Abstracts Poster Abstracts. Challenges and Management of Liver Cirrhosis. October 10 11, 2014 Konzerthaus Freiburg Freiburg, Germany

Transcription

1 Falk Symposium 195 Challenges and Management of Liver Cirrhosis October 10 11, 2014 Konzerthaus Freiburg Freiburg, Germany Abstracts Poster Abstracts

2 FALK FOUNDATION e.v. Leinenweberstr Freiburg Germany 2014 Falk Foundation e.v. All rights reserved.

3 Abstracts of Invited Lectures Poster Abstracts Falk Symposium 195 CHALLENGES AND MANAGEMENT OF LIVER CIRRHOSIS Freiburg, Germany October 10 11, 2014 Scientific Organization: A.L. Gerbes, Munich (Germany) J. Bosch, Barcelona (Spain) M. Pinzani, London (Great Britain) F. Wong, Toronto (Canada)

4 CONTENTS Session I page Fibrosis: Pathophysiology, diagnosis and treatment Chair: L. Castera, Clichy M. Pinzani, London Pathophysiology of liver fibrosis M. Pinzani, London 17 Invasive and non-invasive evaluation of liver fibrosis L. Castera, Clichy 18 Treatment of hepatic fibrosis S.L. Friedman, New York 19 Session II Portal hypertension and complications Chair: J. Bosch, Barcelona T. Sauerbruch, Göttingen Pathophysiology and rational basis of therapy J. Bosch, Barcelona Clinical evaluation and prognosis A. Berzigotti, Barcelona 25 Therapy: Drugs, scopes and TIPS When and how? J.G. Abraldes, Edmonton 26 Session III Kidney problems in cirrhosis Chair: A.L. Gerbes, Munich F. Wong, Toronto 3

5 Pathophysiology of renal dysfunction in cirrhosis E. Solà, P. Ginès, Barcelona 29 Definition and diagnosis of acute kidney injury in cirrhosis F. Wong, Toronto Treatment of hepatorenal syndrome P. Angeli, Padova 32 Session IV Cognitive dysfunction in cirrhosis Chair: D. Häussinger, Düsseldorf R. Jalan, London Novel concepts of pathophysiology of hepatic encephalopathy D. Häussinger, Düsseldorf Clinical relevance of minimal hepatic encephalopathy A critical look P. Ferenci, Vienna; K. Weißenborn, Hannover Treatment of low grade hepatic encephalopathy When and how? R. Jalan, London 39 Session V Bacterial infections in cirrhosis Chair: R. Moreau, Clichy F. Salerno, Milan Infection as trigger for portal hypertension C.J. Steib, Munich 43 Role of infections in acute-on-chronic liver failure R. Moreau, Clichy 44 Treatment of spontaneous bacterial peritonitis F. Salerno, Milan

6 Session VI Hepatocellular carcinoma Chair: J. Bruix, Barcelona B. Göke, Munich Molecular profiling and research of therapeutic targets G.J. Gores, Rochester 49 Current challenges around resection and transplantation (No abstract) V. Mazzaferro, Milan Systemic therapy for hepatocellular carcinoma J. Bruix, Barcelona Presentation of poster prizes A.L. Gerbes, Munich Session VII Practical issues Therapy in patients with cirrhosis Chair: R. Thimme, Freiburg M. Trauner, Vienna Autoimmune hepatitis and chronic cholestatic diseases U. Beuers, Amsterdam 55 NAFLD and NASH M. Trauner, Vienna Hepatitis B R. Thimme, Freiburg Antiviral therapy in patients with hepatitis C virus induced cirrhosis F. Zoulim, P. Pradat, F. Bailly. Lyon 61 List of Chairpersons, Speakers and Scientific Organizers

