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Abstracts Poster Abstracts Falk Symposium 195 Challenges and Management of Liver Cirrhosis October 10 – 11, 2014 Konzerthaus Freiburg Freiburg, Germany
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Page 1: Abstracts Poster Abstracts...Abstracts of Invited Lectures Poster Abstracts Falk Symposium 195 CHALLENGES AND MANAGEMENT OF LIVER CIRRHOSIS Freiburg, Germany October 10 – 11, 2014

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AbstractsPoster Abstracts

Falk FoundationDr. Falk Pharma Falk Symposium 195

Challenges and Management ofLiver Cirrhosis

October 10 – 11, 2014Konzerthaus FreiburgFreiburg, Germany

112116_Falk_Freiburg_Symp195_Abstracts_US.indd 1 18.09.14 09:33

Page 2: Abstracts Poster Abstracts...Abstracts of Invited Lectures Poster Abstracts Falk Symposium 195 CHALLENGES AND MANAGEMENT OF LIVER CIRRHOSIS Freiburg, Germany October 10 – 11, 2014

www.falkfoundation.org

© 2014 Falk Foundation e.V.All rights reserved.

FALK FOUNDATION e.V.Leinenweberstr. 579108 FreiburgGermany

112116_Falk_Freiburg_Symp195_Abstracts_US.indd 2 18.09.14 09:34

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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)

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CONTENTS

page Session I

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 23 – 24

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

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Pathophysiology of renal dysfunction in cirrhosis E. Solà, P. Ginès, Barcelona 29

Definition and diagnosis of acute kidney injury in cirrhosis F. Wong, Toronto 30 – 31

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 35 – 36

Clinical relevance of minimal hepatic encephalopathy – A critical look P. Ferenci, Vienna; K. Weißenborn, Hannover 37 – 38

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 45 – 46

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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 50 – 52

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 56 – 58

Hepatitis B R. Thimme, Freiburg 59 – 60

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 63 – 65

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Poster Abstracts

1. Establishment of a cultivation system mimicking tissue stiffness in chronic liverdiseaseA. 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 hepaticencephalopathy in acute variceal hemorrhageM.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 studyM.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 liverdisease and cryptogenic liver cirrhosisI.H. Bahcecioglu, I. Kal, M. Ispiroglu, M. Yalniz, I.H. Ozercan (Elazig, TR)

5. Upper digestive haemorrhage – Complication of the liver cirrhosisS. 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 MongoliaD. Bekhbold, B. Bayarmagnai, D. Naranjargal, O. Baatarkhuu, Y. Dahgwahdorj(Ulaanbaatar, MN)

7. Evaluation of liver function by NRL972-elimination during peginterferon/RBVtherapy in patients with CHCY. 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 hepatitisand cirrhosis hospitalized in Emergency Hospital BucharestC. Chioncel, A. Popescu, A. Shihab, A. Moldovan (Bucharest, RO)

9. HCV infection and alcohol-metabolizing enzyme gene polymorphism inalcoholic liver cirrhosis among Polish individualsH. Cichoz-Lach, E. Lis, A. Kowalik, K. Celinski, B. Kasztelan-Szczerbinska(Lublin, PL)

10. Azathioprine-induced liver injury in inflammatory bowel disease patientsA. Cucos, A. Blaj, I. Ungureanu, C. Mihai, C. Cijevschi Prelipcean (Iasi, RO)

11. The correlation between liver cirrhosis and biliary lithiasisA. Cucos, I. Ungureanu, A. Blaj, C. Mihai, C. Cijevschi Prelipcean (Iasi, RO)

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12. Presepsin as an indicator of infection in patients with liver cirrhosisA. 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 HBsAginactive carriers through prospective follow-up with transient elastography andquantitative HBsAg assayM. Delle Monache, R. Cecere, C. Francia (Colleferro (Rome), IT)

15. Hepatitis C virus with and without liver cirrhosis: A study of some immunologicalmarkers and serum indicesL.V. Demeshkina, E.V. Zygalo, V.I. Didenko, V.E. Kudryavtseva(Dnipropetrovsk, UA)

16. The challenging diagnosis of minimal hepatic encephalopathy: Does CriticalFlicker Frequency correlate to the Psychometric Hepatic EncephalopathyScore?A. Dillon, Z. Galvin, D. Lowry, S. Stewart (Dublin, IE)

17. Nonalcoholic fatty liver disease (NAFLD) proven by transient elastography inpatients with coronary heart diseaseA. Dragan-Teicu, E. Dragan-Teicu, A. Tudora (Dumbravita, Timisoara, RO)

18. Significance of minimal hepatic encephalopathy in HQRL in patients with livercirrhosisE. Dragan-Teicu, A. Dragan-Teicu, A. Tudora (Timisoara, Sinnicolau, RO)

19. Immunocompromised, experienced chronic hepatitis B patients have slowresponse to tenofovir dipivoxil therapyM. 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 thecardiac ascitesA.C. Dülger, E. Gönüllü, E. Aytemiz (Van, Gaziantep-Nizip, TR)

21. Heme oxygenase-1/carbon monoxide system and blood viscosity in patientswith hepatitis C virus-related cirrhosis: Relation to renal function andhemodynamicsH.A. El Aggan, M.I. Reda, M.M. Rizk (Alexandria, EG)

22. Macrophage inflammatory protein-1 alpha (CC chemokine ligand 3) in patientswith hepatitis C virus-related cirrhosis and hepatocellular carcinoma: Relation totumor progression and angiogenesisH.A. El Aggan, M. Helmy, N. El Deeb, A. Zeid, M. Fawzy (Alexandria, EG)

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23. Transjugular intrahepatic portosystemic shunt (TIPS) in the therapy of refractoryascites: 20 years single-centre experienceT. 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 cirrhosisO. Gavrilescu, M. Dranga, A. Blaj, C. Cijevschi Prelipcean (Iasi, RO)

25. Oral glucose tolerance test and C-reactive protein in nonalcoholic fatty liverdiseaseO. Gavrilescu, I. Ungureanu, A. Blaj, C. Cijevschi Prelipcean, C. Mihai(Iasi, RO)

26. The role of serum endotoxin in the mechanisms of evolution of nonalcoholicfatty liver diseaseN. 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/nonalcoholicsteatohepatitisRaya Ivanova, Radina Ivanova, A. Alexiev, L. Mateva (Sofia, BG)

30. Hepatic fibrosis in patients with hydatidosis in the liverK. Kalinova, G. Stoyanov, M. Gulubova, Y. Ananiev, K. Georgiev(Stara Zagora, Sofia, BG)

31. Prediction of liver cirrhosis with biochemical markers in patients with Wilsondisease. Fibrotest and SOS FSO. Kosseva, E. Kaneti, Z. Krastev, T. Petkova, N. Dimitrova, S. Dragneva(Sofia, BG)

32. Non-invasive predictors of esophageal varices in liver cirrhosisB. Kraja, A. Dhana, A. Babameto, N. Dhigoi, I. Kellici, S. Prifti (Tirana, AL)

33. A national Wilson's disease registry for ScotlandN. Lachlan, S. Campbell, A. Duncan (Edinburgh, Lanarkshire, Glasgow, GB)

34. Serum neuron-specific enolase (NSE) in chronic liver diseasesB. 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)

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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 compensatedliver cirrhosis using liver and spleen stiffness measurements with transientelastography. 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 liverdiseasesM. 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 progressionD. Neagoe, A. Amzolini, M. Popescu, G. Ianosi, L. Sandulescu, A. Farmazon,T. Ciurea (Craiova, RO)

41. The relationship between osteoporosis and fibrosis in NAFLD patientsD. 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 cirrhosisO.B. Nepesova, H.E. Blum, K.B. Nepesova (Ashgabat, TM; Freiburg, DE)

43. Genetic and environmental risk factors for development of hepaticencephalopathy in cirrhoticsN. 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, howmuch 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 alcoholicliver cirrhosisA. Prystupa, M. Szpetnar, A. Boguszewska-Czubara, W. Zaluska (Lublin, PL)

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47. Activity of MMP-2, MMP-8 and MMP-9 in the serum as marker of progressionalcoholic liver disease in the people from Lublin regionA. Prystupa, A. Boguszewska-Czubara (Lublin, PL)

48. Predictive factors for developing hepatocellular carcinoma in patients with livercirrhosisM. 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 nonalcoholicsteatohepatitisE.-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 MongoliaR. Sanduijav (Ulaanbaatar, MN)

53. Differential expression of nicotinamide adenine dinucleotide phosphate oxidase(NOX) in the development of hepatic fibrosisA. 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 B2 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: Anew strategy to protect the liver against ischemia-reperfusion injuryJ. 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 MedicineJ. Sedlacko, Z. Sedlakova, M. Jakabovicova, M. Szantova (Bratislava, SK)

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58. Sarcopenia as predictor of surviving at patients after TIPS (transjugular intra-hepatic 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 hepaticencephalopathyI. 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 cirrhoticpatientsA. Tudora, E. Dragan-Teicu, A. Dragan-Teicu (Timisoara, Dumbravita, RO)

62. FibroTest and its correlation with other laboratory parameters of liver function inpatients with Wilson's diseaseL. Turecky, V. Kupcova, E. Uhlikova, P. Scigulinsky (Bratislava, SK)

63. Oxidative stress and induction of cytochrome P450 in development of diabetichepatopathy in experimental animalsL. Turecky, E. Uhlikova, V. Kupcova (Bratislava, SK)

64. Alpha-2-macroglobulin and laboratory parameters of oxidative stress in patientswith Wilson's diseaseE. Uhlikova, V. Kupcova, P. Scigulinsky, L. Turecky (Bratislava, SK)

65. Low vitamin D levels are associated with increased risk for fatty liver diseaseamong non-obese adultsI. 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 ondamage to the liver and the occurrence of cholestasis in patients withdiagnosed cystic fibrosisS. Wiecek, H. Wos, B. Kordys-Darmolinska, U. Grzybowska-Chlebowczyk(Katowice, PL)

67. Influence of single-nucleotide polymorphisms in TFR2, TF and HFE genes oniron homeostasis and hepatic injury in chronic hepatitis C patientsA. Woziwodzka, A. Bernat, M. Rybicka, J. Markiewicz, K. Sikorska,K.P. Bielawski (Gdansk, PL)

68. Bile duct stenting in teenagers with advanced primary sclerosing cholangitisM. Wozniak, J. Pertkiewicz, K. Zieniewska-Pingwara, M. Woynarowski(Warsaw, PL)

69. Role of hepatitis and other factors precursor to originating the liver cancerA. Yusupbekov, M. Djuraev (Tashkent, UZ)

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70. Some aspects of studying of immune system in patients with primary biliarycirrhosis (PBC)E.V. Zygalo, V.I. Didenko, L.V. Demeshkina, V.E. Kudryavtseva, V.N. Zygalo(Dnipropetrovsk, Kiev, UA)

* = Posters of Distinction

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Session I

Fibrosis: Pathophysiology, diagnosis and treatment

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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 mecha-nism(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) isolat-ed 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) environ-ment and to select animal models able to answer specific pathophysiological ques-tions. This would be essential in order to be able to translate complex basic acquisitions into effective clinical tools.

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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 E-Mail: [email protected]

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. Non-invasive 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.

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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.

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Session II

Portal hypertension and complications

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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 pro-duction of vasoconstrictors (thromboxane A2, 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 pro-liferate, 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 non-selective beta-blockers (NSBBs), vasopressin analogs and somatotatin analogs,

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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.

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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 “decompen-sated” 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.

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Therapies: Drugs, scopes and TIPS – When and how?

Juan G. Abraldes Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada

Variceal bleeding is the most serious complication of portal hypertension. All cirrhotic patients should be screened endoscopically for varices which are present in about 20% of compensated and 60% of patients of decompensated patients at diagnosis. In patients without varices endoscopy surveillance should be continued every 2 years. Patients with high-risk varices (moderate or large in size, or with red color signs, or in Child-Pugh C patients) should be treated with a non-selective beta-blocker to prevent bleeding (propranolol, nadolol or carvedilol). Endoscopic banding ligation is also effective for the prevention of first bleeding and it is first choice in patients with contraindications or intolerant to beta-blockers.

Acute variceal hemorrhage still has a high morality rate (around 15%) and calls for intensive care management and conservative blood transfusion policy. Treatment is based on the combined use of vasoactive drugs, endoscopic band ligation, and prophylactic antibiotics. Failures are best managed by transjugular intrahepatic portosystemic shunt (TIPS). Balloon tamponade or specifically designed covered esophageal stents can be used as a bridge to definitive therapy in unstable patients. Early, preemtive TIPS might be first choice in patients at high risk of failure (Child-Pugh B with active bleeding or Child-Pugh C up to 13 points).

Patients surviving a variceal bleeding are at high risk of rebleeding. Combination of beta-blockers and endoscopic band ligation is the most effective therapeutic approach. Preliminary data suggest that the addition of simvastatin increases survival in these patients.

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Session III

Kidney problems in cirrhosis

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Pathophysiology of renal dysfunction in cirrhosis

Elsa Solà and Pere Ginès Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain

Kidney dysfunction is a common complication of patients with advanced cirrhosis and is associated with poor prognosis. Patients with advanced cirrhosis show circulatory dysfunction which is characterized by reduced systemic vascular resistance due to splanchnic arterial vasodilation, which is caused by portal hypertension. The progressive reduction in systemic vascular resistance leads to effective arterial hypo-volemia. In order to maintain arterial pressure within normal limits in this setting there is activation of systemic vasoconstrictor systems, including renin-angiotensin-aldosterone system, sympathetic nervous system and, in late stages, non-osmotic hypersecretion of vasopressin. Although these systems have positive effects in maintaining arterial pressure, they have negative influence on kidney function, leading to the retention of sodium and solute-free water, and in late stages of the disease, an intense kidney vasoconstriction develops, leading to the decrease of glomerular filtration rate and the development of hepatorenal syndrome (HRS). Moreover, bacterial translocation and the existence of a systemic inflammatory state in patients with advanced cirrhosis may play a role in the impairment of circulatory function. HRS is a unique cause of kidney failure of functional origin that develops in patients with cirrhosis. However, besides HRS, patients with cirrhosis may develop kidney failure due to other causes, including bacterial infections, prerenal kidney failure, shock, use of nephrotoxic drugs or intrinsic kidney diseases. Considering the existence of circulatory dysfunction and some degree of kidney vasoconstriction, patients with advanced cirrhosis have fragile kidney function and are susceptible to develop easily kidney failure associated with other complications of the disease, particularly bacterial infections and gastrointestinal bleeding.

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Definition and diagnosis of acute kidney injury in cirrhosis

Florence Wong GI Division, Department of Medicine, University of Toronto, Canada

Renal dysfunction is a common complication of advanced cirrhosis, occurring in approximately 20% of patients admitted into hospital. Almost all of these are cases of acute renal failure, or more commonly known as acute kidney injury (AKI) nowadays, which if left untreated, is associated with a grave prognosis. The best-known example of AKI in cirrhosis is type 1 hepatorenal syndrome (HRS-1), which has a well-defined pathophysiology, diagnostic criteria, and treatment algorithm. However, there are many more cases of AKI in cirrhosis that do not quite fulfill the diagnostic criteria of HRS-1. We now understand that acute but minor increases in serum creatinine without reaching the levels required for the diagnosis of HRS-1 in cirrhosis also carry an unfavorable prognosis. Other causes of AKI that can occur in cirrhosis include acute tubular necrosis (ATN) especially following hypotensive episodes. Furthermore, many cases of so-called functional renal failure can evolve into structural kidney damage. Therefore, making an accurate diagnosis of AKI in cirrhosis is important in order to provide appropriate treatment. Various learned societies have now looked to concepts from other subspecialties to help improve the definition of AKI.

Since the serum creatinine does not accurately reflect renal function in advanced cirrhosis, related to reduced muscle bulk and interference of its measurement from high bilirubin in decompensated cirrhosis, it has been proposed that a change in serum creatinine rather than the actual creatinine level would be more appropriate to define renal function in cirrhosis. In 2011, the Acute Dialysis Quality Initiatives group and members of the International Ascites Club proposed to define AKI as an increase in serum creatinine by 0.3 mg/dl (26.4 µmol/l) in < 48 hours or by 50% from baseline within the past 6 months (Table 1). HRS-1 was defined as a special form of AKI. Subsequently, it was shown that progression of AKI was also important in determining prognosis. To borrow the concept from the nephrologists’ Acute Kidney Injury Network, various stages of AKI was therefore proposed (Table 2) to describe the severity of AKI in cirrhosis. To define progression of AKI from 1 stage to the next was therefore made possible. There are now many studies in decompensated cirrhosis that have confirmed the accuracy of the definition and staging of AKI in predicting patient outcome. However, one controversy still remains: should a cut-off value of minimum serum creatinine be set in the definition of AKI? The proponents of setting a minimum value of serum creatinine of 1.5 mg/dl (133 µmol/l) in the definition of AKI have suggested that any rise in serum creatinine below this level does not have any impact on patient outcome. However, the opponents of setting such a rigid cut-off value argue that this may deny patients with AKI to receive treatment at an earlier stage of renal dysfunction, and therefore reducing the likelihood for complete recovery. The International Ascites Club is in the process of organizing a consensus on this point, to be followed by further studies to confirm the consensus opinion.

