Thierry Poynard

Natural history of liver fibrosis progression in patients with chronic hepatitis C

BACKGROUNDnOur aim was to assess the natural history of liver fibrosis progression in hepatitis C and the factors associated with this progression.nnnMETHODSnWe recruited 2235 patients from the Observatoire de lHépatite C (OBSVIRC) population, the Cohorte Hépatite C Pitié-Salpétrière (DOSVIRC) population, and the original METAVIR population. All the patients had a biopsy sample compatible with chronic hepatitis C as assessed by the METAVIR scoring system (grades the stage of fibrosis on a five-point scale, F0 = no fibrosis, F4 = cirrhosis, and histological activity on a four-point scale, A0 = no activity, A3 = severe activity). No patient had received interferon treatment before the liver biopsy sample was obtained. We assessed the effect of nine factors on fibrosis progression: age at biopsy; estimated duration of infection; sex; age at infection; alcohol consumption; hepatitis C virus C (HCV) genotype; HCV viraemia; cause of infection; and histological activity grade. We defined fibrosis progression per year as the ratio between fibrosis stage in METAVIR units and the duration of infection (1 unit = one stage, 4 units = cirrhosis).nnnFINDINGSnThe median rate of fibrosis progression per year was 0.133 fibrosis unit (95% CI 0.125-0.143), which was similar to the estimates from previous studies (0.146 to 0.154). Three independent factors were associated with an increased rate of fibrosis progression: age at infection older than 40 years, daily alcohol consumption of 50 g or more, and male sex. There was no association between fibrosis progression and HCV genotype. The median estimated duration of infection for progression to cirrhosis was 30 years (28-32), ranging from 13 years in men infected after the age of 40 to 42 years in women who did not drink alcohol and were infected before the age of 40. Without treatment, 377 (33%) patients had an expected median time to cirrhosis of less than 20 years, and 356 (31%) will never progress to cirrhosis or will not progress for at least 50 years.nnnINTERPRETATIONnThe host factors of ageing, alcohol consumption, and male sex have a stronger association with fibrosis progression than virological factors in HCV infection.

Liver fibrosis in overweight patients

BACKGROUND & AIMSnA common clinical issue is whether overweight patients with abnormal liver function test results should undergo liver biopsy. Although serious liver injury can occur, its prevalence and risk factors are not well known.nnnMETHODSnNinety-three consecutive patients with abnormal liver function tests (but without overt liver disease), body mass index (BMI) > 25 kg/m(2), and no alcoholic, viral, autoimmune, drug-induced, or genetic liver disease were retrospectively studied. Clinical, biological, and histological variables were tested for association with septal fibrosis or cirrhosis.nnnRESULTSnSeptal fibrosis was present in 28 patients (30%) including cirrhosis in 10 (11%). Age >/= 50 years (odds ratio [OR], 14.1), BMI >/= 28 kg/m(2) (OR, 5.7), triglycerides >/= 1.7 mmol/L (OR, 5), and alanine aminotransferase (ALT) >/= 2N (OR, 4.6) were independently associated with septal fibrosis. Among histological features, septal fibrosis was strongly associated with necroinflammatory activity (OR, 44). A score combining age, BMI, triglycerides, and ALT had 100% negative predictive value for septal fibrosis when scoring 0 or 1 (100% sensitivity for a specificity of 47%).nnnCONCLUSIONSnSeptal fibrosis occurs frequently in overweight patients with abnormal liver function tests. A clinicobiological score combining BMI, age, ALT, and triglycerides could improve selection of patients for liver biopsy.

Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome

To update previous overviews of placebo‐controlled double‐blind trials assessing the efficacy and tolerance of smooth muscle relaxants in irritable bowel syndrome.

