patients with chronic hepatitis C and B, alcoholic liver disease, and non-alcoholic fatty liver disease, and were validated in two independent groups including a prospective one. Steatosis was blindly assessed by using a previously validated scoring system. Results: 310 patients were included in the training group; 434 in three validation groups; and 140 in a control group. SteatoTest was constructed using a combination of the 6 components of FibroTest-ActiTest plus body mass index, serum cholesterol, triglycerides, and glucose adjusted for age and gender. SteatoTest area under the ROC curves was 0.79 (SE = 0.03) in the training group; 0.80 (0.04) in validation group 1; 0.86 (0.03) in validation group 2; and 0.72 (0.05) in the validation group 3-all significantly higher than the standard markers: γ-glutamyl-transpeptidase or alanine aminotransferase. The median SteatoTest value was 0.13 in fasting controls; 0.16 in non-fasting controls; 0.31 in patients without steatosis; 0.39 in grade 1 steatosis (0-5%); 0.58 in grade 2 (6-32%); and 0.74 in grade 3-4 (33-100%). For the diagnosis of grade 2-4 steatosis, the sensitivity of SteatoTest at the 0.30 cutoff was 0.91, 0.98, 1.00 and 0.85 and the specificity at the 0.70 cutoff was 0.89, 0.83, 0.92, 1.00, for the training and three validation groups, respectively. Conclusion: SteatoTest is a simple and non-invasive quantitative estimate of liver steatosis and may reduce the need for liver biopsy, particularly in patients with metabolic risk factor.
In experimental models, liver injury induced by ethanol, cytotoxic activity of tumor necrosis fac... more In experimental models, liver injury induced by ethanol, cytotoxic activity of tumor necrosis factor (TNF)-␣ is principally mediated by TNF receptor p55 (TN-FRp55). Among the various mechanisms underlying the toxic effects of TNF-␣, overproduction of reactive oxygen species seems to play a key role in mediating TNF-␣induced cytotoxicity. The aim of this study was to evaluate, in patients with alcoholic liver disease, whether alcohol TNFRp55-mediated hepatotoxicity could account for lipid peroxidation expressed by significant increase in serum thiobarbituric reactive acid substances (TBARS) content, and could be amplified by decrease in blood total glutathione content and decrease in plasma antioxidant protective capacity. METHODS: We studied 27 patients with histological alcoholic liver disease (five fibrosis, six acute alcoholic hepatitis (AAH) without cirrhosis, four cirrhosis without AAH, and 12 cirrhosis with AAH. TNFsRp55 and TNFsRp75 plasma levels were measured using ELISA assays. Plasma lipid peroxidation was evaluated by the content of TBARS. Total glutathione (tGSH) content in blood was determined by a kinetic assay. The sensitivity of erythrocytes to an oxidative stress and the plasma antioxidant protective capacity were simultaneously determined by a simple method. RESULTS: In the 18 patients with mild or severe AAH, the plasma levels of TNFsRp55 were negatively correlated with tGSH and were positively correlated with TBARS, with total bilirubin and with discriminant function. tGSH was positively correlated with plasma selenium. The plasma levels of TNFsRp75 were positively correlated with TBARS and with total bilirubin. There was no significant correlation with the mean inhibitory 50% plasma volume or with the percentage of hemolyzed erythrocytes. CONCLUSIONS: Our data support the notions that, in patients with AAH, TNFsRp55 probably mediates cytotoxicity of TNF-␣, and that cytotoxic effect could be amplified by tGSH depletion in enhancing lipid peroxidation.
Resume De nombreux faits experimentaux plaident en faveur du role des acides gras alimentaires da... more Resume De nombreux faits experimentaux plaident en faveur du role des acides gras alimentaires dans la pathogenie de la maladie alcoolique du foie. Les acides gras polyinsatures potentialisent les alterations hepatiques liees a l'alcool par l'induction du cytochrome P450 2E1, de la cyclo-oxygenase-2 et de la peroxydation lipidique. En revanche, les acides gras satures diminuent la steatose, la necrose, l'inflammation et la fibrose parallelement a la diminution de l'expression du TNF-α, de la cyclo-oxygenase-2 et a la diminution de la peroxydation lipidique. La dilinoleyl-phosphatidylcholine empeche le developpement de la fibrose et de la cirrhose chez le babouin et stimule in vitro l'activite de la collagenase des lipocytes. Il y a peu d'etudes confirmant chez l'homme ces faits experimentaux. Des etudes epidemiologiques suggerent que les acides gras polyinsatures alimentaires sont des facteurs de risque de cirrhose chez l'alcoolique. Les etudes ayant montre que le surpoids etait un facteur de risque de cirrhose alcoolique et que le polymorphisme de l'apolipoproteine E influencait la severite de l'atteinte hepatique chez les cirrhotiques alcooliques sont des arguments importants en faveur de l'intervention des acides gras alimentaires dans la pathogenie de la maladie alcoolique du foie.