7 Poster Abstracts 1. Establishment of a cultivation system mimicking tissue stiffness in chronic liver disease A. Bachmann, K. Bueringer, T. Peccerella, S. Ottinger, S. Müller, J. Rheinländer, T.E. Schäffer, A.K. Nüssler (Tübingen, Heidelberg, DE) 2. Lactulose alone vs. lactulose and rifaximin for the prophylaxis of overt hepatic encephalopathy in acute variceal hemorrhage M.A. Badea, O. Nedelciuc, A. Blaj, A. Cucos, I. Ungureanu, C. Mihai, C. Cijevschi Prelipcean (Iasi, RO) 3. Pentoxifylline for the secondary prophylaxis of overt hepatic encephalopathy: A pilot study M.A. Badea, M. Dranga, O. Nedelciuc, A. Blaj, A. Cucos, I. Ungureanu, C. Mihai, C. Cijevschi Prelipcean (Iasi, RO) 4. Histopathological and metabolic features of patients with non-alcoholic fatty liver disease and cryptogenic liver cirrhosis I.H. Bahcecioglu, I. Kal, M. Ispiroglu, M. Yalniz, I.H. Ozercan (Elazig, TR) 5. Upper digestive haemorrhage Complication of the liver cirrhosis S. Bataga, I. Torok, M. Macarie, A. Negovan, A.-M. Botianu, M. Ciorba, H. Farcas, M. Tilinca (Tirgu-Mures, RO) 6. Re-estimation of prevalence of HCV infection in Mongolia D. Bekhbold, B. Bayarmagnai, D. Naranjargal, O. Baatarkhuu, Y. Dahgwahdorj (Ulaanbaatar, MN) 7. Evaluation of liver function by NRL972-elimination during peginterferon/rbv therapy in patients with CHC Y. Boyanova, K. Antonov, A. Aleksiev, D. Jelev, L. Mateva, Z. Krastev, C. de Mey (Sofia, BG; Mainz-Kastel, DE) 8. Clinical characteristics and outcomes of patients with alcoholic acute hepatitis and cirrhosis hospitalized in Emergency Hospital Bucharest C. Chioncel, A. Popescu, A. Shihab, A. Moldovan (Bucharest, RO) 9. HCV infection and alcohol-metabolizing enzyme gene polymorphism in alcoholic liver cirrhosis among Polish individuals H. Cichoz-Lach, E. Lis, A. Kowalik, K. Celinski, B. Kasztelan-Szczerbinska (Lublin, PL) 10. Azathioprine-induced liver injury in inflammatory bowel disease patients A. Cucos, A. Blaj, I. Ungureanu, C. Mihai, C. Cijevschi Prelipcean (Iasi, RO) 11. The correlation between liver cirrhosis and biliary lithiasis A. Cucos, I. Ungureanu, A. Blaj, C. Mihai, C. Cijevschi Prelipcean (Iasi, RO) 7