A comparison of fibrosis progression in chronic liver diseases

BACKGROUND/AIMSnNo study has compared the liver fibrosis progression rates among chronic liver diseases and the risk factors in order to better organize screening strategies.nnnMETHODSnA total of 4852 patients were retrospectively studied (chronic hepatitis C (HCV) [n=2313], human immunodeficiency virus (HIV)-HCV co-infection (HIV-HCV [n=180]), hepatitis B (HBV [n=777]), alcoholic liver disease (ALD [n=701]), primary biliary cirrhosis (PBC [n=406]), genetic hemochromatosis (GH [n=383]) auto-immune hepatitis (AIH [n=57]) and delta hepatitis (n=35). The fibrosis progression rates were estimated from birth and from the date of exposure, when known, to the first biopsy.nnnRESULTSnThere were highly significant differences in the rates of fibrosis progression, the most rapid being HIV-HCV co-infection (50% cirrhosis percentile at 52 years of age) and the slowest being PBC (50% cirrhosis percentile at 81 years). There was an acceleration of fibrosis progression with aging. Fibrosis progression was slower in females compared with males for HCV, HBV, GH, and PBC. In contrast, in ALD, the fibrosis progression was more rapid in females.nnnCONCLUSIONSnRates of fibrosis progression differ markedly between the predominant causes of chronic liver disease, and according to age and gender. Patients with HIV-HCV co-infection are at particularly high risk of fibrosis progression.

Fibrogenic impact of high serum glucose in chro nic hepatitis C

BACKGROUND/AIMSnThere is considerable variability in the rate of fibrosis progression in patients with chronic hepatitis C, most of which is related to factors so far unknown. We tested the hypothesis that high serum glucose and overweight might contribute to this variability.nnnMETHODSnSeven hundred and ten patients with chronic hepatitis C with a known duration of infection and no hepatitis B virus or human immunodeficiency virus coinfection were studied. Significant fibrosis was defined as bridging fibrosis including cirrhosis. Variables were tested for their association with significant fibrosis.nnnRESULTSnIn univariate analyses both serum glucose and body mass index were associated with fibrosis. In multivariate analyses, age at infection, duration of infection, serum glucose and daily alcohol intake but not body mass index were independently associated with significant fibrosis. Patients with high serum glucose had been contaminated at an older age and had features of the metabolic syndrome, including steatosis more frequently, as well as faster fibrosis progression rates. High serum glucose was associated with intermediate and advanced, but not with early, fibrosis stages. A high serum glucose was associated with a higher relative risk for significant fibrosis than overweight.nnnCONCLUSIONSnHigh serum glucose, is an independent co-factor of fibrosis in chronic hepatitis C with a higher pro-fibrogenic impact than overweight.

Blood neutrophil functions and cytokine release in severe alcoholic hepatitis : effect of corticosteroids

BACKGROUND/AIMSnSeveral observations point to an important role of interactions between polymorphonuclear neutrophils and cytokines in severe alcoholic hepatitis. The polymorphonuclear neutrophil activation status and the local and systemic pro- and anti-inflammatory cytokine responses were quantified. The effect of corticosteroids, widely used in this setting, was evaluated using these parameters.nnnMETHODSnWe studied blood polymorphonuclear neutrophil functions in terms of L-selectin and beta2-integrin expression, H2O2 production and IL-8 and tumor necrosis factor alpha synthesis capacity. We also measured IL-8, tumor necrosis factor alpha and IL-10 plasma and liver tissue levels. Fifteen patients with alcoholic hepatitis were compared to 15 patients with alcoholic cirrhosis without alcoholic hepatitis, and to 10 healthy volunteers. The impact of a 28-day course of corticosteroids on blood neutrophils activation status and cytokine levels was evaluated in patients with alcoholic hepatitis.nnnRESULTSnBlood polymorphonuclear neutrophils were activated, as shown by increased H2O2 production (48+/-6 vs 29+/-6 MFI in healthy controls), and decreased L-selectin expression (300+/-61 vs 449+/-59 in healthy controls). Upon stimulation, polymorphonuclear neutrophils synthesized large amounts of IL-8 (21.7+/-9.2 ng/ml vs 8.8+/-10 ng/ml in healthy controls) and tumor necrosis factor alpha (524+/-132 pg/ml vs 79+/-144 pg/ml in healthy controls). Tumor necrosis factor alpha and IL-8 plasma and tissue levels were markedly increased as IL-10 was barely detectable in alcoholic hepatitis patients, compared to cirrhotic patients and healthy controls. During steroid therapy, plasma levels of the pro-inflammatory cytokine IL-8 fell as early as day 14, while levels of the anti-inflammatory cytokine IL-10 increased on day 21. Finally, polymorphonuclear neutrophil functions returned to normal after treatment.nnnCONCLUSIONnSevere alcoholic hepatitis appears to be associated with polymorphonuclear neutrophil activation and an imbalance between pro- and anti-inflammatory cytokines; during steroid therapy a normalization of these parameters was observed.