Background & Aims: Adipose tissue is an important source of cytokines. Excess weight is an indepe... more Background & Aims: Adipose tissue is an important source of cytokines. Excess weight is an independent risk factor for steatosis, acute alcoholic hepatitis (AAH), and cirrhosis in patients with alcoholic liver disease (ALD). In this study, we investigated the role of adipose tissue in human ALD. Patients and methods: Fifty patients with ALD underwent liver and abdominal subcutaneous adipose tissue biopsies and supplied blood samples for the investigation of cytokine gene expression and secretion, as well as liver histology. Results: The levels of TNF-a and IL-10 in adipose tissue were higher in patients with AAH. IL-10 level in adipose tissue was also correlated with fibrosis score. TNF-a gene expression in adipose tissue was correlated with Maddrey score, blood C-reactive protein (CRP) concentration and liver IL-6 concentration. IL-6 production levels in the liver were higher in patients with AAH and correlated with AAH score, liver histological lesions, liver TNF-a concentration, Maddrey score, and blood CRP concentration. Plasma concentrations of soluble forms of TNF-receptor were correlated with inflammatory lesions in the liver, Maddrey score and fibrosis score. Conclusion: In patients with ALD, inflammation occurs not only in the liver, but also in the adipose tissue. Adipose tissue inflammation is correlated with the severity of pathological features in the liver. Our findings may account for the harmful interactions between body mass index, AAH, fibrosis, and cirrhosis in alcoholic patients.
Background: Liver biopsy is still the gold standard in chronic liver disease, but is invasive, co... more Background: Liver biopsy is still the gold standard in chronic liver disease, but is invasive, costly ($1,000), has a high sampling error (33% for fibrosis and 24% for activity), as well as discordance rates greater than 10% between pathologists for routine scoring systems. FibroTest-ActiTest (FF-AT) are biochemical markers of fibrosis and activity ($90). The aim was to demonstrate, through an overview of diagnostic studies, that FF-AT were cost-effective enough to be used as non invasive alternatives to liver biopsy in patients with chronic hepatitis C (CHC), B (CHB), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Methods: The following diagnostic parameters were assessed: the area under the ROC curves (AUROC), accuracy (AC), kappa statistics (K), and Spearman correlation coefficient (SC). The main end point was the AUROC for the diagnosis of bridging fibrosis (F2F3F4 vs FOF1) and for the diagnosis of moderate/severe necrosis activity (A2A3 vs AOA1). In order to assess the diagnostic value between each stage and grade, all possible combinations of the AUROC were computed. The quality of biopsy was scored according to published criteria: a single fragment, size of 15 mm or more, and 5 or more portal tracts. Specificity and normal values were determined prospectively in blood donors. The prevalence of the abnormal values (outside the 99% percentiles) of the 6 FT-AT components was assessed on 8,540 consecutive tests computed according to standardized procedures between September 2002
A prospective study of apolipoprotein AI has been undertaken in 581 alcoholic patients and in 100... more A prospective study of apolipoprotein AI has been undertaken in 581 alcoholic patients and in 100 controls in order to describe the changes of apolipoprotein AI according to the different stages of the alcoholic liver disease, to correlate the changes to serum liver tests and to estimate its diagnosis and prognostic value. Results showed that apolipoprotein AI concentration is highly related to the degree of liver injury, reaching a maximum in patients with steatosis (229 +/- 90 mg per dl), beginning to decrease in patients with fibrosis (188 +/- 88 mg per dl) and reaching a minimum in patients with severe cirrhosis (91 +/- 46 mg per dl). Apolipoprotein AI had an independent and discriminative value for the diagnosis of fibrosis (p less than 0.001) vs. steatosis and for the diagnosis of cirrhotic vs. noncirrhotic fibrosis (p less than 0.001) or vs. acute alcoholic hepatitis without cirrhosis (p less than 0.001). Cirrhotic patients with apolipoprotein AI less than 100 mg per dl had a lower survival rate at 1 year (62 +/- 7%) than patients with greater value (80 +/- 6%; p less than 0.05), but this prognostic value disappeared in multivariate analysis when other known prognostic factors were taken into account.
