Serum leptin in patients with alcoholic liver disease.

BACKGROUND: The mechanisms by which overweight makes the liver more susceptible to alcoholic liver injury remain to be determined. Therefore, we conducted the following studies to further elucidate the role of leptin in the pathogenesis of steatosis and cirrhosis caused by chronic alcohol consumption in human beings. METHODS: Two-hundred nine consecutive patients with alcoholic liver disease were studied. Serum leptin concentrations were measured by using radioimmunoassay, and the relationships between serum leptin level and liver lesions were studied. Statistical analysis used logistic regressions. RESULTS: When serum leptin, serum cholesterol, and body mass index (BMI) were considered together in the multiple logistic regression analysis, compared with patients with severe steatosis, serum leptin remains significantly lower in patients without steatosis (p<0.05) and in patients with mild or moderate steatosis (p<0.05). When age, serum leptin, serum cholesterol, and steatosis grade were considered together in the logistic regression analysis, serum leptin (p<0.01) and age (p<0.02) were positively and independently correlated with the presence of cirrhosis. After BMI introduction in the statistical model, serum leptin was no more correlated with the presence of cirrhosis. CONCLUSION: In patients with alcoholic liver disease, serum leptin is independently correlated with steatosis grade and might play an important role in severity of fibrosis as fatty liver is more vulnerable than normal liver to factors that lead to fibrosis.

Efficacy of infliximab in Crohn's disease. Results of a retrospective multicenter study with a 15-month follow-up.

OBJECTIVES: To evaluate prescription practices and response to infliximab treatment for Crohn's disease (CD). PATIENTS AND METHODS: The files of CD patients treated with at least one infusion of infliximab treated in gastroenterology units belonging to university teaching hospitals of the Parisian hospitals group (Assistance Publique-Hôpitaux de Paris (AP-HP) during the year 2000 were analyzed retrospectively. RESULTS: One hundred and thirty-seven patients (36.0 +/- 12.7 years, 92 females) from 12 centers were studied. Indication for treatment was fistulae or perianal disease in 39% of patients, active Crohn's disease in 45% and mixed conditions in 16%. Mean follow-up was 15.2 +/- 7.2 months. The overall response rate was 85%. No predictive factor of sustained remission could be identified. The mean time to relapse was to 3.9 +/- 3.1 months. Thirty-eight patients were on maintenance therapy at the end of the follow up; 37% exhibiting progressive lost of response to treatment. Immunosuppressive therapy was added to infliximab in 78% of cases but response to infliximab was not modified by addition of immunosuppressive drugs. Adverse events, most frequently minor, were noted in 23% of the patients. CONCLUSION: This retrospective study confirms the efficacy and safety of infliximab in CD.

Comparison of outcome in patients with cirrhosis and ascites following treatment with albumin or a synthetic colloid: a randomised controlled pilot trail.

BACKGROUND: The question of which colloid (albumin or synthetic colloids) used for plasma expansion following paracentesis or other complications requiring fluid loading in patients with cirrhosis remains controversial. AIMS: To compare outcome and hospital-related cost in patients with cirrhosis treated with 20% human albumin with those treated with a synthetic colloid (3.5% polygeline). METHODS: The primary end point was occurrence of a first liver-related complication. RESULTS: When the trial was prematurely discontinued because of safety concerns about bovine-derived products, 30 patients were assigned to receive albumin and 38 were assigned to receive a synthetic colloid. Sixty-three patients were included for ascites removal by paracentesis and five patients for ascites removal by paracentesis and renal impairment. The median time to first liver-related complication was not significantly longer in the albumin group (20 vs. 7 days). However, the total number of liver-related complications adjusted to a 100-day period was significantly lower in the albumin group. The median hospital cost for a 30-day period was significantly lower in the albumin group (1915 euros vs. 4612 euros). CONCLUSIONS: In patients with cirrhosis and ascites, human albumin appears to be more effective in preventing liver-related complications than synthetic colloid. This may be associated with decreased hospital costs.

Balance between pro and anti-inflammatory cytokines in patients with acute alcoholic hepatitis.