Despite their improvement over serum creatinine in characterizing AKI in cirrhosis, none of these new definitions and diagnostic criteria can differentiate between the different types of AKI. Therefore, investigators have started to explore various renal biomarkers as biological indicators of various disease states. There are now reports

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on the use of renal biomarkers in the diagnosis of the etiology of AKI in patients with cirrhosis, especially in the separation of function renal diseases such as HRS-1 from structural renal damage such as ATN. In the future, we can look forward to a panel of biomarkers to evaluate both glomerular and tubular function, as well as tubular damage, thus allowing us to further define the different types of AKI, and to follow their evolution over time.

Table 1: Proposed diagnosis of acute kidney injury by the Acute Dialysis Quality Initiatives and International Ascites Club

Table 2: Proposed staging of acute kidney injury in cirrhosis

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Treatment of hepatorenal syndrome

Paolo Angeli Department of Medicine, DIMED, Unit of Hepatic Emergencies and Liver Transplan-tation, University of Padova, Italy

Hepatorenal syndrome (HRS) is a functional renal failure that often occurs in patients with cirrhosis and ascites. HRS develops as a consequence of a severe reduction of effective circulating volume due to both an extreme splanchnic arterial vasodilatation and a reduction of cardiac output. There are two different types of HRS. Type-1 HRS, which is often precipitated by a bacterial infection, especially spontaneous bacterial peritonitis, is characterized by a rapidly progressive impairment of renal function. Despite its functional origin, the prognosis of Type-1 HRS is very poor. Type-2 HRS is characterized by a stable or slowly progressive renal failure so that its main clinical consequence is not acute renal failure but refractory ascites and its impact on prognosis is less negative. New treatments (vasoconstrictors plus albumin, trans-jugular portosystemic shunt, molecular adsorbent recirculating system), which were introduced in the past 10 years, are effective in improving renal function in patients with HRS. These treatments and in particular, vasoconstrictors plus albumin which can improve also survival in patients with HRS, have changed the management of this severe complication in patients with advanced cirrhosis. The potential negative impact in responders to pharmacological treatment of HRS on the MELD score, its possible delaying effect on the timing of liver transplantation (LT), should be taken into account promoting a new policy of priority allocation in the waiting list for to LT in these patients.

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Session IV

Cognitive dysfunction in cirrhosis

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Novel concepts of pathophysioloy of hepatic encephalopathy

Dieter Häussinger Heinrich Heine University Düsseldorf, Germany

Hepatic encephalopathy (HE) is a clinical manifestation of a low-grade cerebral edema, which exacerbates in response to ammonia and other precipitating factors, such as inflammatory cytokines, hyponatremia and sedatives and induces an oxidative/nitrosative stress response [1, 2]. There is an auto-amplificatory signaling loop between astrocyte swelling and oxidative stress. The action of different HE-pre-cipitating conditions integrates at the level of astrocyte swelling and the production of ROS/RNS, thereby explaining why fairly heterogeneous conditions can trigger episodes of HE. The consequences of the oxidative/nitrosative stress response are manifold and include protein tyrosine nitration (PTN) [3], RNA oxidation [4], induction of astrocyte senescence [5] and zinc-dependent transcription of genes [6] such as the peripheral benzodiazepine receptor. Its up-regulation enhances the synthesis of neurosteroids which not only positively modulate GABAA receptor activity, but also activate TGR5 in the brain [7], which exerts anti-inflammatory activity in microglia. Microglia is activated in HE in vivo and by ammonia in vitro, but is not reactive [8, 9]. RNA oxidation is found in astrocytes and neurons and oxidized RNA is also found in RNA granules, which participate in postsynaptic local protein synthesis which is involved in memory formation. Most importantly, markers of oxidative/nitrosative stress, PTN, RNA oxidation and senescence can also be shown in human brains from patients with liver cirrhosis and HE, but not in cirrhotics without HE [5, 9, 10]. Gene expression profiling from cerebral cortex from patients without liver disease and cirrhotic patients with and without HE revealed HE-specific sets of 434 and 204 genes which are up- or down-regulated in HE, respectively [9]. These genes are mainly related to oxidative stress and DNA damage defense, cell signaling, apoptosis and anti-inflammation. There is no evidence for an up-regulation of inflammatory cytokines in HE. Ammonia also induces via glutamine formation an increased N-acetyl-glucosaminidation of proteins [11]. This, RNA oxidation, PTN and changes in gene transcription are thought to affect synaptic plasticity in the brain which may explain the slowing of oscillatory networks in the brain which finally accounts for motoric and cognitive symptoms in HE [12]. In line with this, prevention of PTN and RNA oxidation by indomethacin in portal vein ligated rats, an animal model of HE restored locomotor activity in these animals [13].

References:

1. Häussinger D, Schliess F. Pathogenetic mechanisms of hepatic encephalo-pathy. Gut. 2008;57:1156–65.

2. Häussinger D, Görg B. Interaction of oxidative stress, astrocyte swelling andcerebral ammonia toxicity. Curr Opin Clin Nutr Metab Care. 2010;13:87–92.

3. Schliess F, Görg B, Fischer R, Desjardins P, Bidmon HJ, Herrmann A,Butterworth RF, Zilles K, Häussinger D. Ammonia induces MK-801-sensitivenitration and phosphorylation of protein tyrosine residues in rat astrocytes.FASEB J. 2002;16:739–41.

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4. Görg B, Qvartskhava N, Keitel V, Bidmon HJ, Selbach O, Schliess F,Häussinger D. Ammonia induces RNA oxidation in cultured astrocytes and brainin vivo. Hepatology. 2008;48:567–79.

5. Görg B, Karababa A, Shafigullina A, Bidmon HJ, Häussinger D. Ammonia-induced senescence in cultured rat astrocytes and human cerebral cortex inhepatic encephalopathy. Glia. 2014 [in press], doi: 10.1002/ glia.22731.

6. Kruczek C, Görg B, Keitel V, Pirev E, Kroncke KD, Schliess F, Häussinger D.Hypoosmotic swelling affects zinc homeostasis in cultured rat astrocytes. Glia.2009;57:79–92.

7. Keitel V, Görg B, Bidmon HJ, Zemtsova I, Spomer L, Zilles K, Häussinger D.The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain.Glia. 2010;58:1794–1805.

8. Zemtsova I, Görg B, Keitel V, Bidmon HJ, Schror K, Häussinger D. Microgliaactivation in hepatic encephalopathy in rats and humans. Hepatology. 2011;54:204–15.

9. Görg B, Bidmon HJ, Häussinger D. Gene expression profiling in the cerebralcortex of patients with cirrhosis with and without hepatic encephalopathy.Hepatology. 2013;57:2436–47.

10. Görg B, Qvartskhava N, Bidmon HJ, Palomero-Gallagher N, Kircheis G, ZillesK, Häussinger D. Oxidative stress markers in the brain of patients with cirrhosisand hepatic encephalopathy. Hepatology. 2010;52:256–65.

11. Karababa A, Görg B, Schliess F, Häussinger D. O-GlcNAcylation as a novelammonia-induced posttranslational protein modification in cultured rat astro-cytes. Metab Brain Dis. 2013; doi 10.1007/s11011-013-9454-7.

12. Timmermann L, Gross J, Butz M, et al. Mini-asterixis in hepatic encephalopathyinduced by pathologic thalamo-motorcortical coupling. Neurology. 2003;61:689–92.

13. Brück J, Görg B, Bidmon HJ, Zemtsova I, Qvartskhava N, Keitel V, Kircheis G,Häussinger D. Locomotor impairment and cerebrocortical oxidative stress inportal vein ligated rats in vivo. J Hepatol. 2011;54: 251–7.

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Clinical relevance of minimal hepatic encephalopathy – A critical look

Prof. Peter Ferenci, Prof. Karin Weißenborn* Medical University of Vienna, Austria; *Hannover Medical School, Hannover, Germany

Impaired neuropsychiatric function without overt signs of hepatic encephalopathy (HE) is defined as minimal (MHE). In the recent EASL/AASLD clinical practice guidelines [1] MHE (no clinical signs) and grade 1 HE are combined as “covert” HE characterized by the absence of disorientation.

Diagnosis of MHE requires at least two abnormal psychometric and/or neurophysio-logical tests:

The Portosystemic Encephalopathy-Syndrome Test consists of 5 paper-pencil tests evaluating cognitive and psychomotor processing speed and visuo-motor coordina-tion. Computerized versions are available.

The Continuous Reaction Time test (CRT). The CRT index measures the stability of the reaction times.

The Inhibitory Control Test is a computerized test of response inhibition and working memory [2] (www.hecme.tv). Testing requires highly functional patients.

The Critical Flicker Frequency test [3, 4] is the frequency at which a fused light (presented from 60 Hz downwards) appears to be flickering to the observer. It requires several trials, intact binocular vision, absence of red-green blindness and specialized equipment.

The Stroop Test: The Stroop task is a test of psychomotor speed and cognitive flexibility and is available as a Smartphone App [5].

Test should be selected/used depending on the local population norms and avail-ability. Single test results poorly correlate with the clinical impact of the disease [6]. Their interpretation needs an understanding of the patient’s history, current therapy and effect on the patient’s daily activities. A diagnosis of minimal/covert HE does not automatically mean that the affected subject is a dangerous driver [7]. Medical providers are not trained to evaluate “fitness to drive” but should act in the best interests of the patient and society following the local laws. Testing for MHE may detect poor quality of life and reduced socio-economic potential, and predict overt HE development. Thus, it may the basis for counseling patients and caregivers about the disease.

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References:

1. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepaticencephalopathy in chronic liver disease: 2014 Practice Guideline by theAmerican Association for the Study Of Liver Diseases and the EuropeanAssociation for the Study of the Liver. Hepatology. 2014;60(2):715–35.

2. Bajaj JS, Hafeezullah M, Franco J, Varma RR, Hoffmann RG, Knox JF, et al.Inhibitory control test for the diagnosis of minimal hepatic encephalopathy.Gastroenterology. 2008;135(5):1591–1600.

3. Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Häussinger D. Criticalflicker frequency for quantification of low-grade hepatic encephalopathy.Hepatology. 2002;35(2):357–66.

4. Romero-Gómez M, Córdoba J, Jover R, del Olmo JA, Ramírez M, Rey R, et al.Value of the critical flicker frequency in patients with minimal hepatic encephalo-pathy. Hepatology. 2007;45(4):879–85.

5. Bajaj JS, Thacker LR, Heuman DM, Fuchs M, Sterling RK, Sanyal AJ, et al. TheStroop smartphone application is a short and valid method to screen for minimalhepatic encephalopathy. Hepatology. 2013;58(3):1122–32.

6. Montagnese S, Biancardi A, Schiff S, Carraro P, Carlà V, Mannaioni G, et al.Different biochemical correlates for different neuropsychiatric abnormalities inpatients with cirrhosis. Hepatology. 2011;53(2):558–66.

7. Bajaj JS, Stein AC, Dubinsky RM. What is driving the legal interest in hepaticencephalopathy? Clin Gastroenterol Hepatol. 2011;9(2):97–8.

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Treatment of low grade hepatic encephalopathy – When and how?

Rajiv Jalan Institute of Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK; E-Mail: [email protected]

The term low grade hepatic encephalopathy (HE) implies a patient group which has clinical characteristics such that deficits in neurologic function can only be identified when they undergo sensitive neuropsychiatric or neurophysiologic testing. Therefore, this entity is referred to as ‘minimal HE (MHE)’ when no symptoms of HE can be found but there are abnormalities on detailed testing. ‘Covert HE’ on the other hand encompasses patients with MHE who may or may not have subtle neurologic signs. Most of the currently available data is in the MHE population. These patients have markedly reduced quality of life in multiple physical and psychological domains. Their susceptibility to developing overt forms of HE is higher and so are the mortality rates. Treatment options for this condition are however, limited. The mainstay of therapy remains lactulose which was shown in an open label study to reduce the occurrence of the first episode of HE but placebo controlled clinical trials with adequate numbers of patients are unavailable. Probiotics and rifaximin have positive effects on the performance of patients but the lack of suitable placebo, use of different measures of MHE and relatively short-term studies make it difficult to recommend routine therapy. The data notwithstanding, some patients have severe, debilitating quality of life, need to drive for work reasons and do respond to a trial of drugs such as lactulose and rifaximin. In such cases, treatment using these drugs is reasonable. Otherwise, at the present time, routine treatment for patients with MHE is not advisable. Liver transplantation is recommended for patients who fail to respond.

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Session V

Bacterial infections in cirrhosis

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Infection as trigger for portal hypertension

Christian J. Steib University Hospital LMU Munich – Campus Grosshadern, Liver Center Munich, Department of Medicine II, Marchioninistr. 15, 81377 Munich, Germany

Microbial infections are a relevant problem for patients with liver cirrhosis. Different types of bacteria are responsible for different kinds of infections: E. coli and K. pneumoniae are frequently observed for spontaneous bacterial peritonitis (SBP) or urinary tract infections and S. pneumoniae and M. pneumoniae for pulmonal infections. Mortality is higher in infected patients with liver cirrhosis than in patients without infections. Infections in patients with liver cirrhosis are associated with a higher incidence of complications. Earlier studies have already investigated the link between bacterial infections and variceal bleeding in patients with liver cirrhosis, but the underlying pathophysiology was still unclear. Kupffer cells (KC) are the tissue-specific macrophages of the liver and have a prominent location in the sinusoidal layer. Therefore, they are probably the first to come in contact with microbial products arriving the sinusoidal blood flow. Thromboxane A2 has been identified as important vasoconstrictor in cirrhotic livers and interestingly isolated Kupffer cells produce a major amount of thromboxane A2. Accordingly functional relevance for portal pressure increase following activation of non-parenchymal cells has been investigated in different models; additionally simulation of SBP by intraperitoneal lipopolysaccharide administration increased the portal pressure to a higher degree. There is evidence in first experiments that even human bacterial isolates increase thromboxane A2 production in isolated KC. Accordingly different TLR agonists showed relevant increases of thromboxane A2 production in isolated KC and interestingly differences between the varying TLR agonists have been observed.

In conclusion, TLR activation by bacterial products of non-parenchymal liver cells, mainly KC, results in a relevant production of vasoconstrictors. These vaso-constrictors have an important functional role for portal hypertension. These data might explain the pathophysiologic correlation between microbial infections and portal hypertension in patients with liver cirrhosis.

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Role of infections in acute-on-chronic liver failure

Richard Moreau, M.D. Inserm, U1149, Centre de Recherche sur l’Inflammation (CRI), Paris; UMR S1149, Université Paris Diderot-Paris 7, Faculté de Médecine Bichat, Paris; Département Hospitalo-Universitaire (DHU) UNITY, Service d’Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy; Laboratoire d’Excellence (Labex) INFLAMEX, PRES Sorbonne Paris Cité, Paris, France

A proportion of patients hospitalized for an acute complication of cirrhosis have acute-on-chronic liver failure (ACLF) which is characterized by the development of organ failures associated with a high risk of short-term death. The failing organs/systems can be the liver, kidney, brain, coagulation, lungs and circulation. The diagnosis of organ failures is based on a sequential assessment of organ failure (SOFA) scale that has been modified for patients with cirrhosis. ACLF is a syndrome that is distinct from mere acute decompensation of cirrhosis. Bacterial infection is significantly more common in patients with ACLF than in those without (33% vs. 22%, respectively. Infections most commonly associated with ACLF were spontaneous bacterial peritonitis and pneumonia. The process of bacterial infection resulting in organ failure(s) is called severe sepsis or septic shock. The mechanisms by which bacterial infection leads to multiorgan failure are poorly understood. Patients with cirrhosis are at risk of developing sepsis, sepsis-induced organ failure and of dying. There are probably genetic factors but also environmental factors (e.g., infections are more severe with multi-resistant bacteria than with bacteria sensitive to usual antibiotics). Physiologically, sepsis is a pro-inflammatory and pro-coagulant response to invading pathogens. In cirrhosis, sepsis is accompanied by a markedly imbalanced cytokine response (‘cytokine storm’), which converts responses that normally help fight infections into excessive, damaging inflammation. Molecular mechanisms for this excessive pro-inflammatory response are poorly understood. In patients with cirrhosis and severe sepsis, high production of pro-inflammatory cytokines seems to play a role in the development of organ failures. There is some evidence that organ failure may develop in the context of sepsis because of a decrease in tissue tolerance to injury due to the immune response of the host or to direct detrimental effects caused by pathogens.