Early identification of patients with severe (discriminant function &... more Early identification of patients with severe (discriminant function > or = 32) alcoholic hepatitis (AH) not responding to corticosteroids is crucial. We generated a specific prognostic model (Lille model) to identify candidates early on for alternative therapies. Three hundred twenty patients with AH prospectively treated by corticosteroids were included in the development cohort and 118 in its validation. Baseline data and a change in bilirubin at day 7 were tested. The model was generated by logistic regression. The model combining six reproducible variables (age, renal insufficiency, albumin, prothrombin time, bilirubin, and evolution of bilirubin at day 7) was highly predictive of death at 6 months (P < 0.000001). The area under the receiver operating characteristic (AUROC) curve of the Lille model was 0.89 +/- 0.02, higher than the Child-Pugh (0.62 +/- 0.04, P < 0.00001) or Maddrey scores (0.66 +/- 0.04, P < 0.00001). In the validation cohort, its AUROC was 0.85 +/- 0.04, still higher than the other models, including MELD (0.72 +/- 0.05, P = 0.01) and Glasgow scores (0.67 +/- 0.05, P = 0.0008). Patients above the ideal cutoff of 0.45 showed a marked decrease in 6-month survival as compared with others: 25% +/- 3.8% versus 85% +/- 2.5%, P < 0.0001. This cutoff was able to identify approximately 75% of the observed deaths. In the largest cohort to date of patients with severe AH, we demonstrate that the term "nonresponder" can now be extended to patients with a Lille score above 0.45, which corresponds to 40% of cases. Early identification of subjects with substantial risk of death according to the Lille model will improve management of patients suffering from severe AH and will aid in the design of future studies for alternative therapies.
The aim of this study was to assess whether markers of hepatitis B virus or hepatitis C virus inf... more The aim of this study was to assess whether markers of hepatitis B virus or hepatitis C virus infection are independent risk factors for hepatocellular carcinoma in drinkers after adjustment for three known risk factors: cirrhosis, age and male sex. Among 2,015 consecutive drinkers admitted, hepatitis C virus antibodies were found by sensitive radioimmunoassay in 1,259. The following five factors have been identified and ranked as risk factors for hepatocellular carcinoma in unidimensional and regression analysis: cirrhosis (p less than 0.001), age (p less than 0.001), male sex (p less than 0.001), presence of HBsAg (p less than 0.001) and presence of hepatitis C virus antibodies (p less than 0.03). Among drinkers with cirrhosis, the patients with hepatocellular carcinoma were older (64 +/- 11 yr vs. 56 +/- 9 yr; p less than 0.001), were more often male (93% vs. 65%; p less than 0.0001) and had higher prevalence of HBsAg (9% vs. 2%; p = 0.02) and hepatitis C virus antibodies (41% vs. 26%; p = 0.02). A simple algorithm permitted us to identify a high-risk population of drinkers: the male cirrhotic patient older than 50 yr. The relative risk of hepatocellular carcinoma in this selected population was 17.7 (95% confidence interval = 9.0 to 37.5; p less than 0.0001). From a pragmatic point of view, the detection of HBsAg or hepatitis C virus antibodies, although independently associated with hepatocellular carcinoma, is not useful in increasing the diagnostic value of this algorithm because of the poor sensitivity of these tests. The weak relationships observed between hepatitis C virus antibodies and hepatocellular carcinoma needs confirmation by more accurate tests.
Glucocorticoid-induced leucine zipper (GILZ), a recently identified protein induced by glucocorti... more Glucocorticoid-induced leucine zipper (GILZ), a recently identified protein induced by glucocorticoids (GCs), inhibits the nuclear factor B pathway and the activation of monocytes/macrophages by lipopolysaccharides (LPS). This study aimed to elucidate the contribution of GILZ to the pathogenesis of alcoholic hepatitis (AH): we (1) assessed GILZ expression in the livers of patients with AH and (2) treated patients with severe AH with GCs (prednisolone 40 mg/day) and studied the effect of GILZ modulation on circulating monocyte function. We quantified GILZ expression in the livers of 42 consecutive alcoholic patients (21 with and 21 without AH). GILZ messenger RNA (mRNA) levels were lower in the livers of patients with AH versus those without AH (P < 0.05). We collected circulating monocytes from patients with severe AH before and 48 hours after GC treatment to quantify GILZ expression and cytokine secretion. GC treatment induced significantly higher levels of GILZ mRNA than that observed before treatment and impaired LPS-induced tumor necrosis factor-␣ (TNF-␣) and regulated upon activation, normal T cell-expressed secretion (RANTES) by these monocytes. We transfected circulating monocytes with GILZ small interfering RNA (siRNA), specifically blocking GILZ expression, to demonstrate the role of GILZ in mediating GC effect. GILZ siRNA abrogated the effect of GC treatment on LPS-induced TNF-␣ and RANTES secretion. Conclusion: Low expression of GILZ may contribute to liver inflammation in AH. GCs enhance GILZ expression, abrogating macrophage sensitivity to LPS and proinflammatory cytokine secretion. These findings may explain the beneficial effect of GC treatment in patients with severe AH. (HEPATOLOGY 2007;46:1986-1992.) P roinflammatory cytokines play a major role in the pathophysiology of alcoholic hepatitis (AH). Cytokines are produced and released by many cells, including monocytes, macrophages, and-particularly relevant to the liver-Kupffer cells. 1 The proinflammatory cytokine tumor necrosis factor-␣ (TNF-␣), TNF-␣inducible cytokines, and chemokines are critical mediators of the hepatotoxicity of alcohol. Reactive oxygen species and lipopolysaccharide (LPS), 2 a membrane component of gram-negative commensal bacteria present in the digestive tract, are 2 major activators of Kupffer cells in AH. Alcohol ingestion increases intestinal barrier permeability 3 and induces the diffusion of bacterial products into the lumen of the portal vein. LPS is hepatotoxic, and plasma endotoxin concentrations increase in experimental and human AH. 4 AH is a life-threatening condition. Mortality for patients with the most severe forms of AH is 50%-75%. Although glucocorticoid (GC) treatment continues to be discussed, GCs are the only family of drugs that has shown efficacy in improving short-term survival in patients with severe AH, defined as a Maddrey discriminant function Ն 32.