UNLABELLED: The ability of endogenous IL-10 to modulate inflammatory response and to limit hepatotoxicity has been shown in several models of liver injury. AIMS: The objectives of this study were to evaluate the relationship between liver disease and the balance between pro and anti-inflammatory cytokines in acute alcoholic hepatitis. METHODS: Twenty-five patients with pure steatosis, 17 with cirrhosis and mild acute alcoholic hepatitis (discriminant function value<32) and 41 patients with cirrhosis and severe acute alcoholic hepatitis (discriminant function value >=32) were studied. Plasma levels of interleukin 10 (IL-10) and soluble TNF receptors (TNFsRp75 and 55) were analyzed using ELISA assays. Hepatocyte proliferative activity was assessed with proliferating cell nuclear antigen labeling index (PCNA-LI) on formalin-fixed paraffin embedded liver biopsy specimens. RESULTS: In patients with steatosis, cirrhosis with mild and severe acute alcoholic hepatitis, the plasma levels of IL-10 were higher (P<0.05) than in healthy controls. Between day 1 and day 8, the TNFsRp55/IL-10 ratio increased by 137 +/- 47 in the 10 patients with severe acute alcoholic hepatitis treated with prednisolone who died within 2 months and by 9.3 +/- 14 in the 19 patients still alive at 2 months (P=0.031). In patients with severe acute alcoholic hepatitis, PCNA-LI on liver biopsy was negatively correlated with the TNFsRp55/IL-10 ratio increase from day 1 to day 8 (r=- 0.42, P=0.11). PCNA-LI was positively correlated with TNFsRp75/TNFsRp 55 ratio increase from day 1 to day 15 (r=0.52; p<0.05). CONCLUSION: Our data suggest the anti-inflammatory system is up-regulated in patients with alcoholic liver disease. Nevertheless, in patients with severe acute alcoholic hepatitis, IL-10 production seems insufficient to modulate TNF-alpha cytotoxicity mediated by TNFRp55.

Usefulness of routine analysis of ascitic fluid at the time of therapeutic paracentesis in asymptomatic outpatients. Results of a multicenter prospective study.

AIM: The guidelines of the American Association for the Study of Liver Diseases recommend performing exploratory paracentesis on each patient with cirrhosis and chronic ascites. The aim of the study was to evaluate the prevalence of spontaneous bacterial peritonitis and culture-negative neutrocytic ascites in a large population of consecutive asymptomatic cirrhotic ascitic ambulatory patients. METHODS: Patients with cirrhosis and tense ascites hospitalized from January to September 2000 in 5 hepatogastroenterology units prospectively underwent an exploratory paracentesis with cytobacteriological, biochemical and bedside inoculation into aerobic and anaerobic blood culture bottles. Patients studied were not receiving antibiotics except for norfloxacin and had no obvious sign of infection such as fever or hypothermia, chills, unusual abdominal tenderness, de novo or worsening hepatic encephalopathy, recent gastrointestinal bleeding, acute renal failure or marked arterial hypotension. Clinical and biological findings and ascitic fluid cytological and bacteriological results were evaluated at each exploratory paracentesis. The results are given in mean +/- standards deviations with range. RESULTS: Sixty-seven cirrhotic patients (48M/19F, mean age 59 +/- 9 years) had 270 therapeutic paracenteses, preceded by an exploratory aspiration. Fifty-nine patients (88%) had alcoholic cirrhosis. Twenty-five patients (37.3%) received norfloxacin. At first paracentesis 41 (61.2%) and 26 (38.8%) patients were class B and C respectively according to the Child-Pugh classification; the mean Child-Pugh score was 9 +/- 1.5. None had suspicion of infection. The mean number of paracenteses was 5 +/- 4.3 per patient; 59.6% of the paracenteses (161) were compensated with human albumin. Ascitic protein concentration was 17.5 +/- 8.6 g/l, ascitic fluid cell count and number of neutrophils were 127 +/- 155/mm3 and 5.9 +/- 14/mm3 (0-60), respectively. No patient had spontaneous bacterial peritonitis nor culture-negative neutrocytic ascites; 10 cases of monomicrobial bacterascites were observed, all with commensal germs. CONCLUSIONS: In the absence of obvious signs of infection, the prevalence of spontaneous bacterial peritonitis and culture-negative neutrocytic ascites in asymptomatic cirrhotic outpatients with ascites is near 0%. Moreover, for 100 large volume paracenteses, not performing exploratory paracentesis corresponds to a savings of 5,500 euros, without risk for these patients.