Beta-Adrenergic–Antagonist Drugs in the Prevention of Gastrointestinal Bleeding in Patients with Cirrhosis and Esophageal Varices

BACKGROUNDnThe value of beta-adrenergic-antagonist drug therapy for the prevention of initial episodes of gastrointestinal bleeding in patients with cirrhosis and esophageal varices is uncertain, both positive and negative study results having been reported.nnnMETHODSnIn this study, we analyzed data on individual patients from four randomized, controlled trials to assess the efficacy of this treatment. Of the 589 patients studied, 286 received a beta-adrenergic-antagonist drug (propranolol in 203 and nadolol in 83) and 303 received placebo.nnnRESULTSnAfter two years, the mean (+/- SE) percentage of patients who had had no upper gastrointestinal bleeding was 78 +/- 3 percent in the beta-adrenergic-antagonist treatment group and 65 +/- 3 percent in the control group (P = 0.002). The percentage of patients without fatal bleeding was 90 +/- 2 percent in the treatment group and 82 +/- 3 percent in the control group (P = 0.01). The percentage of patients surviving after two years was 71 +/- 3 percent in the treatment group and 68 +/- 3 percent in the control group (P = 0.34). After age and severity of cirrhosis were taken into account, the survival rate was better in the treatment group (P = 0.09). The percentage of surviving patients who had had no bleeding after two years was 62 +/- 3 percent in the treatment group and 53 +/- 3 percent in the control group (P = 0.04). Both propranolol and nadolol prevented a first episode of bleeding. Severe cirrhosis and especially the presence of ascites were associated with bleeding (P less than 0.001) and death (P less than 0.001) in both groups. The efficacy of beta-adrenergic-antagonist therapy in the prevention of bleeding (P less than 0.001) and of fatal bleeding (P = 0.004) and in the prevention of bleeding or death (P = 0.005) was the same after adjustment for cause and severity of cirrhosis, ascites, and size of varices.nnnCONCLUSIONSnPropranolol and nadolol are effective in preventing first bleeding and reducing the mortality rate associated with gastrointestinal bleeding in patients with cirrhosis, regardless of severity.

Propranolol and sclerotherapy in the prevention of gastrointestinal rebleeding in patients with cirrhosis: a meta-analysis

BACKGROUND/AIMSnA meta-analysis of nine selected randomized trials was performed to compare the effects of propranolol and sclerotherapy in the prevention of rebleeding and on survival in patients with cirrhosis.nnnMETHODSnFive end points were assessed: rebleeding, esophageal rebleeding, death, death due to bleeding, and adverse events. Analyses were performed according to the intention-to-treat method. For each end point, heterogeneity and treatment efficacy were assessed by the Der Simonian and Peto methods. When a significant difference was observed, sensitivity analyses were performed by successive stratification according to treatment duration, type of publication, severity of cirrhosis, and methodological quality.nnnRESULTSnThe mean percentage of patients free of rebleeding, the mean survival rate and the mean percentage of patients free of death from bleeding were not significantly different between patients treated with propranolol and those treated by sclerotherapy. The mean percentage of patients free of variceal rebleeding was 39% in propranolol group and 55% in sclerotherapy group (mean difference: 17%, 95% confidence interval: 9-25%, p < 0.001). The mean percentage of patients free of adverse events was significantly higher in the propranolol group than in the sclerotherapy group (mean difference: 22%, 95% confidence interval: 6-38%, p < 0.007).nnnCONCLUSIONnIn patients with cirrhosis and esophageal varices, endoscopic sclerotherapy is more effective than propranolol in preventing variceal rebleeding, but the incidence of adverse events is significantly higher with sclerotherapy. There was no difference in survival between the treatments. Propranolol should be considered as a first choice treatment for preventing rebleeding.

Raised plasma soluble Fas and Fas-ligand in alcoholic liver disease

We measured the soluble forms of these two molecules in the plasma of patients with alcoholic liver disease. We studied 23 patients with severe (Maddrey score >32) biopsyproven AAH (without sepsis, renal failure, haemorrhage, or previous steroid therapy) and 18 patients with severe alcoholic cirrhosis. We included ten patients with chronic hepatitis C without cirrhosis and 20 healthy volunteers as controls. We obtained informed consent from all participants. We collected 5 mL blood in sterile vacuum tubes containing edetic acid and immediately centrifuged at

Relationship between the Fibrotest and portal hypertension in patients with liver disease

Backgroundu2002 The best technique to estimate portal hypertension (PHT) is to measure the hepatic venous pressure gradient (HVPG), which is an invasive method.