Introduction A meta-analysis was performed using individual patient data from the five most recen... more Introduction A meta-analysis was performed using individual patient data from the five most recent randomised controlled trials (RCTs) which evaluated corticosteroids in severe alcoholic hepatitis (Maddrey discriminant function (DF) $32 or encephalopathy). This approach overcomes limitations associated with the use of literature data and improves the relevance of the study and estimates of effect size. Aims To compare 28-day survival between corticosteroid-and non-corticosteroid-treated patients and to analyse the response to treatment using the Lille model. Methods Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n¼3), enteral nutrition (n¼1) or an antioxidant cocktail (n¼1). Results 221 patients allocated to corticosteroid treatment and 197 allocated to non-corticosteroid treatment were analysed. The two groups were similar at baseline. 28-day survival was higher in corticosteroidtreated patients than in non-corticosteroid-treated patients (79.9762.8% vs 65.763.4%, p¼0.0005). In multivariate analysis, corticosteroids (p¼0.005), DF (p¼0.006), leucocytes (p¼0.004), Lille score (p<0.00001) and encephalopathy (p¼0.003) were independently predictive of 28-day survival. A subgroup analysis was performed according to the percentile distribution of the Lille score. Patients were classified as complete responders (Lille score #0.16; #35th percentile), partial responders (Lille score 0.16e0.56; 35the70th percentile) and null responders (Lille $0.56; $70th percentile). 28-day survival was strongly associated with these groupings (91.162.7% vs 79.463.8% vs 53.365.1%, p<0.0001). Corticosteroids had a significant effect on 28-day survival in complete responders (HR 0.18, p¼0.006) and in partial responders (HR 0.38, p¼0.04) but not in null responders. Conclusion Analysis of individual data from five RCTs showed that corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.
Background: Choroidal near-infrared fluorescent angiography can detect vessels in the eye with hi... more Background: Choroidal near-infrared fluorescent angiography can detect vessels in the eye with high resolution. Observation of fluorescent gastrointestinal (GI) vessels by endoscopy may be useful in portal hypertension and bleeding ulcer. We here describe a technique for the detection of fluorescent GI vessels with a CCD camera or a near-infrared video endoscope. Methods: Laparotomy was performed on rats. A tissue target was excited by means of a laser diode. We took pictures of tissue under both white and near-infrared light, both before and after intravenous injection of indocyanine green. Fluorescent light was selected by means of filters placed in front of the lens of a CCD camera or a near-infrared video endoscope. Results: Under near-infrared light and after dye injection, we observed fluorescent vessels in real time and distinguished arterial from venous fluorescence. Conclusions: This device permits visualization of GI vessels, which could be useful for diagnosis of vascular abnormalities during endoscopy and surgery.
Alcoholic liver disease in humans frequently leads to cirrhosis. Experimental models of hepatic f... more Alcoholic liver disease in humans frequently leads to cirrhosis. Experimental models of hepatic fibrogenesis are available, but extrapolation of those findings to human ethanol-induced liver injury is difficult. Hepatic ethanol-induced fibrosis in humans has often been studied in relatively small patient populations. During the past decade, several animal models and human studies have attributed fibrogenesis in the liver to the role played by hepatocytes, Kupffer cells, endothelial cells, and especially stellate cells. To determine the contribution of the main liver cell types to ethanol-induced fibrogenesis. For that purpose, we studied the expression of the following immunologic parameters: smooth muscle-specific alpha actin (SMSA), CD68, CD34, transforming growth factor beta1, intercellular adhesion molecule 1, and collagen types 1 and 3. The Dako LSAB+ kit (peroxidase method) was used. We recently studied a large cohort of patients with alcoholic liver disease in France. In this...