Biomarkers for the prediction of liver fibrosis in patients with chronic alcoholic liver disease.

BACKGROUND & AIMS: The aim of this study was to determine the diagnostic use of noninvasive markers of fibrosis in patients with chronic alcoholic liver disease. METHODS: A total of 221 consecutive patients with an alcohol intake of >50 g/day (median, 100 g/day) and available liver biopsy examination and FibroTest FibroSure (FT) results were included prospectively. Fibrosis was assessed blindly on a 5-stage histologic scale similar to that of the METAVIR scoring system. Hyaluronic acid was measured and used as a standard serum marker of fibrosis. RESULTS: Advanced fibrosis (F2-F4) was present at biopsy examination in 63% of patients. The mean FT value (SE) was F0 = .29 (.05); F1 = .29 (.03), F2 = .40 (.03), F3 = .53 (.04); and F4 = .88 (.02) (P < .05 between all groups, except between F0 and F1). As opposed to FT, there was no significant difference for hyaluronic acid between F2 and F1 and between F2 and F0. For F2-F4 vs. F0-F1, the FT area under the ROC curves (AUROC) = .84 (.03) and .79 (.03) for hyaluronic acid. For the diagnosis of F4, the AUROC was very high, .95 for FT and .93 for hyaluronic acid. The discordances of the 2 stages were attributed to biopsy failures in 26 cases and to FT failures in 13 cases. CONCLUSIONS: In heavy drinkers, FT is a simple and noninvasive quantitative estimate of liver fibrosis. The use of FT may decrease the need for liver biopsy examination.

Mesenteric adenitis and portal vein thrombosis due to Fusobacterium nucleatum.

We report the first description of portal and mesenteric vein thrombosis associated with suppurative mesenteric adenitis in a 71-year-old woman. The bacterium detected in mesenteric lymph nodes was Fusobacterium nucleatum, an anaerobic Gram-negative bacillus. Our patient had a clinical syndrome of pharyngitis and fever preceding portal vein thrombosis. Abdominal symptoms improved with antibiotics and anticoagulant therapy. This location of F. nucleatum in mesenteric lymph nodes provides an interesting insight into the occurrence of septic thrombosis in the portal vein following pharyngo-tonsillar infection.

[Inflammatory bowel disease and latent thrombocythemia: a novel cause of hepatic vein thrombosis?]. / Maladie inflammatoire cryptogénétique de l'intestin et thrombocytémie latente: nouvelle étiologie de thrombose des veines hépatiques?

It has been suggested in previous studies, that inflammatory bowel disease can induce hepatic vein thrombosis. However, the main weakness of those studies was the lack of extensive screening of prothrombotic factors. We report an unusual association of severe inflammatory bowel disease, hepatic vein thrombosis and latent platelet proliferation disorder. Early treatment with heparin and cyclosporin administered intravenously induce a remission of intestinal disease and total disappearance of hepatic vein thrombosis. Extensive screening excluded the classical causes of hepatic vein thrombosis, inherited coagulation disorders and latent polycythemia by culture of erythroid progenitors without added erythropoietin. However, using recent bone marrow culture conditions, we observed spontaneous colony formation of megakaryocyte progenitors revealing latent thrombocythemia. In summary, progress in the diagnosis of haemostasis disorders, will probably confirm that one or more additional predisposing prothrombotic factors are needed to the development of hepatic vein thrombosis in inflammatory bowel disease. This hypothesis could explain the scarcity of this complication in inflammatory bowel disease. Moreover, this case-report suggests that administration of heparin at the onset of the thrombosis may induce a complete regression of the thrombus in hepatic veins.

Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone.