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Treatment of spontaneous bacterial peritonitis

Francesco Salerno, MD Policlinico IRCCS San Donato, Department of Internal Medicine, University of Milan, Italy

Spontaneous Bacterial Peritonitis (SBP) is a bacterial infection typically occurring in patients with cirrhosis and ascites. This peculiarity is due to the high frequency of intestinal translocation, a pathologic event which allows the intestinal bacteria to become able to cross the intestinal barrier colonizing the abdominal ascitic-fluid. The prevalence of SBP in cirrhosis is the first or the second-one among all the bacterial infections occurring in such patients when admitted to hospital, only inferior to urinary tract infections (UTI). SBP is, for the most times, sustained by Gram-negative bacteria such as E. coli, Enterocci, Streptococcus faecalis or faecium. The risk factors to develop a SBP we know are elderly, refractory ascites, variceal bleeding, renal failure (creatinine levels over 1.5 mg/dl), hypoalbuminemia (albumin levels below 2.5 g/ml), bilirubin levels higher than 4 mg/dl, a low concentration of ascitic proteins (< 15 g/l), esophageal variceal bleeding or recurring bleedings, Child-Pugh B or C, a positive anamnesis for previous diagnosis of SBP. This last associa-tion is a current indication to maintain the patient under the protection of a long-term antibiotic prophylaxis with norfloxacin. SBP often leads to acute renal failure – especially episodes of hepatorenal syndrome (HRS) – in about 20–30% of cases, independently of the efficacy of the antibiotic therapy that was undertaken. This subgroup of patients has a very high rate of morta-lity (90%). The infusion of high doses of i.v. albumin (3 grams/kg bw on the first day and 1.5 grams/kg bw on the third day) demonstrated to significantly reduce the episodes of HRS and consequently the risk to die (NEJM, 1999).

The occurrence of bacterial infections seems to be increased in patients with cirrhosis during the last years. Furthermore, many strains of patients’ intestinal micro-biota developed resistance against several classes of antibiotics, often the most frequently used, causing the emergence of Multi-Drug-Resistant agents (MRD).

The use of long-term antibiotic prophylaxis with quinolones, as well as the recent increase of antibiotic therapies, caused the emergence of many infections sustained by Gram-positive bacteria or by Gram-negative bacteria resistant to quinolone, cephalosporins, and sulfamethoxazol-trimethoprim. The most serious mutation now involves strains of Klebsiella that are resistant to more than 90% of drugs.

In cases of MDR-associated SBP, a particularly frequent event, the antibiotic sensi-tivity of quinolones is low and the European Recommendations suggested the prompt use of a second-line antibiotic therapy, including a carbapenem or piperacillin and tazobactam.

The collection of blood, urine, and ascitic fluid for cultural examinations is very important and should be performed promptly after the diagnosis of infection, possibly before starting any antibiotic therapy. Indeed, the chance that a cultural insemination gives a positive result rapidly evanish when it is performed after the antibiotic administration has been already undertaken.

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It is important to underline that an empirical treatment with an ineffective antibiotics is associated with a greater probability for the patient to early die. In one of our recent unpublished studies, about 20% of first-line therapies were empirical, and the morta-lity rate during the first 3-month follow up was significantly superior in this sub-set of patients.

Accordingly to this scenario, it is important that future investigations are aimed to develop more effective means to prevent bacterial infections as SBP in patients with cirrhosis, and to obtain more effectively drug therapies when infection has occurred.

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Session VI

Hepatocellular carcinoma

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Molecular profiling and research of therapeutic targets

Gregory J. Gores, M.D. Division of Gastroenterology and Hepatology, Mayo College of Medicine, Mayo Clinic, Rochester, Minnesota, USA

There has been a world-wind of activity examining and chronicling genetic aber-rations in hepatocellular carcinoma. A large body of information has been amassed. Unfortunately, this information has yet to identify targetable, key, driver mutations in hepatocellular carcinoma. Thus, advances in the treatment of hepatocellular carcinoma have not matched pace with the genetic information available and has fallen far below our original expectations. Mutations in the hepatocellular carcinoma can be classified as those which drive early carcinogenesis such as promoter mutations of the telomerase reversed transcriptase gene, aberrations in beta catenin signaling, modification of key regulators of cell cycle genes, epigenetic modifiers, activation of the AKT/mTOR pathways and low level mutations in stress oxidative pathways and the JAK/STAT signaling cascades. To date, none of the identified pathways have led to clinically meaningful treatment strategies. The only systemic therapy for hepatocellular carcinoma remains sorafenib, a multikinase inhibitor. Recently, a subclass of hepatocellular carcinomas carrying VEGFA amplifications was identified. Those patients with amplification of the VEGFA pathway responded very favorably to sorafenib. Thus, we may have a biomarker identifying patients who are likely to respond to sorafenib. Several biomarkers have been identified which portend a bad prognosis in patients undergoing resection for hepatocellular carcinoma. The 5-gene profile of HN1, RAN, RAMP3, KRT19, and TAF9 was associated with survival times markedly different from those without this signature. Furthermore, immunohistochemistry has identified keratin 19 positive hepatocellular carcinoma since as a distinct subset of this lethal disease. Thus, genetic profiling is identifying and helping to stratify different subsets of this disease which ultimately will prove useful for stratifying patients and treatment paradigms.

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Systemic therapy for hepatocellular carcinoma

J. Bruix Liver Unit, Hospital Clínic, University of Barcelona, Spain

In the last years the management of patients with liver cancer has been improved. The BCLC staging/treatment strategy (Fig. 1) identifies the optimal candidates for each treatment option and sorafenib is the only effective systemic treatment. Others (sunitinib, brivanib, linifanib, everolimus, ramucirumab) have failed in terms of safety/ survival benefit. Some patients at intermediate/ early stage, may be considered for systemic therapy as options of higher priority may have failed or not be feasible. The 800 mg/day is the recommended starting dose. Close follow-up and easy access for the patients so that they can report any adverse event and implement dose adjust-ments is the key point in the management of them. Development of early dermato-logic adverse events has been correlated with better outcome and the pattern of radiologic progression characterizes better the prognosis/outcome of these patients. Treatment beyond progression may be considered if there is no option for a second line research trial. It is important to note that the survival benefits with sorafenib, and likely with other drugs that may become available, may be achieved in the absence of tumor burden reduction, and hence of response to treatment according to conventional criteria. Hence, research is focused to develop new response criteria based in biomarker profiling or functional imaging. Ideally, the stratification of patients according to molecular profile and the availability of better tools to register treatment efficacy and emergence of treatment failure should prime a major improvement of the survival benefits of the patients diagnosed with this cancer.

References:

1. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245–55.

2. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011;53(3):1020–2.

3. EASL-EORTC clinical practice guidelines: management of hepatocellularcarcinoma. J Hepatol. 2012;56(4):908–43.

4. Reig M, Darnell A, Forner A, Rimola J, Ayuso C, Bruix J. Systemic therapy forhepatocellular carcinoma. The issue of treatment stage migration and registra-tion of progression using the BCLC refined RECIST. Semin Liver Dis. 2015 [inpress].

5. Reig M, Rimola J, Torres F, Darnell A, Rodriguez-Lope C, Forner A, et al.Postprogression survival of patients with advanced hepatocellular carcinoma:Rationale for second-line trial design. Hepatology. 2013;58(6):2023–31.

6. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, et al. Guide-lines for the diagnosis and management of intrahepatic cholangiocarcinoma.J Hepatol. 2014;60(6):1268–89.

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7. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al.Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. N EnglJ Med 2010;362(14):1273–81.

* Note that Child-Pugh classification is not sensitive to accurately identify those patients withadvanced liver failure that would deserve liver transplant consideration. Some patients fitting inChild-Pugh B, and even A, may present a poor prognosis because of clinical events not capturedby such system, i.e.: spontaneous bacterial peritonitis, refractory ascites with or withouthepatorenal syndrome, recurrent encephalopathy, severe malnutrition.

** Patients with end-stage cirrhosis due to heavily impaired liver function (Child-Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for livertransplantation. In the, HCC may become a contraindication if exceeding the enlistment criteria.

2–5 learning objectives

– To understand the decision process to indicate treatment in patients with hepato-cellular carcinoma and cholangiocarcinoma.

– To understand the optimal timing for systemic (sorafenib) treatment initiation, thestrategy for dose adjustments because of adverse events and when it is justified tointerrupt treatment.

– To envision the benefits of current therapeutic research in combination withsorafenib or after it.

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2–5 key messages

– The BCLC staging and treatment strategy links survival prediction and preferredtreatment approach in patients with hepatocellular carcinoma.

– Sorafenib is the sole agent that has been shown to improve survival of patientsdiagnosed with hepatocellular carcinoma.

– The efficacy of sorafenib is obtained through a delay in tumor progression.

– Ongoing research should improve the current benefits of treatment both in first linein combination with sorafenib and in second line vs best supportive care.

– Chemotherapy using gemcitabine, cisplatin and 5-fluorouracil improves the sur-vival of patients with cholangiocarcinoma.

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Session VII

Practical issues – Therapy in patients with cirrhosis

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Autoimmune hepatitis and chronic cholestatic diseases

U. Beuers Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, The Netherlands

Autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis are the major autoimmune and chronic cholestatic liver diseases of the adult. They commonly have a slowly progressive course and lead to cirrhosis and liver failure when untreated or not adequately responding to medical treatment. This presentation focuses on the management of these diseases based on clinical studies and guide-lines published until mid-2014.

• Autoimmune hepatitis (AIH) is an inflammatory disease of the liver with a femalepreponderance (≤ 80%). Its diagnostic hallmarks are elevated serum transami-nases, elevated serum IgG, the presence of serum autoantibodies (type 1:ANA, ASMA, anti-SLA/LP; type 2: LKM), and histopathological findings of aninterface hepatitis. Standard treatment of AIH with corticosteroids andazathioprine is successful in up to 80% of patients. 2nd line therapies includemycophenolate mofetil (MMF) for those who do not tolerate azathioprine,tacrolimus and other immunosuppressive regimens. Lack of adequate treatmentresponse may lead to end-stage liver disease requiring liver transplantation.

• Primary biliary cirrhosis (PBC) is an immune-mediated inflammatory disorder ofsmall intrahepatic bile ductules in mostly middle-aged women which progressesto biliary cirrhosis. Its diagnostic hallmarks are elevated serum markers ofcholestasis (γGT, alkaline phosphatase) and antimitochondrial antibodies inserum. Ursodeoxycholic acid (UDCA, 13–15 mg/kg/d) is the standard medicaltreatment for PBC today. For those PBC patients not adequately responding toUDCA, combination treatment with UDCA and budesonide, FXR agonists orPPARα agonists is under study in phase 3 trials. Liver transplantation should beconsidered in decompensated cirrhosis.

• Primary sclerosing cholangitis (PSC) is characterized by chronic inflammationand fibrosis of both intra- and extrahepatic bile ducts in mainly younger menwho often suffer from inflammatory bowel disease (IBD). Diagnostic hallmarkare irregular bile duct obliterations and strictures leading to liver cirrhosis andliver failure. UDCA (15–20 mg/kg/d) improves serum liver tests, but has notbeen shown so far to improve survival. Liver transplantation should beconsidered in late-stage disease.

• Features of ill-defined overlap syndromes of PBC/AIH and PSC/AIH areobserved in up to 10% of patients with PBC and PSC.

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NAFLD and NASH

Michael Trauner, M.D. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; [email protected]

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and comprises a disease spectrum ranging from "simple" hepatic steatosis over steatohepatitis (NASH), more advanced liver fibrosis, cirrhosis to hepatocellular cancer (HCC). NAFLD poses multiple clinical management challenges due to the increasing frequency as emerging epidemic affecting already 40–50% of the population in industrialized countries on the one hand and the considerable heterogeneity of adverse clinical outcomes on the other hand not only including complications of liver cirrhosis and HCC, but also extrahepatic manifesta-tions/complications such as cardiovascular and possibly renal disease.

While simple fatty liver can be considered a generally benign condition – at least from a hepatological point of view (still carrying metabolic and cardiovascular risk) – NASH can progress to fibrosis and end-stage liver disease. About 10–40% of patients with NAFLD have or develop NASH and in 7–25% NASH will progress to cirrhosis and its complications over a 10–20 year period. Overall, morbidity and mortality in NASH patients is significantly higher compared with the general population, mainly due to cardiovascular disease and malignancy, followed by liver-related mortality. NASH appears to have a fibrotic potential similar to that of chronic hepatitis C. At the time of initial biopsy, as many as one-third of NASH patients may have advanced bridging fibrosis and 10–15% already have established cirrhosis. Most cases of cryptogenic cirrhosis can now be attributed to NASH; this link may be missed, since steatosis can disappear at this stage ("burnt NASH"). While several possible explanations for this phenomenon such as diversion of insulin and nutrients from the liver as a result of portal hypertension and the general catabolic state in liver cirrhosis have been brought forward, more recent studies suggest that induction of adiponectin by rising serum bile acid levels may be involved. Importantly, diagnosis of coincidental NASH cirrhosis can also be made during elective surgical procedures (e.g. anti-obesity surgery – high risk of NASH/unsuspected cirrhosis) providing a rationale for intra-operative liver biopsy.

Liver failure is the main cause of morbidity and mortality in NASH-associated cirrhosis and occurs in about 40% of cirrhotic cases within 7–10 years. Other causes of death include sepsis, variceal hemorrhage, or HCC. The overall prognosis of NASH cirrhosis is similar to HCV-cirrhosis, with the exception that HCC appears to be less common. A recent study suggests that patients with NASH-cirrhosis and low MELD score (≤ 15) may have a slower disease progression than patients with HCV- cirrhosis, but are less likely to receive liver transplantation and more likely to die or be taken off the waiting list because of their comorbidity. Patients with HCC in the setting of NASH have less severe liver dysfunction and better overall survival after curative treatment compared to HCV or alcohol-related HCC. In line, increasing evi-dence indicates that HCC may complicate already noncirrhotic NAFLD with mild or absent fibrosis (with nearly 50% of HCC occurring in precirrhotic NASH in some

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studies), greatly expanding the population at risk. NASH may account for 10–40% of HCC and in some regions such as UK NASH has already become the leading cause of HCC. Carriage of the genetic adiponutrin (PNPLA3) rs738409 C>G polymorphism is associated with greater risk of progressive NASH, fibrosis and HCC. This suggests that PNPLA3 genotyping may help to identify patients for closer HCC surveillance by ultrasound, especially in precirrhotic NASH. Importantly, metformin or statins may reduce the risk for HCC. Interestingly, emerging evidence suggests that portal hypertension as a result of cellular ballooning and sinusoidal fibrosis may also be encountered in a significant proportion of precirrhotic NASH, although the clinical relevance still remains to be determined.

Therapy aims at preventing progression of liver fibrosis towards cirrhosis and decompensation (complications of cirrhosis. Weight loss and lifestyle modification have been shown to improve NASH before liver cirrhosis has developed. Currently no established d therapy of NASH exists and drug treatment may be focused at the correction of concurrent metabolic disorders (antidiabetic drugs, statins, antihyper-tensive agents); importantly NAFLD/NASH does not increase the risk for hepatotoxicity of these drugs. However, the beneficial effects of insulin sensitizers (metformin, glitazones) on liver histology (in particular fibrosis) have been disappointing and the effectiveness of these drugs in reversing NASH cirrhosis may be doubted. Vitamin E for NASH patients without diabetes seems to be promising, but is currently not recommended for NASH cirrhosis, diabetic patients or NAFLD without liver biopsy. Apart from insulin resistance associated with NASH, diabetes may also complicate cirrhosis in about 30–40%. Almost no pharmakokinetic data are available for sulfonylureas, metformin and glitazones in patients with liver cirrhosis. Saftey concerns also include the risk of hypoglycemia and lactic acidosis (metformin). Only mild changes in the pharmacokinetics of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors have been reported, probably without major clinical relevance, but larger clinical experience is still lacking. Generally these newer compounds appear to be safe and may even improve NASH, but caution should be recommended, especially in patients with advanced cirrhosis.

Metformin. The beneficial effects of metformin on liver histology in NASH have been disappointing. Although a recent meta-analysis confirmed that metformin reduced risk of HCC in diabetic patients, metformin is frequently discontinued once cirrhosis is diagnosed because of concerns about an increased risk of adverse effects. However, a recent study showed that continuation of metformin after cirrhosis diagnosis reduced the risk of death (HCC, other complications of cirrhosis) while no patients developed metformin-associated lactic acidosis. Moreover, metformin inhibits glutaminase activity which may have protective effects against hepatic encephalo-pathy Therefore, metformin may be worthwhile to be continued in diabetic patients with cirrhosis.