ABSTRACT— Two cases are reported, a daughter and her mother who both have myotonic dystrophy with... more ABSTRACT— Two cases are reported, a daughter and her mother who both have myotonic dystrophy with abnormalities of liver function tests and an important perisinusoidal cell enlargement without other pathologic features. In both cases, the myotonic dystrophy was clinically obvious and confirmed by electromyography. No other causes of perisinusoidal cell enlargement were found including vitamin A intake, psoriasis, viral disease or alcoholism. These observations suggest a genetic linkage and that serum test abnormalities could be associated with a perisinusoidal cell change.
Background: Biopsy is the usual gold standard for liver steatosis assessment. The aim of this stu... more Background: Biopsy is the usual gold standard for liver steatosis assessment. The aim of this study was to identify a panel of biomarkers (SteatoTest), with sufficient predictive values, for the non-invasive diagnosis of steatosis in patients with or without chronic liver disease. Biomarkers and panels were assessed in a training group of consecutive patients with chronic hepatitis C and B, alcoholic liver disease, and non-alcoholic fatty liver disease, and were validated in two independent groups including a prospective one. Steatosis was blindly assessed by using a previously validated scoring system. Results: 310 patients were included in the training group; 434 in three validation groups; and 140 in a control group. SteatoTest was constructed using a combination of the 6 components of FibroTest-ActiTest plus body mass index, serum cholesterol, triglycerides, and glucose adjusted for age and gender. SteatoTest area under the ROC curves was 0.79 (SE = 0.03) in the training group; 0.80 (0.04) in validation group 1; 0.86 (0.03) in validation group 2; and 0.72 (0.05) in the validation group 3-all significantly higher than the standard markers: γ-glutamyl-transpeptidase or alanine aminotransferase. The median SteatoTest value was 0.13 in fasting controls; 0.16 in non-fasting controls; 0.31 in patients without steatosis; 0.39 in grade 1 steatosis (0-5%); 0.58 in grade 2 (6-32%); and 0.74 in grade 3-4 (33-100%). For the diagnosis of grade 2-4 steatosis, the sensitivity of SteatoTest at the 0.30 cutoff was 0.91, 0.98, 1.00 and 0.85 and the specificity at the 0.70 cutoff was 0.89, 0.83, 0.92, 1.00, for the training and three validation groups, respectively. Conclusion: SteatoTest is a simple and non-invasive quantitative estimate of liver steatosis and may reduce the need for liver biopsy, particularly in patients with metabolic risk factor.
In experimental models, liver injury induced by ethanol, cytotoxic activity of tumor necrosis fac... more In experimental models, liver injury induced by ethanol, cytotoxic activity of tumor necrosis factor (TNF)-␣ is principally mediated by TNF receptor p55 (TN-FRp55). Among the various mechanisms underlying the toxic effects of TNF-␣, overproduction of reactive oxygen species seems to play a key role in mediating TNF-␣induced cytotoxicity. The aim of this study was to evaluate, in patients with alcoholic liver disease, whether alcohol TNFRp55-mediated hepatotoxicity could account for lipid peroxidation expressed by significant increase in serum thiobarbituric reactive acid substances (TBARS) content, and could be amplified by decrease in blood total glutathione content and decrease in plasma antioxidant protective capacity. METHODS: We studied 27 patients with histological alcoholic liver disease (five fibrosis, six acute alcoholic hepatitis (AAH) without cirrhosis, four cirrhosis without AAH, and 12 cirrhosis with AAH. TNFsRp55 and TNFsRp75 plasma levels were measured using ELISA assays. Plasma lipid peroxidation was evaluated by the content of TBARS. Total glutathione (tGSH) content in blood was determined by a kinetic assay. The sensitivity of erythrocytes to an oxidative stress and the plasma antioxidant protective capacity were simultaneously determined by a simple method. RESULTS: In the 18 patients with mild or severe AAH, the plasma levels of TNFsRp55 were negatively correlated with tGSH and were positively correlated with TBARS, with total bilirubin and with discriminant function. tGSH was positively correlated with plasma selenium. The plasma levels of TNFsRp75 were positively correlated with TBARS and with total bilirubin. There was no significant correlation with the mean inhibitory 50% plasma volume or with the percentage of hemolyzed erythrocytes. CONCLUSIONS: Our data support the notions that, in patients with AAH, TNFsRp55 probably mediates cytotoxicity of TNF-␣, and that cytotoxic effect could be amplified by tGSH depletion in enhancing lipid peroxidation.