8 12. Presepsin as an indicator of infection in patients with liver cirrhosis A. Cucos, I. Ungureanu, A. Blaj, C. Mihai, C. Cijevschi Prelipcean (Iasi, RO) 13.* Pro-apoptotic and anti-proliferative mechanisms downstream of c-met of the kinase inhibitor tivantinib (ARQ 197) E.N. de Toni, S. Lu, A. Rizzani, F.T. Kolligs, E. Gallmeier, S. Arena, B. Göke, A.L. Gerbes (Munich, DE; Candiolo, IT) 14. Identification of patients with chronic active hepatitis in a population of HBsAg inactive carriers through prospective follow-up with transient elastography and quantitative HBsAg assay M. Delle Monache, R. Cecere, C. Francia (Colleferro (Rome), IT) 15. Hepatitis C virus with and without liver cirrhosis: A study of some immunological markers and serum indices L.V. Demeshkina, E.V. Zygalo, V.I. Didenko, V.E. Kudryavtseva (Dnipropetrovsk, UA) 16. The challenging diagnosis of minimal hepatic encephalopathy: Does Critical Flicker Frequency correlate to the Psychometric Hepatic Encephalopathy Score? A. Dillon, Z. Galvin, D. Lowry, S. Stewart (Dublin, IE) 17. Nonalcoholic fatty liver disease (NAFLD) proven by transient elastography in patients with coronary heart disease A. Dragan-Teicu, E. Dragan-Teicu, A. Tudora (Dumbravita, Timisoara, RO) 18. Significance of minimal hepatic encephalopathy in HQRL in patients with liver cirrhosis E. Dragan-Teicu, A. Dragan-Teicu, A. Tudora (Timisoara, Sinnicolau, RO) 19. Immunocompromised, experienced chronic hepatitis B patients have slow response to tenofovir dipivoxil therapy M. Dreczewski, P. Stalke, K. Sikorska, M. Rybicka, K.P. Bielawski, T. Smiatacz (Gdansk, PL) 20. Evaluation of serum fibrinogen levels as a non-invasive tool to detect the cardiac ascites A.C. Dülger, E. Gönüllü, E. Aytemiz (Van, Gaziantep-Nizip, TR) 21. Heme oxygenase-1/carbon monoxide system and blood viscosity in patients with hepatitis C virus-related cirrhosis: Relation to renal function and hemodynamics H.A. El Aggan, M.I. Reda, M.M. Rizk (Alexandria, EG) 22. Macrophage inflammatory protein-1 alpha (CC chemokine ligand 3) in patients with hepatitis C virus-related cirrhosis and hepatocellular carcinoma: Relation to tumor progression and angiogenesis H.A. El Aggan, M. Helmy, N. El Deeb, A. Zeid, M. Fawzy (Alexandria, EG) 8

9 23. Transjugular intrahepatic portosystemic shunt (TIPS) in the therapy of refractory ascites: 20 years single-centre experience T. Fejfar, V. Safka, V. Jirkovsky, T. Vanasek, S. Sembera, M. Lojik, J. Raupach, V. Chovanec, O. Renc, A. Michl, J. Zizka, A. Krajina, P. Hulek (Hradec Kralove, Ostrava, CZ) 24. Sarcopenia and osteopenia in alcoholic liver cirrhosis O. Gavrilescu, M. Dranga, A. Blaj, C. Cijevschi Prelipcean (Iasi, RO) 25. Oral glucose tolerance test and C-reactive protein in nonalcoholic fatty liver disease O. Gavrilescu, I. Ungureanu, A. Blaj, C. Cijevschi Prelipcean, C. Mihai (Iasi, RO) 26. The role of serum endotoxin in the mechanisms of evolution of nonalcoholic fatty liver disease N. Geyvandova, A. Yagoda, G. Babasheva, Z. Nigiyan (Stavropol, RU) 27.* High frequency of HLA class I antigen processing machinery (APM) component up-regulation in primary hepatocellular carcinoma tumors F. Grizzi, B. Franceschini, S. Di Biccari, P. Bossi, M. Chiriva-Internati, S. Ferrone (Rozzano, IT; Lubbock, Boston, US) 28. How useful are non-targeted liver biopsies in todays clinical practice? M. Heydtmann, A. Bradley, K. Oien (Paisley, Glasgow, GB) 29. Cardiovascular risk factors in nonalcoholic fatty liver disease/nonalcoholic steatohepatitis Raya Ivanova, Radina Ivanova, A. Alexiev, L. Mateva (Sofia, BG) 30. Hepatic fibrosis in patients with hydatidosis in the liver K. Kalinova, G. Stoyanov, M. Gulubova, Y. Ananiev, K. Georgiev (Stara Zagora, Sofia, BG) 31. Prediction of liver cirrhosis with biochemical markers in patients with Wilson disease. Fibrotest and SOS FS O. Kosseva, E. Kaneti, Z. Krastev, T. Petkova, N. Dimitrova, S. Dragneva (Sofia, BG) 32. Non-invasive predictors of esophageal varices in liver cirrhosis B. Kraja, A. Dhana, A. Babameto, N. Dhigoi, I. Kellici, S. Prifti (Tirana, AL) 33. A national Wilson's disease registry for Scotland N. Lachlan, S. Campbell, A. Duncan (Edinburgh, Lanarkshire, Glasgow, GB) 34. Serum neuron-specific enolase (NSE) in chronic liver diseases B. Levitan, A. Astakhin, G. Levitan (Astrakhan, RU) 35.* Cdk5 inhibition improves HCC responsiveness to sorafenib treatment J. Liebl, M. Ardelt, S.M. Ehrlich, S. Zahler, A.M. Vollmar (Munich, DE) 9