Early identification of patients with severe (discriminant function >or=32) biopsy-proven alcoholic hepatitis (AH) who are not responding to corticosteroids would be clinically relevant. Our goal was to develop simple criteria that will help physicians to promptly identify nonresponders to corticosteroids. A total of 238 patients were included. We used 6 months survival as an end point because of the rule requiring 6 months for listing alcoholic patients for transplantation. Overall survival at 1 and 6 months was 85% +/- 2.3% and 64.3% +/- 3.3%, respectively. An early change in bilirubin levels (ECBL) at 7 days (defined as bilirubin level at 7 days lower than bilirubin level on the first day of treatment) was observed in 73% of patients. At 7 days, in patients with ECBL, bilirubin decreased (84 +/- 75 micromol/L [4.94 +/- 4.40 mg/dL]), whereas it increased in patients without ECBL (76.5 +/- 77 micromol/L [4.50 +/- 4.54 mg/dL], P <.0001). Ninety-five percent of patients with ECBL continued to have improved liver function during treatment. At 6 months, survival of patients with ECBL was significantly higher than that of patients without ECBL, 82.8% +/- 3.3% versus 23% +/- 5.8%, P <.0001. On multivariate analysis, ECBL, discriminant function and creatinine were independent prognostic variables, and ECBL had the most important prognostic value. In conclusion, ECBL is a very simple predictive factor for identifying nonresponders. A recommendation to discontinue corticosteroids after 7 days in patients without ECBL, suggested by our results, awaits additional confirmation.

Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH.

BACKGROUND/AIMS: Controversy surrounding the efficacy of corticosteroids in severe alcoholic hepatitis (AH) persists. THE AIMS OF OUR STUDY WERE: (a) to analyze individual data of patients with severe AH discriminant function (DF)> or =32 from the last three randomized controlled trials; and (b) to identify the independent prognostic factors associated with short-term survival. METHODS: Individual data were collected from the three principal investigators. Survival analysis was performed at 28 days using the Kaplan-Meier method and log-rank test. The independent prognostic values were assessed by the proportional hazards regression model. RESULTS: About 102 placebo and 113 corticosteroid patients with DF > or =32 were analyzed. At 28 days, corticosteroid patients had significantly higher survival: 84.6+/-3.4% vs. 65.1+/-4.8%, P=0.001. In univariate analysis, corticosteroid treatment, age, DF, albumin, creatinine and encephalopathy were prognostic factors. In multivariate analysis, age (P=0.0001), serum creatinine (P<0.002) and corticosteroid treatment (P=0.002) were independent prognostic variables. A more dramatic decrease of median serum bilirubin values (micromol/l) was observed at 7 and 14 days in corticosteroid patients (P<0.05) : -76.5 vs. -35 and -105 vs. -45. CONCLUSIONS: Corticosteroids improved short-term survival of patients with severe AH. Age and serum creatinine are independent prognostic factors. Corticosteroids are recommended for patients with severe AH.

Risk factors of fibrosis in alcohol-induced liver disease.

In patients with nonalcoholic steatohepatitis (NASH), age, obesity, and diabetes mellitus are independent predictors of the degree of fibrosis. The relative risk for fibrosis adjusted for sex was also associated with increasing grade of Perls stain. The aim of this study was to determine whether the risk factors for fibrosis described in NASH are also risk factors in alcohol-induced liver disease. A total of 268 alcoholic patients with negative hepatitis B virus and hepatitis C virus serology underwent liver biopsy. Fibrosis was assessed semiquantitatively by a score fluctuating between 0 to 8. Liver iron overload was assessed by Perls staining and graded in 4 classes. We have used multivariate regression with partial correlation analysis to assess the variability of fibrosis score according to the value of 7 variables: sex, age, body mass index (BMI) in the past year before the hospitalization when the patient was asymptomatic, daily alcohol intake over the past 5 years, total duration of alcohol abuse, Perls grade, and blood glucose level. In the multivariate regression, fibrosis score was positively correlated with age (P =.001), BMI (P =.002), female sex (P <.05), Perls grade (P <.05), and blood glucose level (P <.05). Twenty percent of the variability of fibrosis score was explained by the 7 variables. In conclusion, after adjustment for daily alcohol intake and total duration of alcohol abuse, BMI, Perls grade, and blood glucose are also independent risk factors for fibrosis in alcohol-induced liver disease, raising therapeutic implications for the management of these patients.