Resume De nombreux faits experimentaux plaident en faveur du role des acides gras alimentaires da... more Resume De nombreux faits experimentaux plaident en faveur du role des acides gras alimentaires dans la pathogenie de la maladie alcoolique du foie. Les acides gras polyinsatures potentialisent les alterations hepatiques liees a l'alcool par l'induction du cytochrome P450 2E1, de la cyclo-oxygenase-2 et de la peroxydation lipidique. En revanche, les acides gras satures diminuent la steatose, la necrose, l'inflammation et la fibrose parallelement a la diminution de l'expression du TNF-α, de la cyclo-oxygenase-2 et a la diminution de la peroxydation lipidique. La dilinoleyl-phosphatidylcholine empeche le developpement de la fibrose et de la cirrhose chez le babouin et stimule in vitro l'activite de la collagenase des lipocytes. Il y a peu d'etudes confirmant chez l'homme ces faits experimentaux. Des etudes epidemiologiques suggerent que les acides gras polyinsatures alimentaires sont des facteurs de risque de cirrhose chez l'alcoolique. Les etudes ayant montre que le surpoids etait un facteur de risque de cirrhose alcoolique et que le polymorphisme de l'apolipoproteine E influencait la severite de l'atteinte hepatique chez les cirrhotiques alcooliques sont des arguments importants en faveur de l'intervention des acides gras alimentaires dans la pathogenie de la maladie alcoolique du foie.
Background & Aims: Adipose tissue is an important source of cytokines. Excess weight is an indepe... more Background & Aims: Adipose tissue is an important source of cytokines. Excess weight is an independent risk factor for steatosis, acute alcoholic hepatitis (AAH), and cirrhosis in patients with alcoholic liver disease (ALD). In this study, we investigated the role of adipose tissue in human ALD. Patients and methods: Fifty patients with ALD underwent liver and abdominal subcutaneous adipose tissue biopsies and supplied blood samples for the investigation of cytokine gene expression and secretion, as well as liver histology. Results: The levels of TNF-a and IL-10 in adipose tissue were higher in patients with AAH. IL-10 level in adipose tissue was also correlated with fibrosis score. TNF-a gene expression in adipose tissue was correlated with Maddrey score, blood C-reactive protein (CRP) concentration and liver IL-6 concentration. IL-6 production levels in the liver were higher in patients with AAH and correlated with AAH score, liver histological lesions, liver TNF-a concentration, Maddrey score, and blood CRP concentration. Plasma concentrations of soluble forms of TNF-receptor were correlated with inflammatory lesions in the liver, Maddrey score and fibrosis score. Conclusion: In patients with ALD, inflammation occurs not only in the liver, but also in the adipose tissue. Adipose tissue inflammation is correlated with the severity of pathological features in the liver. Our findings may account for the harmful interactions between body mass index, AAH, fibrosis, and cirrhosis in alcoholic patients.
Background: Liver biopsy is still the gold standard in chronic liver disease, but is invasive, co... more Background: Liver biopsy is still the gold standard in chronic liver disease, but is invasive, costly ($1,000), has a high sampling error (33% for fibrosis and 24% for activity), as well as discordance rates greater than 10% between pathologists for routine scoring systems. FibroTest-ActiTest (FF-AT) are biochemical markers of fibrosis and activity ($90). The aim was to demonstrate, through an overview of diagnostic studies, that FF-AT were cost-effective enough to be used as non invasive alternatives to liver biopsy in patients with chronic hepatitis C (CHC), B (CHB), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Methods: The following diagnostic parameters were assessed: the area under the ROC curves (AUROC), accuracy (AC), kappa statistics (K), and Spearman correlation coefficient (SC). The main end point was the AUROC for the diagnosis of bridging fibrosis (F2F3F4 vs FOF1) and for the diagnosis of moderate/severe necrosis activity (A2A3 vs AOA1). In order to assess the diagnostic value between each stage and grade, all possible combinations of the AUROC were computed. The quality of biopsy was scored according to published criteria: a single fragment, size of 15 mm or more, and 5 or more portal tracts. Specificity and normal values were determined prospectively in blood donors. The prevalence of the abnormal values (outside the 99% percentiles) of the 6 FT-AT components was assessed on 8,540 consecutive tests computed according to standardized procedures between September 2002
A prospective study of apolipoprotein AI has been undertaken in 581 alcoholic patients and in 100... more A prospective study of apolipoprotein AI has been undertaken in 581 alcoholic patients and in 100 controls in order to describe the changes of apolipoprotein AI according to the different stages of the alcoholic liver disease, to correlate the changes to serum liver tests and to estimate its diagnosis and prognostic value. Results showed that apolipoprotein AI concentration is highly related to the degree of liver injury, reaching a maximum in patients with steatosis (229 +/- 90 mg per dl), beginning to decrease in patients with fibrosis (188 +/- 88 mg per dl) and reaching a minimum in patients with severe cirrhosis (91 +/- 46 mg per dl). Apolipoprotein AI had an independent and discriminative value for the diagnosis of fibrosis (p less than 0.001) vs. steatosis and for the diagnosis of cirrhotic vs. noncirrhotic fibrosis (p less than 0.001) or vs. acute alcoholic hepatitis without cirrhosis (p less than 0.001). Cirrhotic patients with apolipoprotein AI less than 100 mg per dl had a lower survival rate at 1 year (62 +/- 7%) than patients with greater value (80 +/- 6%; p less than 0.05), but this prognostic value disappeared in multivariate analysis when other known prognostic factors were taken into account.