10 36.* Use of beta-blockers is associated with improved 30 day survival in patients with spontaneous bacterial peritonitis P. Lutz, H.-D. Nischalke, B. Krämer, B. Langhans, S. Schlabe, J. Nattermann, A. Hoerauf, C.P. Strassburg, U. Spengler (Bonn, DE) 37. Non-invasive diagnosis of oesophageal varices in patients with compensated liver cirrhosis using liver and spleen stiffness measurements with transient elastography. An interim analysis. M. Mela, E. Saprikis, J. Anastasiou, A. Christidou, E. Antipa, N. Viazis, D. Karamanolis (Athens, GR) 38. A 20-years experience in the long-term treatment with UDCA in cholestatic liver diseases M. Miloshevski, V. Serafimoski, V. Calovska Ivanova, R. Popova Jovanovska, M. Trajkovska, M. Genadieva-Dimitrova, B. Todorovska, D. Janevska, A. Karadzova (Skopje, MK) 39.* Determination of serum 3-hydroxyisobutyrate, a possible biomarker for the catabolism of branched-chain amino acids in skeletal muscles, in patients with liver cirrhosis T. Miyazaki, A. Honda, T. Ikegami, Y. Matsuzaki (Ibaraki, JP) 40. The role of fibrosis scores and transient elastography in NAFLD progression D. Neagoe, A. Amzolini, M. Popescu, G. Ianosi, L. Sandulescu, A. Farmazon, T. Ciurea (Craiova, RO) 41. The relationship between osteoporosis and fibrosis in NAFLD patients D. Neagoe, M. Popescu, G. Ianosi, A. Amzolini, A. Genunche, A. Farmazon, T. Ciurea (Craiova, RO) 42. Features of correction of maldigestia syndrome at the patients with cirrhosis O.B. Nepesova, H.E. Blum, K.B. Nepesova (Ashgabat, TM; Freiburg, DE) 43. Genetic and environmental risk factors for development of hepatic encephalopathy in cirrhotics N. Oruc, C. Aktan, M. Keskin, N.G. Unal, A. Ozturk, H. Aydin, H.A. Celik, O. Ozutemiz (Izmir, TR) 44.* Hepatic stellate cells are the major source of collagen in murine models of liver fibrosis C.H. Österreicher, U.J. Lemberger, R. Mahon, T. Rülicke, M. Trauner, E. Casanova (Vienna, AT) 45. Vitamin B supplementation in patients with alcohol-related disease: When, how much and how long? N. Padmakumar, S. Crompton, R. Blackwell, K. Padmakumar, G. Lipscomb (Bolton, GB) 46. Activity of MMP1, MMP13 and amino acid metabolism in patients with alcoholic liver cirrhosis A. Prystupa, M. Szpetnar, A. Boguszewska-Czubara, W. Zaluska (Lublin, PL) 10