Statins are not only safe in NAFLD/NASH but may also be beneficial in chemo-preventing and even slowing the growth of HCC. The pleiotropic actions of statins on endothelial cell function reduce portal pressure, effects which are even additive to beta-blockers.

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Nuclear bile acid receptor (FXR) ligands lower portal pressure by reducing intra-hepatic resistance, their antifibrotic effects and may also have beneficial effects on gut permeability preventing bacterial overgrowth and translocation in animal models. While UDCA is not effective in NASH, FXR ligands currently undergo clinical evaluation for treatment of NASH and portal hypertension. These compounds may target several pathophysiologically relevant events in progression of NASH towards cirrhosis, decompensation and HCC. norUDCA is no ligand for FXR, but may be another promising bile acid-based future therapeutic strategy for NASH.

Simtuzumab is a novel biological targeting Lysyl Oxidase-like 2 (LOXL-2) enzyme cross-linking collagen type 1. It is currently tested in various fibrotic conditions includ-ing NASH and may offer a novel antifibrotic therapeutic strategy.

Bariatric surgery may improve NASH, although it is not recommended as primary treatment of NASH. Patients with more advanced liver disease may be at risk for postoperative decompensation (possibly due to mobilization of lipotoxic fatty acids during postoperative weight loss). Careful preoperative evaluation is mandatory to exclude advanced liver disease.

Liver transplantation. The proportion of patients with NASH undergoing liver transplantation has steadily increased over the recent years and NASH has already become the third most common indication in the US. Importantly, this may still be an underestimation of the proportion of NASH progressing towards end-stage liver disease, since many patients may not be listed for transplantation due to older age and associated comorbidities such as obesity, complications of diabetes, or malignancies. Outcomes for patients undergoing a liver transplant for NASH are as good as those for other indications. However, patients with NASH are more likely to die from cardiovascular complications or sepsis, calling for a more aggressive management after transplantation. Risk factors for NAFLD can persist and may even exacerbate after liver transplantation by immunosuppression. Weight reduction prior to transplantation or bariatric surgery during transplantation may be reasonable strategies to improve patient outcome.

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Hepatitis B

Robert Thimme Department of Medicine, Clinic for Medicine II, University Hospital Freiburg, Germany

With up to 400 million affected people worldwide, chronic hepatitis B virus (HBV) infection is still a major health care problem. In low-prevalence countries (e.g., Western countries), infection occurs mainly by sexual contacts and percutaneously, for example, by needle sharing among injecting drug users. The risk of establishing a persistent, lifelong infection is very high if HBV infection is acquired perinatally (approximately 90%). By contrast, in adults about 90% spontaneously clear the infec-tion and only a minority of patients develops chronic infection. Importantly, however, chronic infection can progress to liver cirrhosis in about one third of chronically infected patients. During the last decade, several novel therapeutic approaches have been developed and evaluated. In most regions of the world, interferon-α IFN-α), and nucleos(t)ide analogues (NUCs) are currently approved. Despite major improvements, none of the existing therapies is optimal since viral clearance is rarely achieved. Clinically, the antiviral therapy should improve the quality of life and survival of chronically HBV infected patients with liver cirrhosis by preventing disease progres-sion to decompensated cirrhosis, end-stage liver disease, HCC, and death. Current therapies aim for a sustained suppression of viral replication that usually results in a reduced histological activity of chronic hepatitis and biochemical remission. Conse-quently, the risk of progression to cirrhosis decreases together with the incidence of HCC in non-cirrhotic and to a lesser extent also in cirrhotic patients. The end point of HBV therapy differs between patient groups. The European Association for the Study of the Liver (EASL) distinguishes between three serological constellations: 1. In HBeAg-positive and HBeAg-negative patients, the ideal end point is sustained

HBsAg loss with or without seroconversion to anti-HBs.2. In HBeAg-positive patients, durable seroconversion to anti-HBe is a satisfactory

end point.3. In HBeAg-positive patients who do not achieve an anti-HBe seroconversion, a

maintained undetectable HBV DNA level on treatment with NUCs or a sustainedundetectable HBV DNA level after IFN-α therapy is the next most desirable endpoint.

In theory, the ideal goal of antiviral therapy for chronically HBV infected patients would be a complete HBV elimination including HBsAg loss and seroconversion to anti-HBs. However, the elimination of viral cccDNA from the nucleus of infected hepatocytes cannot be achieved by any of the currently available drugs. The indica-tion for therapy is based mainly on the combination of the criteria serum HBV DNA levels, ALT levels and histological grade and stage. Clearly, patients with elevated serum ALT levels and/ or active necroinflammation in liver biopsy should be considered for antiviral therapy. Patients with compensated or decompensated cirrhosis have a clear indication for antiviral therapy as long as HBV DNA is detectable in the serum. In Europe and the US, seven drugs are currently approved for the treatment for chronic hepatitis B, namely conventional IFN-α, pegylated IFN-α and the NUCs lamivudine, adefovir, entecavir, telbivudine, and tenofovir.

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Compared with NUCs, the advantage of IFN treatment is a finite duration of treatment, the absence of resistance, and a higher rate of anti-HBe and anti-HBs seroconversion. Disadvantages are the moderate antiviral effect, need of sub-cutaneous injection, and significant side effects. These include, among others influenza-like symptoms (e.g., fatigue, myalgias, and fever), cytopenia, depression, anxiety, irritability, and autoimmune disorders. In addition, IFN increases the risk of sepsis and decompensation in patients with advanced cirrhosis and is therefore contraindicated in patients with decompensated liver cirrhosis. In patients with compensated cirrhosis, however, IFN can be used. NUCs are competitive inhibitors of the HBV polymerase. Since their structure is similar to the natural nucleotides, these agents are integrated in the DNA during viral replication. NUCs are orally administered drugs that have a potent antiviral effect and are usually well tolerated. This is also true in patients with liver cirrhosis. The main drawbacks of these drugs are the indefinite duration of treatment and lower rates of anti-HBe and anti-HBs seroconversion compared to IFN-α. The risk of resistance differs with a low risk for entecavir and tenofovir, a moderate risk for adefovir, and a high risk for lamivudine and telbivudin. Based on these characteristics, most recent guidelines recommend tenofovir and entecavir as NUCs of first choice. Importantly, for both drugs regression of severe fibrosis and even cirrhosis has been shown after long-term treatment.

Many questions, however, remain unanswered on the optimal treatment of patients with liver cirrhosis and chronic hepatitis B with a nucleoside versus IFN-α. Both forms of treatment have benefits and the choice should be selected and tailored. In addition, stopping rules can be implemented in patients who fail interferon.

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Antiviral therapy in patients with hepatitis C virus induced cirrhosis

Fabien Zoulim, Pierre Pradat, François Bailly Hepatology Department, Hospices Civils de Lyon, INSERM Unit 1052 – Cancer Research Center of Lyon (CRCL), Lyon University, France

Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferonα monotherapy in the early 90s to the approval of telaprevir and boceprevir based triple therapies with pegylated interferon-α and ribavirin in 2011, the chances of curing patients infected with HCV genotype 1 have improved dramatically to reach approximately 70%. Significant further improvements, which may cure virtually all hepatitis C patients with an all oral, interferon-free regimen are becoming progressively available.

Historically, Peg-IFN/ribavirin combination therapy of patients with liver cirrhosis was associated with lower virological rates and worse safety profile. The advent of the first protease inhibitor based triple therapy was long expected, but the promise fell rapidly because of the numerous side effects and the requirement for intensive clinical management in cirrhotic patients.

The newer direct acting antivirals (DAAs) target the viral polymerase with either nucleos(t)ide analogues or non-nucleosidic inhibitors, the viral protease, and the viral NS5A protein. Several clinical trials have now shown that a combination of sofosbuvir (nucleosidic polymerase inhibitor) with daclatasvir or ledipasvir (NS5A inhibitors), or sofosbuvir with simeprevir (protease inhibitor), or a combination of ABT-450 (protease inhibitor) with ritonavir (ABT-450/r), the non-nucleoside polymerase inhibitor ABT-333 and the NS5A inhibitor ABT-267, can achieve sustained virologic response in up to 95% of naive patients or previously treated patients, even in patients who failed prior treatment with first generation protease inhibitors. The best treatment regimen allow to achieve comparable results even in cirrhotics, while other regimen still require ribavirin or longer treatment duration to achieve optimal results. This improved risk/benefit ratio justifies early access programs of IFN-free regimen for cirrhotic patients.

The remaining difficult-to-treat patients are cirrhotics infected with HCV genotype 3 and those with decompensated cirrhosis, for whom novel DAA combinations should be evaluated in clinical trials.

As new DAAs are becoming available in early access treatment programs, treatment strategy studies are being performed to optimize treatment regimens with respect to the choice of DAAs and treatment duration, based on viral genotypes, prior treatment exposure, and the presence of liver cirrhosis. This should allow in a near future to: i) decrease the complications of HCV induced cirrhosis, ii) perform liver transplan-tation in virally cured patients, iii) rescue patients in the worst clinical situation (decompensated cirrhosis, HCV recurrence on liver graft).

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List of Chairpersons, Speakers and Scientific Organizers

Juan G. Abraldes M.D. Associate Professor of Medicine Division of Gastroenterology (Liver Unit) University of Alberta 1-51 Zeidler Ledcor Building Edmonton, Alberta T6G-2X8 Canada

Dr. Paolo Angeli Associate Professor of Internal Medicine Department of Medicine University of Padova Via Giustiniani, 2 35128 Padova Italy

Dr. Annalisa Berzigotti Hospital Clinic de Barcelona Liver Unit Villarroel, 170 08036 Barcelona Spain

Prof. Dr. Ulrich Beuers Univ. van Amsterdam, Tytgat Institute for Liver & Intestinal Research Department of Gastroenterology & Hepatology, G4-216 Meibergdreef 9 1105 AZ Amsterdam The Netherlands

Prof. Dr. Jaime Bosch Hospital Clinic de Barcelona Liver Unit Villarroel, 170 08036 Barcelona Spain

Prof. Dr. Jordi Bruix Hospital Clinic de Barcelona Liver Unit Villarroel, 170 08036 Barcelona Spain

Dr. Laurent Castera Hôpital Beaujon Service d‘Hépatologie Université du Général Leclerc 100, Bd. Général Leclerc 92118 Clichy France

Scott L. Friedman, M.D. Professor of Medicine Dean for Therapeutic Discovery Icahn School of Medicine at Mount Sinai Box 1123 1425 Madison Ave. Room 11-70C New York, NY 10029 USA

Prof. Dr. Alexander L. Gerbes Medizinische Klinik II Klinikum der Universität München – Großhadern Marchioninistr. 15 81377 München Germany

Prof. Dr. Pere Ginès Hospital Clinic de Barcelona Liver Unit Villarroel, 170 08036 Barcelona Spain

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Prof. Dr. Burkhard Göke Medizinische Klinik II Klinikum der Universität München – Großhadern Marchioninistr. 15 81377 München Germany

Gregory J. Gores, M.D. Professor of Medicine Division of Gastroenterology & Hepatology Mayo Clinic 200 First Street SW Rochester, MN 55905 USA

Prof. Dr. Dieter Häussinger Klinik für Gastroenterologie, Hepatologie und Infektiologie Universitätsklinikum Düsseldorf Moorenstr. 5 40225 Düsseldorf Germany

Prof. Dr. Rajiv Jalan Liver Failure Group UCL Institute for Liver and Digestive Health UCL Medical School Royal Free Hospital Rowland Hill Street London NW3 2PF Great Britain

Prof. Dr. Vincenzo Mazzaferro GI Surgery and Liver Transplant Unit National Cancer Institute Via Venezian 1 20133 Milan Italy

Prof. Dr. Richard Moreau Hôpital Beaujon Service d‘Hépatologie Université du Général Leclerc 100, Bd. Général Leclerc 92118 Clichy France

Prof. Dr. Massimo Pinzani UCL Insitute for Liver and Digestive Health Royal Free Hospital U3 Pond Street London NW3 2QG Great Britain

Dr. Francesco Salerno Department of Internal Medicine and Hepatology Policlinico IRCCS San Donato University of Milan Via Morandi 30 20097 San Donato Milanese Italy

Prof. Dr. Tilman Sauerbruch Medizinische Klinik I Universitätsklinikum Bonn Sigmund-Freud-Str. 25 53127 Bonn Germany

Dr. Christian Steib Medizinische Klinik II Klinikum der Universität München – Großhadern Marchioninistr. 15 81377 München Germany

Prof. Dr. Robert Thimme Innere Medizin II Universitätsklinikum Freiburg Hugstetter Str. 55 79106 Freiburg Germany

Prof. Dr. Michael Trauner Klinische Abteilung für Gastroenterologie & Hepatologie Medizinische Universität Wien Währinger Gürtel 18–20 1090 Wien Austria

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Prof. Dr. Karin Weißenborn Neurologie Medizinische Hochschule Hannover Carl-Neuberg-Str. 1 30625 Hannover Germany

Prof. Dr. Florence Wong University of Toronto Toronto General Hospital 9N/983 200 Elizabeth Street Toronto, Ontario M5G 2C4 Canada

Prof. Dr. Fabien Zoulim Hepatology Department INSERM U 1052 Lyon University 151, cours Albert Thomas 69003 Lyon France

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POSTER ABSTRACTS

Poster Numbers 1 – 70 (* = Posters of Distinction)

Author Index to Poster Abstracts

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1

Establishment of a cultivation system mimicking tissue stiffness in chronic liver disease

A. Bachmann1, K. Bueringer1, T. Peccerella2, S. Ottinger2, S. Mueller2, J. Rheinlaender3, T.E. Schäffer3, A.K. Nüssler1 1BG Unfallklinik Tübingen, Germany 2University of Heidelberg, Germany 3Institute of Applied Physics, University of Tübingen, Germany

Background: The healthy liver has a stiffness ranging from 3–6 kPa. In chronic liver disease the extracellular matrix increases tissue stiffness and changes the biotrans-formation capacity. To investigate the concatenation between these processes we developed a polyacrylamide-based extracellular matrix (PAA) with a defined stiffness of 3.5 kPa (healthy liver), 8.2 kPa (fibrosis stage F0/F1) and 24 kPa (cirrhotic liver). For a comparison with standard cultivation conditions we included the 2D cultivation which is currently the gold standard for primary human hepatocytes (pHH).

Methods: The stiffness of the PAA gels was validated with atomic force microscopy. In a first step the survival of pHH onto these gels was investigated with a life-dead staining, resazurin conversion and AST/LDH measurement. To evaluate hepatocyte function and biotransformation capacity we measured transporter activity, glucose and urea production. In addition to monitor cell morphology we performed immuno-fluorescence staining with ZO-1, F-actin and Hoechst.

Results: Measurement of the resazurin conversion revealed that cultivation of hepatocytes on matrices with different stiffness was well tolerated and cell damage could not be detected (LDH, AST). However, morphological evaluation of hepato-cytes showed alterations with increasing matrix stiffness like accumulation of stress fibers and changes in the localization of ZO1. On PAA gels corresponding to healthy liver (3.5 kPa) ZO1 was localized at the bile canaliculi while with increasing matrix stiffness it dislocated to the cell-cell boarders. In addition, pHHs on PAA gels had higher transporter activity (MRP-1, MDR-1) than under 2D conditions. Interestingly we could not observe any differences in the capability of glycolysis and gluconeo-genesis, while detoxification of urea was higher on PAA gels.

Conclusions: Our first morphological tests and analysis of the biotransformation capacity indicate that our PAA gels deliver an environment for the pHH closer to the tissue in vivo properties than the existing gold standard.

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2

Lactulose alone vs. lactulose and rifaximin for the prophylaxis of overt hepatic encephalopathy in acute variceal hemorrhage

Mircea Alexandru Badea, Otilia Nedelciuc, Andreea Blaj, Cucos Alexandru, Ungureanu Irina, Catalina Mihai, Cristina Cijevschi Prelipcean Institute of Gastroenterology and Hepatology, “St. Spiridon Hospital” Iasi, Romania University of Medicine and Pharmacy Grigore T. Popa, Iasi, Romania

Introduction: Acute variceal hemorrhage (AVH) is known to precipitate the development of overt hepatic encephalopathy (OHE). Although lactulose and rifaximin are key therapeutic agents used for the treatment of hepatic encephalo-pathy there is little data about the role of lactulose and rifaximin for the prevention of OHE after AVH. Our aim was to determine the efficacy of lactulose and rifaximin versus lactulose alone for the prevention of OHE after AVH.

Methods: In this prospective case-control study we enrolled 84 cirrhotic patients with AVH. Subjects were divided into two equal groups (n = 42) with similar age, gender, liver disease and variceal bleed characteristics. Group 1 (Gp-1) received lactulose alone and Group 2 (Gp-2) lactulose and rifaximin. All patients received standard AVH treatment according to Baveno 5 guidelines. The primary end-point was the develop-ment of OHE in the first 120 hours after study enrollment.