Early identification of patients with severe (discriminant function &amp;amp;amp;amp;amp;amp;... more Early identification of patients with severe (discriminant function &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 32) alcoholic hepatitis (AH) not responding to corticosteroids is crucial. We generated a specific prognostic model (Lille model) to identify candidates early on for alternative therapies. Three hundred twenty patients with AH prospectively treated by corticosteroids were included in the development cohort and 118 in its validation. Baseline data and a change in bilirubin at day 7 were tested. The model was generated by logistic regression. The model combining six reproducible variables (age, renal insufficiency, albumin, prothrombin time, bilirubin, and evolution of bilirubin at day 7) was highly predictive of death at 6 months (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.000001). The area under the receiver operating characteristic (AUROC) curve of the Lille model was 0.89 +/- 0.02, higher than the Child-Pugh (0.62 +/- 0.04, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.00001) or Maddrey scores (0.66 +/- 0.04, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.00001). In the validation cohort, its AUROC was 0.85 +/- 0.04, still higher than the other models, including MELD (0.72 +/- 0.05, P = 0.01) and Glasgow scores (0.67 +/- 0.05, P = 0.0008). Patients above the ideal cutoff of 0.45 showed a marked decrease in 6-month survival as compared with others: 25% +/- 3.8% versus 85% +/- 2.5%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001. This cutoff was able to identify approximately 75% of the observed deaths. In the largest cohort to date of patients with severe AH, we demonstrate that the term &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;nonresponder&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; can now be extended to patients with a Lille score above 0.45, which corresponds to 40% of cases. Early identification of subjects with substantial risk of death according to the Lille model will improve management of patients suffering from severe AH and will aid in the design of future studies for alternative therapies.
The aim of this study was to assess whether markers of hepatitis B virus or hepatitis C virus inf... more The aim of this study was to assess whether markers of hepatitis B virus or hepatitis C virus infection are independent risk factors for hepatocellular carcinoma in drinkers after adjustment for three known risk factors: cirrhosis, age and male sex. Among 2,015 consecutive drinkers admitted, hepatitis C virus antibodies were found by sensitive radioimmunoassay in 1,259. The following five factors have been identified and ranked as risk factors for hepatocellular carcinoma in unidimensional and regression analysis: cirrhosis (p less than 0.001), age (p less than 0.001), male sex (p less than 0.001), presence of HBsAg (p less than 0.001) and presence of hepatitis C virus antibodies (p less than 0.03). Among drinkers with cirrhosis, the patients with hepatocellular carcinoma were older (64 +/- 11 yr vs. 56 +/- 9 yr; p less than 0.001), were more often male (93% vs. 65%; p less than 0.0001) and had higher prevalence of HBsAg (9% vs. 2%; p = 0.02) and hepatitis C virus antibodies (41% vs. 26%; p = 0.02). A simple algorithm permitted us to identify a high-risk population of drinkers: the male cirrhotic patient older than 50 yr. The relative risk of hepatocellular carcinoma in this selected population was 17.7 (95% confidence interval = 9.0 to 37.5; p less than 0.0001). From a pragmatic point of view, the detection of HBsAg or hepatitis C virus antibodies, although independently associated with hepatocellular carcinoma, is not useful in increasing the diagnostic value of this algorithm because of the poor sensitivity of these tests. The weak relationships observed between hepatitis C virus antibodies and hepatocellular carcinoma needs confirmation by more accurate tests.