11 47. Activity of MMP-2, MMP-8 and MMP-9 in the serum as marker of progression alcoholic liver disease in the people from Lublin region A. Prystupa, A. Boguszewska-Czubara (Lublin, PL) 48. Predictive factors for developing hepatocellular carcinoma in patients with liver cirrhosis M. Pumnea, E.C. Rezi (Sibiu, RO) 49.* Calcitriol inhibits activation of hepatic stellate cells in vitro and ameliorates hepatic damage in vivo F.P. Reiter, S. Hohenester, J.M. Nagel, R. Wimmer, L. Wottke, M. Trauner, C. Rust, G.U. Denk (Munich, DE; Vienna, AT) 50. Effects of Iovastatin and pentoxifylline treatment in patients with nonalcoholic steatohepatitis E.-C. Rezi, R.-G. Mihaila, L. Nedelcu, O. Fratila, C. Domnariu (Sibiu, Brasov, Oradea, RO) 51.* Development of hepatitis B virus quasispecies in association with nucleos(t)ide analogue treatment determined by MALDI-TOF MS M. Rybicka, P. Stalke, A. Woziwodzka, D. Marcin, T. Smiatacz, K.P. Bielawski (Gdansk, PL) 52. Surgical treatment results of HCC in Mongolia R. Sanduijav (Ulaanbaatar, MN) 53. Differential expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX) in the development of hepatic fibrosis A. Santra, B.C. Chakraborty, D. Bishnu, S. Santra, G.K. Dhali, A. Chowdhury (Kolkata, IN) 54.* Cellular mechanism of hepatic stellate cells activation with conditioned medium derived from isoniazid treated cytochrome P450 2E1 overexpressing hepatocytes S. Santra, A. Chowdhury, D. Bishnu, G.K. Dhali, A. Santra (Kolkata, IN) 55.* Activation of Toll-like receptors (TLR) on isolated Kupffer cells (KC) and sinusoidal endothelial cells (SEC) of the liver: Opposing effects on the production of the vasoconstrictor thromboxane B 2 J. Schewe, L. Selzner, I. Liss, B. Göke, A.L. Gerbes, C.J. Steib (Munich, DE) 56. Ischemic postconditioning (IPostC) in fibrotic livers following warm ischemia: A new strategy to protect the liver against ischemia-reperfusion injury J. Schewe, I. Liss, L. Selzner, M.-C. Makeschin, B. Göke, A.L. Gerbes, C.J. Steib (Munich, DE) 57. DILI in 1-year analysis of 3rd Department of Medicine J. Sedlacko, Z. Sedlakova, M. Jakabovicova, M. Szantova (Bratislava, SK) 11

12 58. Sarcopenia as predictor of surviving at patients after TIPS (transjugular intrahepatic portosystemic shunt) S. Sembera, V. Jirkovsky, A. Krajina, T. Fejfar, J. Zizka, V. Chovanec, M. Lojik, J. Raupach, V. Safka, T. Vanasek, O. Renc, P. Hulek (Hradec Kralove, CZ) 59. Optimization of the treatment of patients with liver cirrhosis and chronic hepatic encephalopathy I. Skrypnyk, G. Maslova (Poltava, UA) 60. Who gets referred to a liver clinic and are we making best use of resources? A. Tohani, M. Lander, A. Rochford, A. Dias (London, GB) 61. Transient elastography in detecting minimal hepatic encephalopathy in cirrhotic patients A. Tudora, E. Dragan-Teicu, A. Dragan-Teicu (Timisoara, Dumbravita, RO) 62. FibroTest and its correlation with other laboratory parameters of liver function in patients with Wilson's disease L. Turecky, V. Kupcova, E. Uhlikova, P. Scigulinsky (Bratislava, SK) 63. Oxidative stress and induction of cytochrome P450 in development of diabetic hepatopathy in experimental animals L. Turecky, E. Uhlikova, V. Kupcova (Bratislava, SK) 64. Alpha-2-macroglobulin and laboratory parameters of oxidative stress in patients with Wilson's disease E. Uhlikova, V. Kupcova, P. Scigulinsky, L. Turecky (Bratislava, SK) 65. Low vitamin D levels are associated with increased risk for fatty liver disease among non-obese adults I. Ungureanu, O. Gavrilescu, A. Blaj, M. Dranga, C. Cijevschi Prelipcean (Iasi, RO) 66. An assessment of the influence of the mutation of the SERPINA 1 gene on damage to the liver and the occurrence of cholestasis in patients with diagnosed cystic fibrosis S. Wiecek, H. Wos, B. Kordys-Darmolinska, U. Grzybowska-Chlebowczyk (Katowice, PL) 67. Influence of single-nucleotide polymorphisms in TFR2, TF and HFE genes on iron homeostasis and hepatic injury in chronic hepatitis C patients A. Woziwodzka, A. Bernat, M. Rybicka, J. Markiewicz, K. Sikorska, K.P. Bielawski (Gdansk, PL) 68. Bile duct stenting in teenagers with advanced primary sclerosing cholangitis M. Wozniak, J. Pertkiewicz, K. Zieniewska-Pingwara, M. Woynarowski (Warsaw, PL) 69. Role of hepatitis and other factors precursor to originating the liver cancer A. Yusupbekov, M. Djuraev (Tashkent, UZ) 12