Results: A total of 18 patients (21.4%) developed OHE: 12 patients (28.5%) in Gp-1 and 4 patients (9.5%) in Gp-2. (p = 0.04). The median time period until development of OHE was 55 hours and the median grade of OHE was 2 (ranging from 1 to 4). Higher baseline model for end stage liver disease score (19.1 ± 4.2 vs. 15.9 ± 4.5 p = 0.03), Child-Pugh score (9.9 ± 1.3 vs. 9.1 ± 1.5, p = 0.05), serum creatinine (1.9 ± 1.8 vs. 1.1 ± 1.5, p = 0.02), total bilirubin (2.8 ± 1.4 vs. 1.6 ± 1.7 mg/dl, p = 0.01) and venous amonia level (105.3 ± 19.8 vs. 92.1 ± 17.5 µmol/l, p = 0.007) were observed in patients who developed OHE as compared to patients who did not developed OHE. 12 patients (15.4%) died: 7 patients in Gp-1 (16.6%) and 5 patients (11.9%) in Gp-2.

Discussion/Conclusion: Lactulose and rifaximin is superior to lactulose alone for the prevention of OHE in cirrhotic patients with AVH.

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3

Pentoxifylline for the secondary prophylaxis of overt hepatic encephalopathy: A pilot study

Mircea Alexandru Badea, Mihaela Dranga, Otilia Nedelciuc, Andreea Blaj, Cucos Alexandru, Ungureanu Irina, Catalina Mihai, Cristina Cijevschi Prelipcean Institute of Gastroenterology and Hepatology, “St. Spiridon Hospital” Iasi, Romania University of Medicine and Pharmacy Grigore T. Popa, Iasi, Romania

Introduction: Inflammation plays a substantial role in the development and exacer-bations of hepatic encephalopathy. Pentoxifylline reduces inflammation and innate immunity by inhibiting TNF-alpha and leukotrienes. The aim of this study was to determine whether pentoxifylline has a benefic role in the secondary prevention of overt hepatic encephalopathy (OHE).

Methods: We performed a prospective case-control study which included 128 cirrhotic patients who recovered from an episode of OHE. Subjects were divided into two equal groups (n = 64), with similar age, gender, social and disease characteristics. The first group received rifaximin alone 1200 mg/day (R-G) and the second group received rifaximin 1200 mg/day plus pentoxifylline 800 mg/day (RP-G) for three months. The primary end-point was the development of OHE during this period.

Results: A total of 23 patients suffered a breakthrough episode of hepatic ence-phalopathy as it follows: 16 patients in the R-G and 7 patients in the RP-G (p = 0.04). OHE developed predominantly in patients with viral cirrhosis (n = 6) as compared with alcoholic cirrhosis (n = 1), in the RP-G (p < 0.1). The number of patients with OHE exacerbations increased with aggravating Child Pugh score: class A (n = 3), class B (n = 6) and class C (n = 14).

Discussion/Conclusion: Pentoxifylline may be effective for secondary prophylaxis of OHE in patients with cirrhosis. A more pronounced effect was noticed in subjects with alcoholic etiology of the liver disease.

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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 Firat University, Faculty of Medicine, Division of Gastroenterology, Elazig, Turkey

Aim/background: In this study we aimed to examine the features of non-alcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis cases and to associate with each other. Also the patients grouped by their histopathological features. The clinical and laboratory findings compared between the patient groups.

Methods: We worked to explain the signs and which features starting cirrhotic progression. 71 patients were examined which have followed up in Fırat University Hospital Gastroenterology Clinic, 37 of these were have NAFLD and 34 of these were have cryptogenic liver cirrhosis. In these patients hepatic function tests, hepatitis markers, autoantibodies, Body mass ındex (BMI), waist circumference, lipid parameters, ferritin, fasting blood glucose, HbA1c, HOMA-IR and hepatic histo-pathology commented.

Results: The mean age of cryptogenic cirrhosis patient group have found significantly higher (p = 0.034). While the diabetic patient ratio was 27% in NAFLD group, the ratio was 50% in cryptogenic cirrhosis patient group. (p = 0.04). In crypto-genic cirrhosis group prothrombine time, bilirubins and fasting blood glucose was significantly high. (in order p = 0.0001, p = 0.005, p = 0.008). But albumin was determined as low. (p = 0.0001). The insulin resistance measured by using HOMA-IR index. In NAFLD group, mean HOMA-IR index was found 2.48 ± 1.81 (n = 30) and in cryptogenic cirrhosis group 7.2 ± 9.04 (n = 29). When the patient in NAFLD group compared with their grade and stage, mean ALT value was significantly high in grade 2–3 patients. There was no significantly difference in BMI, waist circumference, lipid parameters and hypertension prevalence commented. Histopathological examina-tions of the patients with cryptogenic cirrhosis are showed such features which can be also seen in non-alcoholic steatohepatitis pericellular fibrosis (n = 10), perivenular fibrosis (n = 4), perisinusoidal fibrosis (n = 3), steatosis (n = 9), lobular inflammation (n = 8), hepatocellular ballooning (n = 13), wide lipogranuloma (n = 3), giant mitochondria (n = 2), Mallory bodies (n = 5) and glycogene nucleus (n = 6).

Conclusıon: As a result NAFLD and cryptogenic cirrhosis is overlapping and in association with each other, such as metabolic syndrome criteria like diabetes mellitus, obesity, hypertension and hyperlipidemia. Some cases with cryptogenic cirrhosis have histopathological findings that can be seen in NAFLD even in the cirrhotic stage. İn this cirrhotic progression, DM and insulin resistance is seems to be the most important factor. Similar metabolic and histopathologic findings supports significant proportion of the patients with cryptogenic cirrhosis depends on the NAFLD.

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5

Upper digestive haemorrhage – Complication of the liver cirrhosis

Bataga Simona, Imola Torok, Melania Macarie, Anca Negovan, Ana-Maria Botianu, Marius Ciorba, Hunor Farcas, Mariana Tilinca University of Medicine and Pharmacy Tirgu-Mures, Romania

Introduction: Liver cirrhosis of all etiologies is still one of the major emergencies in a Gastroenterology Clinic. One of the most important complications of the liver cirrhosis is the upper digestive haemorrhage. From the first February 2013 in our 1200 beds hospital an endoscopy unit has been established for 24 hours emergencies. The purpose of the paper is to follow-up the number of digestive haemorrhages on a year, and to follow-up the liver cirrhosis haemorrhages.

Methods: A retrospective study has been done to follow-up the upper and lower endoscopies done in emergency in one year. Endoscopies were made in 1275 patients, and in 575 (45.1%) patients active haemorrhage was diagnosed

Results: From the 575 patients with digestive haemorrhages, in 428 (33.57%) was found upper digestive haemorrhage and in 147 lower digestive haemorrhage (11.53%). From the patients with upper digestive haemorrhage 194 were at patients with liver cirrhosis (45.33%). From these patients, in 131 (67.53%) bleeding was from esophageal varices and 63 (32.47%) was non-variceal. Mean age of the patients was 62.3 years, 61% being men. 54% of the patients with liver cirrhosis were alcoholic, 43% viral and the rest 3% other etiologies. In patients with esophageal varices 121 (92.36%) have bleeding just from these and band ligation was made. In 10 (7.63%) patients gastric varices were present, the bleeding was hard to stop, 5 patients needed surgery, and 3 patients died.

Discussion/Conclusion: Haemorrhage from varices is still an important complica-tion of the liver cirrhosis. Band ligation is important to be made in emergency. The haemorrhage from the gastric varices is more difficult to manage, and mortality is higher.

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6

Re-estimation of prevalence of HCV infection in Mongolia

Bekhbold Dashtseren1, Bayarmagnai Bold1, Naranjargal Dashdorj2, Baatarkhuu Oidov, Dahgwahdorj Yagaanbuyant1 1Department of Infecious Disease, Mongolian National University of Medical Sciences (MNUMS), 2Onom Foundation, Ulaanbaatar, Mongolia

There is well known that viral hepatitis infection is endemic in Mongolia.

Purpose of study: To assess a tendency of prevalence changing of HCV infection in Mongolian adults aged more 20 years old.

Method and Subjects: The design of this study was cross-sectional. The samples randomly selected from 8 somons of 340 somons of Mongolia and 8 horoo of 117 horoo from Ulaanbaatar City. From each somons and horoo 70–80 subjects were randomly selected. Totally 1158 subject (aged 20–70) were included, 659 of them were female. All participants on-site tested for anti-HCV using rapid tests (CTK Biotech, San-Diego, USA). Also, 5–10 ml of blood was drawn. After back in labo-ratory, all serum re-tested for anti-HCV by ELISA and HCV-RNA.

Results and Discussion: In serum of 128 (11.1%) subjects tested positive for anti-HCV. There was compared the results with data obtained us in 2003 (table).

Year Age group 20–29 30–39 40–49 50–59 ≥ 60 Total 2003 n 332 225 223 210 172 1158

anti-HCV + (n/%) 7/2,11 6/2.66 15/6.73 40/19.05 57/33.14 125/10.79 2013 n 218 273 182 107 43 823

anti-HCV + (n/%) 31/14.2 45/16.5 57/31.3 41/38.3 23/53.5 197/23.94

For more precise estimation of prevalence of HCV infection there was calculated by direct standardization. In 2003, in Mongolia lived approximately 290,000 subjects aged more 20 years old, with anti-HCV and 200,000 (15.6%) subjects with HCV infection. Then, after 10 years or 2013, in Mongolia living aged more 20 years old 174,000 subjects with anti-HCV and 122,000 (10.0%) subjects with HCV infection.

Conclusion: Prevalence of HCV infection among the Mongolian population (aged more 20 years old) is high, but it decreased during 10 years from 15.6% to 10.0%. Prevalence significantly increases by age.

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7

Evaluation of liver function by NRL972-elimination during peginterferon/RBV therapy in patients with CHC

Y. Boyanova1; K. Antonov1, A. Aleksiev1, D. Jelev1, L. Mateva1, Z. Krastev1, C. de Mey2 1Clinic of Gastroenterology, St Ivan Rilski University Hospital, Sofia, Bulgaria 2ACPS – Applied Clinical Pharmacology Services, Mainz-Kastel, Germany

Introduction: Fluorescein Lisicol (NRL972) is a fluorescent-labelled bile salt with hepatic biliary excretion without entero-hepatic recycling or biotransformation. Its plasma concentration ratio 30/10 minutes after a 2 mg NRL972 bolus injection (CR = C(30):C(10)) is an investigational marker of hepatic biliary transporter function. The aim of study was to evaluate NRL972-CR in CHC-patients treated with PegIFN/RBV.

Methods: 98 CHC patients received 12-month PegIFN/RBV therapy with further 6-month post-treatment follow-up.

Results: For 10 patients viral response could not be evaluated; in 16 patients it could not be assessed whether response was maintained. In 41 there was sustained viral response (SVR), in 31 it was not (nSVR). In SVR, CR slightly improved on-treatment from baseline (median CR: 0.33; range: 0.19–0.63) to month-12 (median CR: 0.30; range: 0.14–0.58); distinct improvement was seen 6 months after treatment (median CR: 0.25; range: 0.10–0.47). In nSVR-patients, median CR improved from baseline (median CR: 0.43; range: 0.23–0.80) to month-12 (median CR: 0.38; range: 0.14–0.77); this improvement was sustained up to 6 months after treatment (median CR: 0.39; range: 0.21–0.77). At month-6 post-therapy, 11/41 SVR-patients and 9/31 nSVR-patients had a CR-improvement of at least 0.10 from pretreatment baseline; in contrast there was worsening in CR by at least 0.10 in only 2/41 SVR- and 2/31 nSVR-patients.

Discussion/Conclusion: The goal of viral eradication is to improve liver function. PegIFN/RBV treatment appears to achieve this even in patients who fail to achieve sustained response. The effect was most evident 6-months post-therapy.

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8

Clinical characteristics and outcomes of patients with alcoholic acute hepatitis and cirrhosis hospitalized in Emergency Hospital Bucharest

Camelia Chioncel, Adelina Popescu, Amjed Shihab, Andrei Moldovan Clinical Emergency Hospital Bucharest, Bulgaria

Alcohol related liver diseases are among the most common liver diseases. Alcoholic hepatitis carries a far worse prognosis with a high associated mortality.

Introduction: Maddrey score over 32 identifies patients with severe alcoholic hepatitis who have a 30-day mortality rate higher than 30%.

Methods: We studied patients admitted in the first 4 months of 2014 in Gastro-enterology Unit of Emergency Clinical Hospital Bucharest and we found from 1040 patients 100 alcoholics, and 55 of them had alcoholic acute hepatitis. Some of patients had also cirrhosis. 76.92% of patients were men and 23.07% women, 53.84% lived in a town and 46.15% at countryside. All the patients had an over 10 years’ alcohol intake of 40–400 g pure alcohol daily. All the patients had jaundice, abdominal pain, tender hepatomegaly, tachycardia some of them had hepatic encephalopathy and some also developed alcoholic sevrage. They received induction cortisonic therapy (after checking for infections), followed by decreasing corticotherapy, antibiotherapy, pentoxifylline, PPI, supplement of caloric intake if necessary, to obtain jaundice regression and blood tests normalization.

Results: We found that induction time was longer for noncirrhotics than for cirrhotics, but the treatment was longer for cirrhotics (due to complications of cirrhosis during corticotherapy-such as variceal/ulcer bleeding, spontaneous bacterial peritonitis, encephalopathy). Average Maddrey score showed that cirrhotics need a lower score to acute alcoholic hepatitis than non-cirrhotics. Also the mortality was higher for cirrhotics.

Discussion/Conclusion: Our conclusions were that corticoids reduce very well the inflammatory response of alcoholic hepatitis but ultimately, prognosis of alcoholic liver disease depends on abstinence from alcohol.

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9

HCV infection and alcohol-metabolizing enzyme gene poly-morphism in alcoholic liver cirrhosis among Polish individuals

Halina Cichoż-Lach, Emilia Lis, Agnieszka Kowalik, Krzysztof Celiński, Beata Kasztelan-Szczerbińska Department of Gastroenterology Medical University in Lublin, Poland

Introduction: Infection with hepatitis C virus (HCV) has been proposed as one of the co-factors which contribute to the development of liver disease in individuals chronically abusing alcohol. HCV infection increases a risk of development of alcoholic liver disease and causes a serious course of disease. The epidemiological studies show that the frequency of HCV infection in patients with alcoholic liver cirrhosis reaches 40%. The aim of the study was to evaluate in the Polish population the frequency of HCV infection in patients with alcoholic liver cirrhosis and study the relationship between HCV infection and the alcohol dehydrogenase (ADH1B, ADH1C), CYP2E1 and aldehyde dehydrogenase 2 (ALDH2) genetic polymorphisms.

Methods: 116 patients with alcoholic liver cirrhosis participated in this study. HCV infection was diagnosed based on presence of antibodies to HCV-related antigen (using the first generation test kit) in all patients and in 6 cases HCV-RNA genomes were detected using the RT-PCR method. Genotyping of the ADH, ALDH2 and CYP2E1 was performed using RT-PCR method on white cell DNA.

Results: HCV infection was present in 24.1% of patients with alcoholic liver cirrhosis. HCV infection was found to be significantly more frequent in patients with ADH1C*1/*1 and ADH1B*1/*1 genotypes compared to the participants with ADH1C*1/*2, ADH1C*2/*2 and ADH1B*1/*2 genotypes, and was 34.6% and 25.0% respectively. The differences in the frequency of HCV infection between patients with CYP2E1*1/*1 and CYP2E1*1/*2 genotypes were not statistically significant. In none examined patients homozygotic ADH1B*2/*2 and CYP2E1*2/*2 genotypes were detected. All examined patients were ALDH2*1/*1 homozygotic.

Discussion/Conclusion: Our studies suggest that in the Polish population examined the frequency of HCV infection was 24.1% in patients with alcoholic liver cirrhosis. ADH1C*1/*1 and ADH1B*1/*1 genotypes favored the infection due to HCV. Genetic polymorphism of CYP2E1 and ALDH2 shows no correlation with HCV infection in patients with alcoholic liver cirrhosis.

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10

Azathioprine-induced liver injury in inflammatory bowel disease patients

Cucos Alexandru, Andreea Blaj, Irina Ungureanu, Catalina Mihai, Cristina Cijevschi Prelipcean University of Medicine and Pharmacy Grigore T. Popa, Iasi, Romania “St. Spiridon” Hospital, Institute of Gastroenterology and Hepatology Iasi, Romania

Introduction: The aim of the study was to evaluate the incidence of abnormal liver test (LTs) or hepatotoxicity in a group of inflammatory bowel disease (IBD) patients and, specifically, to assess the incidence of azathioprine (AZA)-induced liver injury in a follow-up study.

