Interface hepatitis in PBC: Prognostic marker and therapeutic target
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1 Interface hepatitis in PBC: Prognostic marker and therapeutic target Raoul Poupon Service d Hépatologie, Hôpital Saint-Antoine, Paris Faculté de Médecine Pierre & Marie Curie, Paris
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7 Key features of piecemeal necrosis adapted from Bianchi L. et al. 1988
8 Wang et al. Exp Mol Pathol 2001
9 Grading severity of PMN Minimal: Not present in all portal tracts (PT) Patchy distribution Moderate: Present and restricted at the periphery of at least half of the PT Severe: Necrosis surrounding more than half of the circumference of the majority of PT and along fibrous septa
10 Prevalence of lymphocytic and biliary piecemeal necrosis
11 Grading severity of PMN Minimal: Focal alteration of the periportal plate in some portal tracts. Moderate: Diffuse alteration of the periportal plate in some portal tracts or Focal lesions around all portal tracts. Severe: Diffuse alteration of the periportal plate in all portal tracts.
12 Relationships between fibrosis and other elementary histological lesions Fibrosis Elementary lesions P* Interlobular bile duct lesions Biliary cell necrosis NS Paucity (prevalence) Ductular proliferation Lymphocytic piecemeal necrosis Mononuclear portal and periportal inflammation *P values for the Jonckheere-Terpstra test For each lesion, the mean value in the scoring system was calculated Degott et al. Hepatology 1999
13 Biochemistries according to severity of bile duct paucity and lymphocytic PMN in PBC Poupon et al. J Hepatol 1999
14 FibroScan TM Mode A-scan Pressure Gauge ID patient Median IQR
15 Impact of 2-year UDCA treatment on histology in PBC Poupon et al. NEJM 1991
16 Effect on fibrosis Corpechot et al. Hepatology 2000
17 Analysis of factors assessed under UDCA therapy affecting histological stage progression Univariate analysis Stage at diagnosis S. bilirubin S. albumin Biochemical response to UDCA ILBD paucity L. PMN grade Multivariate analysis Stage at diagnosis S. bilirubin L. PMN grade
18 Time profile of cirrhosis development
19 Time profile of cirrhosis development
20 Pathophysiological events in PBC
21 The inflammatory process in cholangiopathies Schuppan et al. 1998, Fava et al. 2005
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23 Ductal cholestasis
24 Mechanisms of action of UDCA
25 Mechanisms of action of UDCA
26 Mechanisms of action of UDCA
27 Therapeutic targets in inflammatory cholangiopathies Cholestasis Immune activation Fibrogenesis 1. Procholestatic cytokines 1. T cell activation and proliferation 1. Profibrogenic cytokines 2. Ductal secretion 3. Canalicular secretion 4. Liver cell protection 2. Effector cell trafficking 3. Cytokin effector mechanisms 4. CD40 activation 2. Fibrogenic signal transduction 3. Stellate cell apoptosis 4. Vasoactive mediators antagonist
28 Emerging targeted therapies 1. Immune activation blockers 2. Ductal choleresis inducers 3. Nucleoreceptor modulators
29 UDCA / Budesonide for PBC Leuschner et al. Gastroenterology 1999
30 UDCA / Budesonide for PBC Leuschner et al. Gastroenterology 1999
31 Emerging targeted therapies 1. Immune activation blockers 2. Ductal choleresis inducers 3. Nucleoreceptor modulators
32 Hofmann et al. Hepatology 2005
33 norudca - UDCA in mdr2 KO mice Fickert et al. Gastroenterology 2006
34 Emerging targeted therapies 1. Immune activation blockers 2. Ductal choleresis inducers 3. Nucleoreceptor modulators
35 Biliary function of the liver
36 Bile acid transport and adaptative response to cholestasis
37 Nuclear receptors and their inducers
38 Effects of RIFA and UDCA on hepatobiliary transport systems and metabolizing enzymes Marschall et al. Gastroenterology 2005
39 Nuclear receptors and their inducers
40 Protection against ANIT-induced necrosis by GW4064 Liu et al. J Clin Invest 2003
41 Protection against ANIT-induced hepatotoxicity by GW4064 Liu et al. J Clin Invest 2003
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44 Wang et al. Exp Mol Pathol 2001
45 Sensitivity, specificity and predictive values of AST activity for the diagnosis of moderate to severe LPM Cutoff value Sensitivity Specificity PPV NPV Likelihood ratio Corpechot et al. Liver Int 2004
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