13 70. Some aspects of studying of immune system in patients with primary biliary cirrhosis (PBC) E.V. Zygalo, V.I. Didenko, L.V. Demeshkina, V.E. Kudryavtseva, V.N. Zygalo (Dnipropetrovsk, Kiev, UA) * = Posters of Distinction 13

14 Session I Fibrosis: Pathophysiology, diagnosis and treatment 15

15 Pathophysiology of liver fibrosis Massimo Pinzani, MD, PhD, FRCP Sheila Sherlock Chair of Hepatology, Director, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London NW3 2QG, UK Progressive accumulation of fibrillar extracellular matrix (ECM) in the liver is the consequence of reiterated liver tissue damage due to infective (mostly hepatitis B and C viruses), toxic/drug-induced, metabolic and autoimmune causes and the relative chronic activation of the wound healing reaction. The process may result in clinically evident liver cirrhosis and hepatic failure. Cirrhosis is defined as an advanced stage of fibrosis, characterized by the formation of regenerative nodules of liver parenchyma that are separated by and encapsulated in fibrotic septa and associated with major angio-architectural changes. Although cirrhosis is the common result of progressive fibrogenesis, there are distinct patterns of fibrotic development, related to the underlying disorders causing the fibrosis. These different patterns of fibrogenic evolution are related to different factors and particularly: 1. the topographic localization of tissue damage, 2. the relative concentration of pro-fibrogenic factors, and 3. the prevalent pro-fibrogenic mechanism(s). In addition, these different patterns imply the participation of different cellular effectors of the fibrogenic process. The mechanisms responsible for the fibrogenic evolution of chronic liver diseases can be summarized in three main groups: chronic activation of the wound healing reaction, oxidative stress-related molecular mechanisms, and the derangement of the so-called epithelial-mesenchymal interaction leading to the generation of reactive cholangiocytes and peribiliary fibrosis. Most of the knowledge on the cell and molecular biology of hepatic fibrosis derives from in vitro studies employing culture of activated hepatic stellate cells (HSC) isolated from rat, mouse or human liver. It is now evident that other ECM-producing cells, i.e. fibroblasts and myofibroblasts of the portal tract and circulating fibrocytes, are likely to contribute to liver fibrosis. More recently the attention is progressively shifting to the pro-fibrotic microenvironment of the liver with increasing interest for the role of immune cells and specific subsets of macrophages regulating the progression or the regression of fibrosis, the role of intestinal microbiota, and the influence of tissue stiffness. Other major areas of development include the role of tissue hypoxia and the establishment of an anaerobic pro-inflammatory environment and the influence of epigenetic modification in conditioning the progression of fibrosis. From the methodological point of view, it is necessary to establish in vitro models employing exclusively human cells possibly cultured in a 3D (rather than 2D) environment and to select animal models able to answer specific pathophysiological questions. This would be essential in order to be able to translate complex basic acquisitions into effective clinical tools. 17