Methods: All IBD patients followed for at least 1 year were included in this retrospective study. LTs including alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyl transferase, and bilirubin were periodically monitored. "Abnormality-of-LTs" was defined as LTs between N (upper limit of the normal range) and 2 N, and "liver injury/hepatotoxicity" as LTs > 2 N.

Results: A total of 176 patients were included and 65 received AZA; 24 patients and 7 presented abnormality of LTs or hepatotoxicity, respectively, during follow-up. 15 of 24 patients with abnormal LTs received AZA and 3 of 7 patients with hepato-toxicity were AZA treated. The most frequent explanation for abnormal LTs or hepatotoxicity was AZA treatment (18 patients). Most patients (13) spontaneously normalized LTs despite maintaining AZA. These drugs were withdrawn due to hepatotoxicity (LTs > 5 N and lack of decrease despite 50% dose reduction) in 10% of the patients and all of them normalized LTs. 3 patients (15%) normalized LTs after 50% dose reduction.

Discussion/Conclusion: In IBD patients, AZA treatment induces abnormality of LTs in a relatively high proportion of the cases, but the development of true hepato-toxicity/liver injury is exceptional. Moreover, most of the cases of thiopurine-induced hepatotoxicity in IBD patients are mild, and the abnormalities in LTs spontaneously return to normal values despite AZA being maintained, therapy withdrawal being necessary in only approximately 10% of the patients.

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11

The correlation between liver cirrhosis and biliary lithiasis

Cucos Alexandru, Irina Ungureanu, Andreea Blaj, Catalina Mihai, Cristina Cijevschi Prelipcean University of Medicine and Pharmacy Grigore T. Popa, Iasi, Romania “St. Spiridon” Hospital, Institute of Gastroenterology and Hepatology, Iasi, Romania

Introduction: Liver cirrhosis is considered to be a risk factor for biliary lithiasis (BL). The pathogenic factors involved in BL in cirrhotic patients are vesicular wall fibrosis (witch leads to decreased gallbladder motility), biliary tract infections, chronic hemo-lytic status, conjugated bilirubin deficiency (due to hepatic lesions). The aim of the study was to evaluate the correlation between BL and cirrhosis.

Methods: The study group included 96 cirrhotic patients hospitalized in the Institute of Gastroenterology and Hepatology Iasi, during 1 January 2013 until 31 December 2013 (46 with compensated cirrhosis and 50 with decompensated cirrhosis). BL was diagnosed with ultrasound scan.

Results: The middle age of the patients was 47 years old. 51 were man and 45 women BL was present in 23 patients. 31% of the female cirrhotics presented biliary lithiasis, compared to 17% of the male cirrhotics. BL was revealed in only 8 out of 42 patients aged under 55 (19%) and in 15 out of 54 patients aged over 55 (27%). Out of the 23 cirrhotic patients with BL 34% were aged under 55 years old and 66% over 55 years old. Only 5 out of 46 patients with compensated cirrhosis had BL and 18 out of 50 patients with decompensated cirrhosis were diagnosed with BL. 21% of the patients presenting BL were compensated cirrhotics, while 79% of the cases represented decompensated cirrhotics.

Discussion/Conclusion: The percentage of BL was higher in female cirrhotics. BL was more frequent in patients over 55 years old. Decompensated liver cirrhosis was more frequently assessed with BL, compared to compensated cirrhosis.

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12

Presepsin as an indicator of infection in patients with liver cirrhosis

Cucos Alexandru, Irina Ungureanu, Andreea Blaj, Catalina Mihai, Cristina Cijevschi Prelipcean University of Medicine and Pharmacy Grigore T. Popa, Iasi, Romania “St. Spiridon” Hospital, Institute of Gastroenterology and Hepatology Iasi, Romania

Introduction: Sensitive biomarkers are required for early diagnosis of infection in patients with liver cirrhosis. Soluble CD14 subtype (sCD14-ST), also known as presepsin, is a novel and promising biomarker that has been shown to increase significantly in patients with infection. The aim of the study was to determine the diagnostic accuracy of presepsin measurement for bacterial infections in patients with liver cirrhosis of all causes.

Methods: A total of 86 patients were enrolled in this study, 41 patients with decompensated cirrhosis (DC), 45 with compensated cirrhosis (CC). Presepsin was measured in serum of all patients. Clinical data was gathered by reviewing the patients' medical charts. I considered a high presepsin level over 500 pg/ml.

Results: 40 patients had documented infection. 29 (72%) with DC and 11 (28%) with CC. SBP and spontaneous bacteraemia occurred in 16 patients (40%), urinary tract infections (UTI) represented 14 of patients (35%) with 85% women. Lower respiratory tract infections and pneumonia represent 12.5% of patients. 5 patients had skin and soft tissue infections (12.5%). Presepsin levels were higher in cirrhotic patients with bacterial infection – 35 out of 40 patients (87.5%), than those without infection (3 out of 46 patients = 6.5%). All 29 patients with DC and infection had high level presepsin, and 9 out of 11 (81%) with CC and infection. High presepsin levels had 15 out of 16 patients with SBP (94%), 12 out of 14 patients with UTI (85%), 4 out of 5 patients with respiratory tract infection(80%) and 2 out 5 patiens with skin and soft tissue infection(40%).

Conclusion: Presepsin provided satisfactory diagnostic accuracy in differentiating bacterial infections in patients with all causes of liver cirrhosis. Presepsin on its own is a sensitive test for the presence of bacterial infections in cirrhosis (decompensated or compensated).

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13*

Pro-apoptotic and anti-proliferative mechanisms downstream of c-MET of the kinase inhibitor tivantinib (ARQ 197)

Enrico N. De Toni1, Shuai Lu1, Antonia Rizzani1, Frank T. Kolligs1, Eike Gallmeier1, Sabrina Arena2, Burkhard Göke1, Alexander L. Gerbes1 1Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Marchioninistr. 15, 81377 Munich, Germany 2Department of Oncology, IRCC, Institute for Cancer Research and Treatment and University of Torino, Candiolo, Italy

Objective: Tivantinib is a c-MET inhibitor which demonstrated clinical benefit as a second-line treatment of hepatocellular carcinoma (HCC). Since its efficacy in this study was predicted by elevated expression of c-MET, a phase-3 trial of tivantinib has been initiated to recruit c-MET-high patients only. However, recent evidence showed that the anticancer activity of tivantinib is not determined by its capability to inhibit c-MET suggesting that c-MET is a response predictor of this agent rather than its actual target. In spite of extensive clinical investigation, the mechanisms of action of tivantinb still remain to be elucidated.

Design and Results: We thus assessed the mechanisms underlying the anticancer properties of tivantinib. Tivantinib causes apoptosis and cell cycle arrest by inhibiting the anti-apoptotic molecules Mcl-1, Bcl-xl and by increasing the expression of Cyclin B1. These changes occurred independently of c-MET. However, we found that tivantinib might antagonize the antiapoptotic effects of c-MET activation since stimulation of c-MET by its ligand HGF enhanced the expression of Mcl-1 and Bcl-x1.

Conclusions: We confirm previous reports showing that the activity of tivantinib is independent of c-MET and describe for the first time Mcl-1, Bcl-xl and Cyclin B1 as effectors of its antineoplastic effects in HCC cells. We suggest that these molecules are considered as possible and potentially more reliable response predictors. Since c-MET activation increases the expression of Mcl-1 and Bcl-xl, we suggest that the predictive effect of c-MET expression at least in part reflects the c-MET-driven overexpression of these molecules in in c-MET-high patients.

Correspondence to: PD Dr. Enrico De Toni, Medizinische Klinik und Poliklinik 2, Klinikum Großhadern, Forschungslabor B - 5 E01, Raum 308, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 München, Germany Telephone: +49 (0)89-7095-3178. E-Mail: [email protected]

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Identification of patients with chronic active hepatitis in a population of HBsaA inactive carriers through prospective follow-up with transient elastography and quantitative HBsAg assay

Marco Delle Monache, Roberto Cecere, Chiara Francia Liver & Infectious Diseases Unit, ASL RMG, Colleferro (Rome), Italy

Introduction: Liver biopsy is currently not recommended in inactive hepatitis B carriers. Non-invasive methods could be an alternative in this setting. The aim of this prospective study was to evaluate the usefulness of transient elastography (FibroScan®) and some common biochemical markers of fibrosis, individual or combined into algorithms (AST/ALT, PLT, APRI, Forns Index, FIB4) for excluding significant fibrosis in putative inactive HBsAg carriers. Furthermore we investigated the correlation of viral load and quantitative HBsAg with liver stiffness.

Methods: This spontaneous, observational study involves an Outpatients Liver Unit from Central Italy equipped with FibroScan® (Echosens, Paris): Liver and Infectious Diseases Unit of ASL RMG, Colleferro (Rome). Inclusion criteria were: persistent HBsAg for at least 12 months, persistently normal ALT levels (determined monthly for 6 months at entry and every 6 months after), HBV DNA < 2000 IU/ml for at least 3 years. We prospectively evaluated, from March 2011 to May 2014, 104 inactive HBsAg carriers. In all subjects, liver stiffness was measured by an experienced operator by executing at least 10 valid measurements. We excluded patients for whom the Success Rate of liver stiffness measurements was < 60% and with an Inter Quartile Range > 30%. Liver histology, when obtained, was evaluated for necro-inflammation and fibrosis according to Ishak scores. HBV DNA will be determined by Real Time PCR (Cobas® Taqman® 48 Roche Molecular Diagnostics) and quantitative HBsAg was detected through Elecsys Quant® HBsAg II assay Roche.

Results: One-hundred and four patients have been enrolled, 59 male, the mean age was 49 ± 13, HBV DNA was persistently < 2000 IU/ml in 78/104, but 25/104 carriers at the moment of the elastometry showed an episodic bleep of viral load: between 2000 and 20,000 IU/ml in 22, and > 20,000 IU/ml in 3. Mean Liver Stiffness (LS) was 5.9±1.8 Kpa, 17 pts (16.3%) had LS > 7.5 (cut-off for significant fibrosis).The LS was not statistically different between pts with HBV DNA levels < 2000 IU/ml and those with HBV DNA > 2000 IU/ml (5.5 ± 2 vs 6 ± 1.8). Follow-up: All patients were followed up to 24–36 months; in those with HBV DNA > 2000 ≤ 20,000 and/or a LS > 4.3 KPa, HBV DNA levels were determined every 6 months. In pts either with LS > 7.5 KPa or HBV DNA > 20,000 IU/ml or with a significant increase in LS during follow up (> 1.5 KPa), levels of HBsAg were measured with a quantitative assay (18/104). Twenty-five pts had HBV DNA > 2000 IU/ml, 72 pts had LS > 4.3 KPa and 19 pts had both parameters. Thirteen pts showed HBsAg levels > 1000 IU/ml at baseline or during the follow-up, while 7/104 (6.7%) had toghether LS > 7.5 KPa, HBV DNA > 2000 IU/ml and HBsAg > 1000 IU/ml. In these pts was performed liver biopsy that revealed an Ishak score ≥ 3 in all cases, therefore an antiviral therapy was begun.

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Discussion/Conclusion: This study demonstrates that HBsAg inactive carriers are characterized by a low grade of liver fibrosis, as revealed by Fibroscan, slightly higher than that of normal population, and the routinely application of this technique during the follow up of pts can be helpful to discriminate cases with a value > 7.5 Kpa in whom a closer determination of HBV DNA/HBsAg levels can identify “false” inactive carriers, with an active liver disease, that, when confirmed by liver histology, requires an antiviral therapy.

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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 State Institution “Institute of Gastroenterology of National Academy of Medical Sciences of Ukraine", Dnipropetrovsk, Ukraine

Immune reactivity is considered to play the significant role in development liver cirrhosis in patients with hepatitis C. The aim was to study of some immune markers and serum indices to figure out of their quantitative differences in patients with hepatitis C virus with and without liver cirrhosis.

Materials and Methods: Cell populations, such as CD3, CD19, CD4, CD8, and CD16, were determined by using monoclonal antibodies. Circulating immune complex (CIC) was studied by V. Haskova method. Assessment of matrix metalloproteinase 1 (MMP-1), tissue inhibitor of metallo-proteinase 1 (TIMP), transforming growth factor beta (TGF-β), interleukin-6 (IL-6), and interleukin-10 (IL-10) levels measured by using immune enzyme-linked kits.

Results: 41 patients with hepatitis C virus and 30 healthy people were studied and included into control group. All patients were divided into 2 groups: without liver cirrhosis (group 1, n = 16) and without ones (group 2, n = 25). It was established that patients of both group had decrease of T-lymphocytes compared with control group (р1 < 0.001, р2 < 0.001), including СD3, СD4, СD8, and СD4/СD8 ratio. At the same time the CIC was 1.5 times significantly higher in group 2 than in group 1 (р < 0.05). The significant decrease of IL-10 and simultaneous increase of IL-6 in group 2 compared with control group can to testify about essential immune disorders. Significant reduction of MMP-1 in groups 1 and 2 compared with control (р1 < 0.05, р2 < 0.001) was revealed. TIMP-1 almost didn’t differ from norm: 677.7 ± 134.2 and 544.8 ± 95.8 ng/ml, consequently, versus control group (528 ± 51.42 ng/ml). At the same time, MMP-1/TIMP-1 ratio was almost in 2 times lower in group 1 and 3.7 times lower in group 2 comparing with control people. TGF-β was significantly increased in patietns of both groups, especially in group 2. Thus, the more expressed changes were revealed in patients with hepatitis C virus with liver cirrhosis than without one.

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The challenging diagnosis of minimal hepatic encephalopathy: Does Critical Flicker Frequency correlate to the Psychometric Hepatic Encephalopathy Score?

Audrey Dillon, Zita Galvin, Damien Lowry, Stephen Stewart Centre for Liver Disease, Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland

Introduction: The early diagnosis and treatment of minimal hepatic encephalopathy (MHE) has been associated with improved quality of life and driving ability. Despite this, the presence of MHE is not yet routinely tested for in everyday clinical practice. The Psychometric Hepatic Encephalopathy Score (PHES) is considered by International Society of Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) to be the test of choice in diagnosis of MHE. We aim to compare Critical Flicker Frequency (CFF) to PHES in the diagnosis of MHE. We also aim to calculate an optimal CFF threshold in our population. There is no internationally validated CFF threshold, but a recent meta-analysis proposed a threshold of 38 or 39 Hz.

Methods: A prospective cohort study began enrolment in July 2012 and 132 patients with compensated cirrhosis have been enrolled. Patients with overt neuropsychiatric disturbance, or any clinical sign of decompensation were excluded. CFF was determined using the portable Lafayette model 12021. Following a practice run, flicker frequency was determined as a mean of 10 attempts. PHES was performed using pen-and-paper and results compared to United Kingdom normative data. A score of 2 or more standard deviations below the mean diagnosed MHE. Statistical analysis was performed using SPSS v22.

Results: 115 same day CFF-PHES pairs were recorded in 90 patients. All patients with more than 1 test were tested at at least 6 month intervals. All patients had Child Pugh Score < 9. 23/115 (20%) patients had MHE by PHES. The median CFF was 54.09 (13.53–67.72) Hz. Using a threshold of 39 Hz, 85/115 (73.4%) patients had MHE; using a threshold of 38 Hz, 78/115 (67.8%) had MHE. There was no correlation between raw PHES and CFF results (Spearman rho = 0.128, p = 0.171). There was also no correlation between those with and without MHE by PHES and CFF with mean CFF in those with MHE 33.7 Hz, and those without, 36.6 Hz (ANOVA, p = 0.11). The area under the ROC curve for CFF to detect MHE as detected by PHES was 0.644 (p = 0.033). Sensitivity and Specificity of CFF to detect MHE at the threshold of 38Hz are 83% and 29%, and at threshold of 39 Hz, 83% and 36%, respectively. An optimum threshold of 34 Hz in our population was chosen from the point on the ROC curve that maximised sensitivity and specificity (65%, 65%). Using this threshold, 48/115 (41.7%) of patients had MHE.

Discussion/Conclusion: CFF does not correlate to the PHES score. It is therefore not suitable as a replacement for PHES in the diagnosis of MHE. It may reflect other neuropsychological defects and may have a role as an adjunct to PHES in clinical practice.

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Nonalcoholic fatty liver disease (NAFLD) proven by transient elastography in patients with coronary heart disease

Dragan-Teicu Alina – CMI Dr Dragan, Dragan-Teicu Emil, Tudora Adriana – Medlife Genesys Hospital, Arad, Romania

Introduction: Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in developed counties. Assessment of the degree of fibrosis, in patients with liver steatosis is important for the clinical outcome of the patient, both from the point of view of the progression to cirrhosis and developing comorbidities such as cardiovascular diseases. Therefore, non-invasive tests were developed in order to provide useful information to discriminate NAFLD from NASH, quantifying the degree of liver fibrosis. LSMs using transient elastograpy (TE) have intrinsic limitation of subcutaneous adipose tissue making the method difficult to perform in obese subjects. We aimed to identify a correlation between the liver involvement in patients presenting NAFLD and cardiovascular comorbidities (mainly coronary heart disease).