Glucocorticoid-induced leucine zipper (GILZ), a recently identified protein induced by glucocorti... more Glucocorticoid-induced leucine zipper (GILZ), a recently identified protein induced by glucocorticoids (GCs), inhibits the nuclear factor B pathway and the activation of monocytes/macrophages by lipopolysaccharides (LPS). This study aimed to elucidate the contribution of GILZ to the pathogenesis of alcoholic hepatitis (AH): we (1) assessed GILZ expression in the livers of patients with AH and (2) treated patients with severe AH with GCs (prednisolone 40 mg/day) and studied the effect of GILZ modulation on circulating monocyte function. We quantified GILZ expression in the livers of 42 consecutive alcoholic patients (21 with and 21 without AH). GILZ messenger RNA (mRNA) levels were lower in the livers of patients with AH versus those without AH (P < 0.05). We collected circulating monocytes from patients with severe AH before and 48 hours after GC treatment to quantify GILZ expression and cytokine secretion. GC treatment induced significantly higher levels of GILZ mRNA than that observed before treatment and impaired LPS-induced tumor necrosis factor-␣ (TNF-␣) and regulated upon activation, normal T cell-expressed secretion (RANTES) by these monocytes. We transfected circulating monocytes with GILZ small interfering RNA (siRNA), specifically blocking GILZ expression, to demonstrate the role of GILZ in mediating GC effect. GILZ siRNA abrogated the effect of GC treatment on LPS-induced TNF-␣ and RANTES secretion. Conclusion: Low expression of GILZ may contribute to liver inflammation in AH. GCs enhance GILZ expression, abrogating macrophage sensitivity to LPS and proinflammatory cytokine secretion. These findings may explain the beneficial effect of GC treatment in patients with severe AH. (HEPATOLOGY 2007;46:1986-1992.) P roinflammatory cytokines play a major role in the pathophysiology of alcoholic hepatitis (AH). Cytokines are produced and released by many cells, including monocytes, macrophages, and-particularly relevant to the liver-Kupffer cells. 1 The proinflammatory cytokine tumor necrosis factor-␣ (TNF-␣), TNF-␣inducible cytokines, and chemokines are critical mediators of the hepatotoxicity of alcohol. Reactive oxygen species and lipopolysaccharide (LPS), 2 a membrane component of gram-negative commensal bacteria present in the digestive tract, are 2 major activators of Kupffer cells in AH. Alcohol ingestion increases intestinal barrier permeability 3 and induces the diffusion of bacterial products into the lumen of the portal vein. LPS is hepatotoxic, and plasma endotoxin concentrations increase in experimental and human AH. 4 AH is a life-threatening condition. Mortality for patients with the most severe forms of AH is 50%-75%. Although glucocorticoid (GC) treatment continues to be discussed, GCs are the only family of drugs that has shown efficacy in improving short-term survival in patients with severe AH, defined as a Maddrey discriminant function Ն 32.
Introduction A meta-analysis was performed using individual patient data from the five most recen... more Introduction A meta-analysis was performed using individual patient data from the five most recent randomised controlled trials (RCTs) which evaluated corticosteroids in severe alcoholic hepatitis (Maddrey discriminant function (DF) $32 or encephalopathy). This approach overcomes limitations associated with the use of literature data and improves the relevance of the study and estimates of effect size. Aims To compare 28-day survival between corticosteroid-and non-corticosteroid-treated patients and to analyse the response to treatment using the Lille model. Methods Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n¼3), enteral nutrition (n¼1) or an antioxidant cocktail (n¼1). Results 221 patients allocated to corticosteroid treatment and 197 allocated to non-corticosteroid treatment were analysed. The two groups were similar at baseline. 28-day survival was higher in corticosteroidtreated patients than in non-corticosteroid-treated patients (79.9762.8% vs 65.763.4%, p¼0.0005). In multivariate analysis, corticosteroids (p¼0.005), DF (p¼0.006), leucocytes (p¼0.004), Lille score (p<0.00001) and encephalopathy (p¼0.003) were independently predictive of 28-day survival. A subgroup analysis was performed according to the percentile distribution of the Lille score. Patients were classified as complete responders (Lille score #0.16; #35th percentile), partial responders (Lille score 0.16e0.56; 35the70th percentile) and null responders (Lille $0.56; $70th percentile). 28-day survival was strongly associated with these groupings (91.162.7% vs 79.463.8% vs 53.365.1%, p<0.0001). Corticosteroids had a significant effect on 28-day survival in complete responders (HR 0.18, p¼0.006) and in partial responders (HR 0.38, p¼0.04) but not in null responders. Conclusion Analysis of individual data from five RCTs showed that corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.
Background: Choroidal near-infrared fluorescent angiography can detect vessels in the eye with hi... more Background: Choroidal near-infrared fluorescent angiography can detect vessels in the eye with high resolution. Observation of fluorescent gastrointestinal (GI) vessels by endoscopy may be useful in portal hypertension and bleeding ulcer. We here describe a technique for the detection of fluorescent GI vessels with a CCD camera or a near-infrared video endoscope. Methods: Laparotomy was performed on rats. A tissue target was excited by means of a laser diode. We took pictures of tissue under both white and near-infrared light, both before and after intravenous injection of indocyanine green. Fluorescent light was selected by means of filters placed in front of the lens of a CCD camera or a near-infrared video endoscope. Results: Under near-infrared light and after dye injection, we observed fluorescent vessels in real time and distinguished arterial from venous fluorescence. Conclusions: This device permits visualization of GI vessels, which could be useful for diagnosis of vascular abnormalities during endoscopy and surgery.
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Papers by Sylvie Naveau