16 Invasive and non-invasive evaluation of liver fibrosis Laurent Castera, M.D., Ph.D. Service d Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, INSERM U773, Université Denis Diderot Paris-7, Clichy, France laurent.castera@bjn.aphp.fr The prognosis and management of chronic liver diseases greatly depend on the amount and progression of liver fibrosis with the risk of developing cirrhosis. For many years, liver biopsy has been considered as the reference standard for staging of fibrosis. There are two clinically-relevant endpoints, i.e. the presence of significant fibrosis which is an indication for antiviral treatment in chronic viral hepatitis and the presence of cirrhosis which is an indication for specific monitoring of complications related to portal hypertension and to the increased risk of developing hepatocellular carcinoma. Liver biopsy is however an invasive procedure with rare but potentially life-threatening complications, which is prone to sampling errors. These limitations as well as the availability of powerful viral tools and new antiviral drugs have led to the development over the past decade of non invasive methodologies for the assessment of fibrosis. These methods rely on two distinct but complementary approaches: 1) a biological approach based on the dosage of serum biomarkers of fibrosis; 2) a physical approach based on the measurement of liver stiffness for which transient elastography (TE) has been the pioneer technique used. Noninvasive methods have been initially studied and validated in chronic hepatitis C but are now increasingly used in other chronic liver diseases, resulting in a significant decrease in the need for liver biopsy. 18

17 Treatment of hepatic fibrosis Scott L. Friedman MD Professor of Medicine and Dean for Therapeutic Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA The increasing evidence that fibrosis is a dynamic and reversible process, the clarification of the underlying sources and mediators of fibrosis progression, and advances in non-invasively assessing fibrosis have generated enthusiasm towards developing effective anti-fibrotic drugs, although none are approved yet. In reality, there may already be many existing drugs with well-established safety profiles, whose mechanism of action will be also anti-fibrotic even though they have been developed for other indications. Increasingly, such targets for repurposed drugs can be uncovered using high throughput methods combined with big data analysis. Key challenges include the decades-long natural history of chronic liver disease that will require long-term pharmacologic intervention to prevent or reverse cirrhosis, and the lack of a standardized, accepted non-invasive endpoints for fibrosis assessment. There are several therapeutic target classes in developing anti-fibrotic agents: Eliminate the cause of injury and their mediators Attenuate hepatocyte injury Hepatoprotectants Reduce inflammation and the immune response Target specific signaling receptor-ligand interaction, intracellular signaling Reduce fibrogenesis, inhibit matrix synthesis Resolve fibrosis by increasing scar matrix degradation stimulating apoptosis or reversion of stellate cells bone marrow or cell transplantation Regulatory challenges in developing novel drugs A key challenge limiting progress in the testing of anti-fibrotic drugs is the lack of sufficient endpoints that are noninvasive, yet correlate well with clinical outcomes. Currently, all clinical trials of anti-fibrotic drugs require liver biopsy to assess fibrosis before and after treatment. However, biopsy is prone to sampling variability that is not necessarily mitigated by collagen morphometry. Moreover, in trials that include patients who are clinically stable, reliance on clinical events as a hard endpoint is desirable but not realistic, as few patients will have decompensating events during the study interval. Stratification of risk for progression should ideally be incorporated into clinical trial design, but this is not yet possible. While genetic determinants of fibrosis progression have been well validated in HCV a similar fibrosis risk score has been elusive in NASH, probably because the disease is multifactorial and not due to identical etiologies in all patients, even though their clinical expression may be similar. Despite the challenges, increasing cooperation among stakeholders in fibrosis therapeutics development is likely to foster improvements in trial design that accelerate drug approval. 19