Methods: We studied 68 patients with NAFLD and coronary heart disease proven at coronarography: 19 women (27.9%) and 49 men (72.1%), mean age 45.1 ± 4 years. In all patients LSMs by TE was performed.

Results: Mean value of LSMs was 11.32 ± 2.91kPa (vs. 4.8 ± 1.3kPa in normal subjects). 24 (36.2%) cases were F0, 14 (21.1%) F1, the remaining 30 (42.7%) patients presented significant fibrosis (F ≥ 2). The LSMs of patients with F0 (36.2% of patients), F1 (21.1%), F2, F3, and F4 disease were 5.3 ± 0.9, 6.47 ± 1.4, 7.8 ± 1.2, 11.41 ± 2.5, and 25.98 ± 8.55 kPa, respectively (p < 0.0001 by analysis of variance). Patients with F3 and F4 disease had significantly higher LSM than those with less fibrosis. When we studied the influence of the degree of liver fibrosis and steatosis expressed as liver stiffness on the degree of CHD (a single or multiple vessels involved), we found that patients with multiple vessels involved had higher LSM values (p < 0.0001).

Discussion/Conclusion: The routinely noninvasive assessment of liver injury (NAFLD) in patients with CHD might be important, a significant percentage of patients with multiple vessel involvement being classified in our case having severe fibrosis F ≥ 3 (p <  0.0001).

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Significance of minimal hepatic encephalopathy in HQRL in patients with liver cirrhosis

Dragan-Teicu Emil – Medlife Genesys Hospital Arad, Dragan-Teicu Alina – CMI Dr Dragan-Teicu, Tudora Adriana – Medlife Genesys Hospital, Arad, Romania

Introduction: The aim of this study was to investigate the presence of minimal hepatic encephalopathy (MHE) and the impairment in HRQL

Methods: We studied 77 consecutive patients with LC from 3 private outpatient departments (47.5% women, 52.5% males) and 50 healthy volunteers (mean age 53.37 ± 5.4 years. Subjects from both the control group and LC group underwent PHES evaluation. HRQL in patients with LC was assessed using the standard Chronic Liver Disease Questionnaire (CLDQ) consisting of 6 scales scores for abdominal symptoms, fatigue, systemic symptoms, activity, emotional function and worry.

Results: Mean age and education years for cirrhotic patients was 63.5 ± 2.1 and 11 ± 4 years, respectively, and for healthy subjects 44.45 ± 10.1 and 10.1 ± 3.8 years respectively (in neither of these groups PHES was not correlated with education years (p = 0.74) or age (p = 0.67) and there were no differences between men and women (p = 0.69). Acording to Child-Pugh classification (CPC) 44 (56.4%) patients were CPC-A, 27 (35.18%) were CPC-B, and only 6 (7.4%) as CPC-C. In all, PHES was -0.48 ± 2.93, and MHE was identified in 41 (53.7%) patients. Average CLDQ score was 5.3 (abdominal symptoms: 5.5, fatigue: 4.5, systemic symptoms: 5.2, activity: 4.7, emotional function: 5.5, W: 4.8). When compared to a general population sample, all domains of health-related quality of life were reduced in CLD, mainly in witch concerns fatigue (p = 0.005), systemic symptoms (p = 0.005) and the activity (p = 0.004). MHE cirrhotic patients presented an impaired HRQL, compared to non-MHE patients (6.2 ± 1.3 vs. 4.4 ± 2.1, p < 0.001).Severe dysfunctions (higher scores) were identified mainly for activity score (5.2 ± 1.25 vs. 4.2 ± 0.15, p < 0.01), systemic symptoms (5.7 ± 2.01 vs. 4.7 ± 0.82, p < 0.001) and emotional functioning score (6.4 ± 2.51 vs. 5.5 ± 0.73). In addition, patients in CPC-C had a worse QOL vs. those in CPC-A or CPC-B (3.9 ± 0.25, 4.7 ± 1.7, and 6.8 ± 1.6, respectively, p < 0.01).

Discussion/Conclusion: Cirrhotic patients are at high risk for developing MHE, in relation with the degree of liver function. In our study, the group with decompemsated LC (B or C) had a higher proportion of MHE (61% vs. 39%, p = 0.007) and thus a HRQL impairement. PHES is a simple tool in assessing MHE.

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Immunocompromised, experienced chronic hepatitis B patients have slow response to tenofovir dipivoxil therapy

Marcin Dręczewski1, Piotr Stalke1, Katarzyna Sikorska1, Magda Rybicka2, Krzysztof Piotr Bielawski2, Tomasz Smiatacz1

1Department of Infectious Diseases, Medical University of Gdansk, ul. Smoluchowskiego 18, 80-214 Gdansk, Poland 2Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, ul. Kladki 24, 80-822 Gdansk, Poland

Introduction: Hepatitis B virus (HBV) infection affecting about 2 billion people worldwide is still a global health problem. The effect of antiviral therapy is difficult to predict and the patients achieve it after a varied time of therapy. Unfortunately, some National Health Service reimburses the costs of antiviral therapy only when HBV DNA is undetectable after 12 months of therapy. The aim of this study was to analyze the influence of past or active immuno-suppression on the efficiency of antiviral therapy in chronic HBV infected patients.

Methods: 45 consecutive HBV infected patients (33 male; 12 female) were qualified to tenofovir dipivoxil (TDF) therapy in 2012–2013, accordingly to Polish National Health Service (NFZ) recommendation. Patients were switched to TDF because of unsuccessful lamivudine or entecavir therapy. The concentration of HBV DNA and ALT activity were analyzed at week 0, 12, 24 and 48. Patients were divided into two groups: immunocompromised (active or past immunosuppression, chemotherapy, bone marrow transplantation) and immunologically healthy. The therapy was continued after week 48 if viral load was undetectable (NFZ recommendation).

Results: Only patients after chemotherapy have significantly higher prevalence HBeAg (p = 0.043) than a control group. Age and sex distribution, liver fibrosis and inflammation, baseline ALT activity and viral load were similar. Viral load at week 48 was significantly higher in the immunocompromised patients (p = 0.03). After 48 weeks therapy viral load decreased in immunocompromised and healthy patients near 4 log versus 7 log respectively. Undetectable HBV DNA at week 48 was not significantly more frequent in healthy (43%) versus immunocompromised (27%) patients. Seroconversion of HBsAg and HBeAg was not observed.

Discussion/Conclusion: Immunocompromised patients have slower response to TDF than healthy subjects. Undetectable viral load at week 48 should not be used as a marker of the lack of response, because all patients reached significantly drop of viral load.

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Evaluation of serum fibrinogen levels as a non-invasive tool to detect the cardiac ascites

A.C. Dülger1, E. Gönüllü2, E. Aytemiz3 1Yuzuncuyil University School of Medicine, Division of Gastroenterology, Van, Turkey 2Yuzuncuyil University School of Medicine, Division of Hepatology, Van, Turkey 3Training and Research Hospital of Anesthesiology and Reanimation, State Hospital Division of Internal Medicine, Gaziantep-Nizip, Turkey

Introduction: The most common hepatic causes of ascites are cirrhosis, severe ethanol-related hepatitis and thrombosis of hepatic vascular tracts. Cardiac ascites is developed mostly due to heart failure as well as constrictive pericarditis. In both cases, serum-ascites albumin gradient (SAAG) will be more than 1.1 mg/dL. However, differentiation between cirrhotic ascites and that secondary to cardiac causes including advanced heart failure can be difficult in most patients. We therefore examined the differention between cirrhotic ascites and cardiac ascites.

Aims and Methods: In this prospective study, laboratory features in the period between January 2009 and May 2014 were studied in patients with high gradient ascites due to both cardiac failure and viral hepatitis-related cirrhosis. In this time scale the cases were composed of 25 females and 35 males. There were 20 patients (mean age: 60.55 ± 12.85; 10 female) with cardiac ascites and were 40 patients (mean age: 56.55 ± 16.93; 15 female) with viral hepatitis related-cirrhotic ascites. Cardiac failure was diagnosed using echocardiography and cardiologic examination.

In viral hepatitis group, 27 patients had HBV, 7 had HDV and 6 had HCV. Serum fibrinogen levels and ascitic fluid analysis were performed for each patient.

Results: Mean ascitic albumin levels in cardiac ascites group were higher than cirrhotic group (1.16 ± 0.4 vs. 0.48 ± 0.36, p < 0.001). The mean SAAG was 2.13 ± 0.49 in cirrhotic group, and was 1.95 ± 0.52 in cardiac group. The mean serum fibrinogen level in cardiac ascites group was significantly higher than cirrhotic group (333.45 ± 175.34 mg/dl vs. 206.85 ± 113.92 mg/dl; p < 0.001).

Conclusion: Serum fibrinogen levels were significantly higher in cardiac ascites group as compared to cirrhotic group. At to date, there is no medical report about relationship between cardiac ascites and serum fibrinogen levels. Our results suggest for the first time that the admission serum levels of fibrinogen may be used as a non-invasive diagnostic marker among patients with cardiac failure-related ascites.

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Heme oxygenase-1/carbon monoxide system and blood viscosity in patients with hepatitis C virus-related cirrhosis: Relation to renal function and hemodynamics

Hayam A. El Aggan1, Mohamed I. Reda2, Mohamed M. Rizk3 Departments of Medicine1, Radiodiagnosis2 and Clinical Pathology3, Faculty of Medicine, University of Alexandria, Egypt

Introduction: Heme oxygenase-1 (HO-1) is a microsomal enzyme that has hemodynamic effects and may play a role in the pathogenesis of renal diseases. The present work was designed to study the plasma levels of HO-1 and its product carbon monoxide (CO) in patients with hepatitis C virus (HCV)-related cirrhosis in relation to renal function and hemodynamics.

Methods: Thirty patients with HCV-related cirrhosis and 15 healthy subjects were included in the study. The severity of liver disease was assessed using Child-Pugh and Model for End-Stage Liver Disease (MELD) scores. Renal function was evaluated by serum creatinine (sCr) level, estimated glomerular filtration rate (eGFR) and urine sodium concentration (UNa). Plasma HO-1 levels were measured using commercially available enzyme-linked immunosorbent assay. Blood carboxyhemo-globin (COHB) concentration, an index of CO production, was assayed by spectrophotometry. Blood viscosity was measured using viscometer. Renal hemodynamics including renal artery peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MnV), resistive index (RI), pulsatility index (PI) and renal blood flow (RBF) were measured using Doppler ultrasonography. Wall shear stress in the renal artery was calculated on the basis of arterial diameter, center-line velocity waveform and blood viscosity.

Results: Plasma HO-1 levels, blood COHB concentration and blood viscosity were significantly higher in patients with HCV-related cirrhosis than in healthy subjects (P < 0.001) and in patients with ascites than in the non-ascitics (P < 0.0001). The increases in plasma HO-1 levels and blood COHB concentration showed positive correlations with Child-Pugh and MELD scores, blood viscosity, sCr and renal artery RI, PI and wall shear stress and negative correlations with eGFR, UNa concentration, RBF and renal artery EDV and MnV (P < 0.05).

Discussion/Conclusion: The increased HO-1 activity with enhanced endogenous CO generation may play an important role in the development of renal dysfunction in HCV-related cirrhosis and could be a potential therapeutic target.

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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

Hoda El Aggan1, Myriam Helmy2, Nevine El Deeb3, Ahmed Zeid1, Mohamed Fawzy1 Departments of Medicine (Hepatobiliary Unit)1, Clinical Pathology2 and Pathology3, Faculty of Medicine, University of Alexandria, Alexandria, Egypt

Introduction: Chemokines have recently been implicated in inflammation-associated cancinogenesis. The present work was designed to study the role of macrophage inflammatory protein-1 alpha/CC chemokine ligand 3 (MIP-1alpha/CCL3), a potent macrophage chemoattractant, in the pathogenesis of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) in relation to tumor progression and angiogenesis.

Methods: Thirty patients with HCV-related cirrhosis (15 patients with HCC and 15 patients without HCC) and 15 healthy subjects were enrolled in the study. Serum MIP-1alpha/CCL3 levels were measured using enzyme-linked immunosorbent assay and its sensitivity and specificity in the diagnosis of HCC was determined by plotting receiver-operating characteristic curve. Histological tumor grading was evaluated and the surrounding cirrhotic liver tissue was examined to assess histological activity grade and steatosis grade. Expressions of MIP-1alpha/CCL3, CD68 (for tumor-associated macrophages [TAM]) and CD105 (for determination of microvessel density [MVD]) were studied in HCC and surrounding cirrhotic liver tissue by immunohistochemistry.

Results: Serum MIP-1alpha/CCL3 levels were significantly higher in cirrhotic patients with and without HCC than in healthy subjects and in HCC patients than in patients without HCC (P < 0.001). The sensitivity and specificity of serum MIP-1alpha/CCL3 in the diagnosis of HCC were 100% and 93.3% respectively at a cut-off value of 17.5 pg/ml. HCV-related HCCs showed significant increases in MIP-1alpha/CCL3 expression, TAM count and MVD compared with surrounding cirrhotic liver tissues (P < 0.001). The MIP-1alpha/CCL3 expression in HCCs showed positive correlations with serum MIP-1alpha/CCL3 levels, tumor size, stage and histological grade and intratumoral TAM count and MVD. Also, TAM count was directly correlated with MVD in HCCs (P < 0.05).

Discussion/Conclusion: MIP-1alpha/CCL3 plays an important role in the develop-ment and progression of HCC in patients with HCV-related cirrhosis, possibly, through migration of macrophages to tumor microenvironment and enhancement of angiogenesis. MIP-1alpha/CCL3 may also serve as a potential serum biological marker and a useful therapeutic target for HCC.

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Transjugular intrahepatic portosystemic shunt (TIPS) in the therapy of refractory ascites: 20 years single-centre experience

T. Fejfar1, V. Safka2, V. Jirkovsky1, T. Vanásek1, S. Sembera1, M. Lojík3, J. Raupach3, V. Chovanec3, O. Renc3, A. Michl3, J. Zizka3, A. Krajina3, P. Hulek1,4 12nd Department of Internal Medicine and Gastroenterology, University Hospital Hradec Kralove, Czech Republic 2Department of Physiology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic 3Department of Radiology, University Hospital Hradec Kralove, Czech Republic 4Department of Internal Medicine, Faculty of Medicine, University of Ostrava, Czech Republic

Introduction: Refractory ascites is one of the most severe complications of portal hypertension and is associated with high mortality. When ascites becomes refractory, liver transplantation, large volume paracentesis with albumin substitution or non-surgical portocaval shunt creation – transjugular intrahepatic portosystemic shunt, are the treatment options. The role of TIPS is still discussed.

Aim: To assess outcome of patients treated by TIPS for refractory ascites retrospectively in one centre.

Methods: From January 1992 to February 2014, 361 patients (66% of men, mean age 56 years) underwent TIPS for refractory ascites. By Child-Pugh and MELD score were classified (61% B and 39% C, MELD and Na-MELD 16 and 20, respectively).The most common reason of liver cirrhosis was alcohol abuse (63%). The effect on ascites at one month and total survival were analysed.

Results: TIPS were placed in 99% cases successfully. No mortality due to procedure was noted. Mean portosystemic gradient was reduced from 21 mmHg to 8 mmHg (60% reduction). Mean follow up was 23.2 months. In 78% patients the treatment response without need of other paracentesis was noted (in this group in 14% the recurrence of ascites was noted because of TIPS stenosis and by PTA resolved successfully). In 19% of patients effect couldn´t be assessed because of death up to one month (11.3%) or because of loss of follow-up. Only in 3% of patients no effect was noted. Survival at one, three, six and twelve months was 88.7%, 76%, 68.5% and 56.8%. Cumulative survival at 24 months by Kaplan-Meyer was 48%. Cumulative survival was better predicted by MELD than Child-Pugh score (p < 0.001, p = 0.08, LogRank test)

Conclusion: TIPS is highly effective in the treatment of refractory ascites in patients suffering from liver cirrhosis and has become a part of routine clinical practice.

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Sarcopenia and osteopenia in alcoholic liver cirrhosis

O. Gavrilescu, M. Dranga, A. Blaj, C. Cijevschi Prelipcean University of Medicine and Pharmacy Grigore T. Popa, Iasi, Romania ”St. Spiridon” Hospital, Iasi, Romania

Background: Patients with liver cirrhosis are prone to sarcopenia and osteopenia. Sarcopenia represents the loss of muscle mass and strength, and is considered as well as osteopenia secondary to malnutrition. The aim of the study was to determine the prevalence of sarcopenia and osteopenia in alcoholic liver cirrhosis patients and its relationship.