18 Session II Portal hypertension and complications 21

19 Pathophysiology and rational basis of therapy Jaime Bosch, MD, PhD Professor of Medicine, Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic- IDIBAPS, University of Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) Portal hypertension is a common complication of chronic liver disease. Its relevance comes from the fact that it determines most complications leading to death or liver transplantation in patients with liver cirrhosis: bleeding from esophageal or gastric varices, ascites and renal dysfunction, sepsis, and hepatic encephalopathy. Portal hypertension results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: a) distortion of the liver vascular architecture (due to the liver disease causing nodule formation, remodeling of liver sinusoids, fibrosis, angiogenesis and vascular occlusion), and b) increased hepatic vascular tone due to sinusoidal endothelial dysfunction, which results in a defective production of endogenous vasodilators, mainly nitric oxide (NO), and increased production of vasoconstrictors (thromboxane A 2, cysteinyl-leukotrienes, angiotensin II, endothelins and activated adrenergic system). Hepatic endothelial dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress, and determines loss of the normal phenotype of sinusoidal endothelial cells (SEC) that become proliferative, pro-thrombotic, pro-inflammatory and vasoconstrictor. The cross-talk between SEC and hepatic stellate cells (HSC) induces activation of the later, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis, which further increase the hepatic vascular resistance and worsens liver failure by interfering with liver parenchyma perfusion. An increased blood flow through the portal system, due to splanchnic vasodilatation, further contributes to increase portal pressure. This is an adaptive response to decreased effective hepatocyte perfusion, and is maximal once portal pressure has increased sufficiently as to promote the development of intrahepatic shunts and portal systemic collaterals (including varices) (at a portal-pressure gradient > 10 mmhg), through which portal blood flow by-passes the liver. Rational therapy for portal hypertension aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments, while architectural disruption and fibrosis can be ameliorated by a variety of anti-fibrogenic drugs and anti-angiogenic strategies. Several drugs in this category are currently under investigaton in phase II-III randomized controlled trials. Sinusoidal endothelial dysfunction is ameliorated by statins and other drugs increasing NO availability; of note, simvastatin has already been proved effective in a randomized controlled trial. Splanchnic hyperemia can be counteracted by nonselective beta-blockers (NSBBs), vasopressin analogs and somatotatin analogs, 23

20 drugs that until recently were the only available treatments for portal hypertension, but that are not very effective in initial stages of cirrhosis. There is experimental and clinical evidence indicating that the more effective reduction of portal pressure is obtained by combining agents acting on these different pathways. It is likely that the treatment of portal hypertension will evolve to use etiological treatments together with anti-fibrotic agents and/or drugs improving sinusoidal endothelial function in initial stages of cirrhosis (pre-primary prophylaxis), while NSBBs will be added in advanced stages of the disease. 24

21 Clinical evaluation and prognosis Annalisa Berzigotti CIBERehd, Hepatic Hemodynamic Laboratory, Hospital Clinic, Barcelona, Spain The natural history of liver cirrhosis is characterized by a long asymptomatic stage ( compensated cirrhosis ) with low mortality, followed by a symptomatic decompensated phase characterized by the clinical consequences of liver failure and portal hypertension (ascites, variceal bleeding, sepsis, jaundice, hepatic encephalopathy) and by high mortality. The clinical evaluation should focus on differentiating patients with high vs. low risk of progressing to the next clinical stage in order to provide early the best available management. In compensated patients, portal hypertension, liver dysfunction, and nutritional status independently concur at defining the risk of clinical decompensation. Measurement of hepatic venous pressure gradient (HVPG) is indicated at this stage to diagnose clinically significant portal hypertension (CSPH; HVPG 10 mmhg), above which clinical complications can appear, and further refine risk stratification (HVPG 16 mmhg is associated to increased death risk). Furthermore, upper GI endoscopy is recommended to demonstrate gastroesophageal varices requiring treatment. Among non-invasive methods suggested for replacing/reducing the use of HVPG and endoscopy for diagnosing CSPH and varices, liver stiffness measurement combined with spleen diameter and platelet count seems promising, holding 80 90% accuracy. Other laboratory parameters also provide important data: even small decreases of plasma albumin are a powerful negative prognostic marker. Finally, increased body mass index raises the risk of clinical decompensation independent of CSPH and liver function: obese patients show a 3-fold risk vs. normal weight patients. Alcohol drinking, iron overload and diabetes are also important co-factors further worsening prognosis which should be researched and treated. 25