Methods: We included 58 cases with alcoholic liver cirrhosis (33 female/35 male; median age of 50 years ± 15; body mass index [BMI] 20.36 ± 3.6) and 30 healthy volunteers (15 female/15 male; median age 50 years ± 15; BMI 23.2 ± 2.7). Sarcopenia was assessed by handgrip strength (estimate muscle strength) and dual-energy x-ray absorptiometry (DXA) (estimate lean body mass) and defined as a skeletal muscle index (SMI) below 5.45 kg/m2 for women and 7.26 kg/m2 for men. Osteopenia was defined as a T-score for bone mineral density (BMD) below -1.0 measured by DXA.

Results: We found sarcopenia in 56.2% of liver cirrhosis and osteopenia in 47.9% vs. 15% and 5% of controls, respectively (P < 0.01). Well as BMD was significantly lower in patients with alcoholic liver cirrhosis than in controls (35 kg ± 5 vs. 50 kg ± 10; 5,9 kg/m2 ± 1,2 vs. 6,4 kg/m2 ± 1,5; -1,7 g/cm2 ± 0,6 vs. 0,9 g/cm2 ± 0,3; P < 0.01). Sarcopenic patients had significantly (P < 0.01) lower BMI (19.64 vs. 21.9) than non-sarcopenic patients; 74% of sarcopenic patients were also osteopenic.

Conclusions: Sarcopenia and osteopenia is a common complication of liver cirrhosis. Screening for sarcopenia and osteopenia may play an important role in the evaluation of liver cirrhosis patients.

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Oral glucose tolerance test and C-reactive protein in nonalcoholic fatty liver disease

O. Gavrilescu, I. Ungureanu, A. Blaj, C. Cijevschi Prelipcean, C. Mihai University of Medicine and Pharmacy Grigore T. Popa, Iasi, Romania ”St. Spiridon” Hospital, Iasi, Romania

Non-alcoholic fatty liver disease (NAFLD) is a clinical term that includes simple fatty liver (SFL) and non-alcoholic steatohepatitis (NASH), ultimately leading to cirrhosis, hepatocellular carcinoma and end-stage liver failure. Insulin resistance plays a central role in the pathogenesis of NAFLD, regarded as the hepatic feature of the metabolic syndrome. Subclinical inflammation has been suggested as a possible connective mechanism between glycoregulation disorders and NAFLD.

Aim: To evaluate the subclinical inflammation and glycoregulation disorders in patients with ultrasonographical and FibroMAX diagnosed NAFLD.

Material and Methods: Sixty-four patients with ultrasonographical and FibroMAX diagnosed NAFLD were enrolled in a prospective study. Thirty-six (56.2%) patients with NAFLD had an alanine aminotransferase (ALT) level of > 40 IU/mL were considered to have NASH, 28 (43.7%) patients presented normal liver function test results and were considered to have SFL. The control group was represented by 70 healthy subjects without ultrasonographical NAFLD diagnosis. Fasting glucose, oral glucose tolerance test (OGTT) and C-reactive protein (CRP) levels were performed for each patient. Statistical analysis was based on student t-test and chi-square test.

Results: The prevalence of glycoregulation disorders (fasting glucose and OGTT) was significantly higher in patients with NAFLD comparing to control group (p < 0.05), respectively in patients with NASH compared to SFL group. Medium CRP levels were higher in patients with NAFLD as compared to the control group (0.68 mg/dL vs. 0.34 mg/dL, respectively; P < 0.05). Patients with SFL presented lower CRP levels compared to NASH group.

Conclusions: NAFLD is at risk for developing glycoregulation disorders compared with controls. CRP level is associated with an increase liver injury and can be used as a non-invasive marker for NAFLD.

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The role of serum endotoxin in the mechanisms of evolution of nonalcoholic fatty liver disease

N. Geyvandova, A. Yagoda, G. Babasheva, Z. Nigiyan Department of Hospital Therapy, Stavropol State Medical University, Russia

Introduction: The aim of the study was to determine the clinical significance of serum levels of endotoxin (ET), TNF-α and endothelin-1 (E-1) in patients with nonalcoholic fatty liver disease (NAFLD).

Methods: 140 patients with NAFLD were examined. All patients were divided into 2 groups: group I (n = 88) consisted of patients with hepatic steatosis, group II (n = 52) of patients with nonalcoholic steatohepatitis (NASH). In 9 patients of group IIdefined fibrosis grade 4 (liver cirrhosis, LC). The content of ET was determined by chromogenic method Hbt LAL, E-1, and TNF-α levels in the blood were studied by ELISA.

Results: In group I of patients content of endotoxin did not exceed the normal values (0.87 ± 0.19 and 0.28 ± 0.08 U/ml respectively; р = 0.26). In group II of patients blood values of ET were higher than in healthy volunteers (2.27 ± 0.65 U/ml; р = 0,001) and than in patients of group I. The maximum value of the ET noted in liver cirrhosis – 3.05 ± 0.97 U/ml. Level E-1 in the group I was normal, and with NASH exceeded the appropriate parameters of healthy volunteers and patients with hepatic steatosis – 0.78 ± 0.12 fmol/ml. TNF-α levels were elevated in all patients with most prominent values in group II, reaching maximum values in LC. There was a positive correlation between ET and TNF-α in patients with NASH (rs = 0.352), and between parameters of ET and E-1 (rs = 0.294). In the group I we did not find any one of the above correlations.

Discussion/Conclusion: In patients with NAFLD evolution of steatosis in steatohepatitis and further in liver cirrhosis is accompanied by an increase in degree of endotoxinemia. In NASH increase of endotoxin in blood leads to an increase of TNF-α, and it may be associated with endothelial dysfunction.

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27*

High frequency of HLA class I antigen processing machinery (APM) component up-regulation in primary hepatocellular carcinoma tumors

Fabio Grizzi, PhD1, Barbara Franceschini, BSc1, Sonia Di Biccari, BSc1, Paola Bossi, MD1, Maurizio Chiriva-Internati, PhD2, Soldano Ferrone, MD, PhD3 1Humanitas Clinical and Research Center, Rozzano, Milan, Italy 2Texas Tech University Health Science Center Medical School, Lubbock, TX, USA 3Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Malignant transformation of cells is associated with down-regulation of HLA class I APM components in most of the tumors. These defects are clinically relevant, since they are frequently associated with the clinical course of the disease. Only in a few tumors malignancy is associated with the up-regulation of HLA class I antigens. Among them is hepatocellular carcinoma (HCC). The frequency of HLA class I APM component up-regulation and its clinical significance in HCC are not known. These topics were investigated in the present study, since the resulting information may contribute to assess the therapeutic efficacy of T cell-based immunotherapy for the treatment of HCC. Twenty-one surgically resected primary HCC tumors and autologous adjacent non-malignant tissues were stained with a unique panel of monoclonal antibodies which recognize HLA class I APM components. The staining patterns of the malignant tumors were compared to those of the autologous non-malignant tissues. To assess the functional significance of changes in HLA class I APM component expression in HCC tumors, the results of immunohistochemical staining were correlated with the extent of CD8+ cytotoxic T-lymphocyte infiltrate, quantified with a computer-aided image analysis system. In all the HCC tumors, malignant hepatocytes expressed high levels of HLA class I APM components. In contrast these molecules were not detected in normal hepatocytes, although they displayed a low expression in some apparently normal hepatocytes adjacent to the HCC tumor. The HLA class I APM component up-regulation in HCC was associated with the extent of CD8+ T cell infiltrate, although this association did not reach the level of statistical significance. Our results corroborate the information in the literature about the lack of HLA class I antigen expression in hepatocytes. Furthermore our study shows for the first time that APM components are also not detectable in normal hepatocytes. Lastly our study shows that HLA class I APM component up-regulation is very frequent in HCC. Its association with T-cell infiltrate, although not statistically significant, is compatible with the possibility that HCC cells are recognized by CD8+ T lymphocytes. If so, HCC should represent an attractive target to apply T cell-based immunotherapy.

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How useful are non-targeted liver biopsies in todays clinical practice?

Mathis Heydtmann1, Aisling Bradley1 and Karin Oien2 1Department of Gastroenterology, RAH Paisley, Corsebar Road, Paisley, PA2 9PN, Scotland, UK 2Department of Pathology, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TF, Scotland, UK

Introduction: With advancing diagnostic tools liver biopsy is performed less frequently in many clinical scenarios. Treatment decisions often don't depend on histology but on less invasive tests such as virology and liver stiffness measure-ments. Here the practice of a clinical hepatologist was reviewed with regards to diagnostic yield and usefulness for management decisions.

Methods: The electronic and paper casenotes of all patients who underwent a non-targeted liver biopsy under a single hepatologist (MH) in a District General Hospital within the last 2 years were reviewed with regards to pre- and post- biopsy diagnoses as well as quality of the biopsy samples.

Results: 17 non-targeted liver biopsies were performed (13 female, 76%). Average patient age was 52 years (range: 21–82). 7 patients were thought to be cirrhotic on clinical grounds. There were 2 adverse events (1 muscle biopsy and 1 patient with pain). The average biopsy length was 18 mm (range: 1–60 mm) with a low number of portal tracts in 3 (5 or less). Indications for liver biopsy were unclarity/overlap of diagnoses of parenchymal liver disease (16 patients) or a significant treatment decision (possible stop of immunosuppressants in 1 patient). On review of pre- and post-biopsy diagnosis the biopsy led to a significant change in diagnosis in 6 patients, the severity of liver disease was changed by the biopsy in 6 patients (4 worse, 2 improvement). The diagnosis was merely confirmed in 2 patients and in 1 patient there was no useful diagnostic information due to small sample size.

Discussion/Conclusion: In a busy hepatological practice with over 1000 patients with chronic liver disease non-targeted liver biopsies were done in very selected cases. Main indications include diagnostic uncertainties and overlap disease rather than disease severity. In our practice biopsies were done in rarer hepatological conditions but less frequently in viral liver disease. Nodular regenerative hyperplasia was found in 2 patients with unexplained portal hypertension and clinical management was changed in most cases but in 1 biopsy sample the yield was too low for diagnosis and 1 patient had pain as a complication of biopsy. Improvements with regards to procedure safety and sample size need to be considered.

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Cardiovascular risk factors in nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Raya Ivanova1, Radina Ivanova2, Assen Alexiev2, Lyudmila Mateva2 1Clinic of Cardiology, Alexandrovska University Hospital, 2Clinic of Gastroenterology, St. Ivan Rilsky University Hospital, Medical University, Sofia, Bulgaria

Introduction: In last years the relationship between nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases has been investigated intensively. The aim of this study was to evaluate the cardiometabolic risk factors and carotid intima-media thickness (c-IMT), a marker of subclinical atherosclerosis, in patients with primary NAFLD without known cardiovascular disease.

Methods: A total of 403 NAFLD patients (n = 141 with histological diagnosis: nonalcoholic steatosis – 21 and nonalcoholic steatohepatitis/NASH – 120) and 241 healthy controls (HC) without steatosis were investigated. The cardiovascular risk (CVR) was assessed by evaluation of metabolic syndrome and its components, lipids, lipoprotein (a), oral glucose tolerance test (OGTT), insulin and others. Carotid Doppler ultrasound was done (NAFLD-80, HC-40).

Results: In NAFLD there were more often and more severe changes in all cardiometabolic risk factors (obesity, metabolic syndrome, arterial hypertension, dyslipidemia, prediabetes and diabetes) compared to HC (p = 0.0001). NAFLD was closely related with insulin resistance (82%) and abdominal obesity (91%). We found no differences in the frequency and the levels of most metabolic parameters in comparison of young and middle aged patients. Obesity and type 2 diabetes mellitus led only to quantitative differences in some of CVR factors. Increased Lp(a) was found in 24% in NAFLD group. GGT changes showed the strongest relationship with atherogenic dyslipidemia and glucose disturbances, followed by AST. Histological degrees of steatosis and activity, and also fibrosis stage were related with profound metabolic changes. Increased c-IMT was observed in 73% of NAFLD patients and showed correlation with cholesterol, triglycerides and LDL-cholesterol values, but no relation with the presence of hypertension, obesity, diabetes.

Disccusion/Conclusion: NAFLD is a condition with increased cardiovascular risk, especially in cases with severe steatosis and advanced morphological changes. All patients with NAFLD are needed of early cardiovascular risk evaluation and aggressive treatment of underlying CVR factors.

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Hepatic fibrosis in patients with hydatidosis in the liver

K. Kalinova, G. Stoyanov*, M. Gulubova, Y. Ananiev, K. Georgiev General and Pediatric Surgery, Thracian University, Medical Faculty, Stara Zagora, Bulgaria *Medical University, Sofia, Bulgaria

Introduction: Fibrosis is part of a dynamic process associated with the continuous deposition and resorption of extracellular matrix, mainly fibrillar collagen. This retrospective study summarizes our 20-year experience in a number of debatable topics, concerning the surgical treatment of liver hydatidosis and status before and after treatment with scolicidal agents in ruptured hydatid liver cysts.

Methods: We performed a retrospective clinical study for a period of 20 years. Two-hundred-two patients had been admitted to hospital and underwent surgical treatment for hepatic echinococcosis during that period. One-hundred were males (48%) and 102 (52%) females. The age of the patients included in the retrospective study varies between 5 and 80 years (mean age 40.1 ± 7.9). In 19 patients we found multiple echinococcosis of the liver (2–8 cysts). The right hepatic lobe is three times more frequently engaged than the left one. Combined echinococcosis is found in 14 patients. We use histological investigation for liver tissue before treated with antiscolicidal agents the cysts and after this for proving effect of this agents on rupturated cysts with biliary tree.

Results: Systematic histological studies over operated patients and in experiment on white infantile mouse have revealed very serious liver alterations, when affected by echinococcosis. Alterations advance with disease progress and lead to cytological alterations in the organ in significant percent of the patients. Echinococcosis is accepted as etiological factor for cirrhosis, role for activated hepatic stellate cells in hydatidosis as well as demonstrating that antigens are able to regulate this trans-differentiation process. Caustic sclerosing cholangitis in the liver with complicated hydatidosis has an earlier onset of symptoms and a more rapidly progressive nature than primary sclerosing cholangitis by toxin in the water of cysts. In foresight, serum alkaline phosphatase should be monitored and, when raised, a retrograde endoscopic cholangiogram and/or a liver biopsy should be performed.

Discussion/Conclusion: Study of the hepatic stellate cell and its interaction with parasite-derived antigens may be pivotal in our understanding of the pathology associated with echinococcosis, as well as revealing new information on the trans-differentiation process in this cell type. Early diagnosis and surgical treatment is recommended for prevention of development of cirrhosis and irreversible changes in the organ. Intensification of the prophylactic measures among population for reducing of morbidity is also recommended.

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Prediction of liver cirrhosis with biochemical markers in patients with Wilson disease. Fibrotest and SOS FS

Kosseva O, Kaneti E, Krastev Z, Petkova T, Dimitrova N, Dragneva S Gastroenterology Clinic, University Hospital "St. Ivan Rilski", Sofia, Bulgaria

Introduction: There is no data about the predictive value of noninvasive serum fibrotic markers in patients with Wilson disease.

Aim: 1. To determine the diagnostic utility of Fibrotest and SOS FS as predictor of cirrhosis in patients with Wilson disease. Proposed by us SOS FS (SOfia Simple Fibrotic Score) representing the difference between the levels of alpha2-macroglobulin and haptoglobin was validated as noninvasive fibrotic markers in patients with HBV and HCV liver diseases 2. To investigate if there is difference between serum levels of transaminases and fibrotic biochemical markers between patients with Wilson disease and HCV with same fibrotic stage

Methods: Routine liver function tests and serum levels of alpha2-macroglobulin, haptoglobin, apolipoprotein A1, ceruloplasmin and IgG (measured by immuno-turbidimetry) were compared between 10 cirrhotic patients with Wilson disease, confirmed by genetic analysis and 16 HCV patients with histological proven cirrhosis. Nonparametric statistic methods were used.

Results: Alpha2-macroglobulin, haptoglobin and apolipoprotein A1 did not show significant difference between the groups. Significantly higher were the mean ranks of ALT, AST, GGT, total bilirubin, coeruloplasmin and IgG in HCV-group vs. Wilson. In the all 10 patients with Wilson disease Fibrotest and SOS FS correctly predict cirrhosis.

Discussion/Conclusion: Non-invasive tests based on biochemical markers – hapto-globin, apolipoprotein and alpha2-macroglobulin validated in viral hepatitis could be useful to predict cooper overload related fibrosis. Further investigations are needed.

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Non-invasive predictors of esophageal varices in liver cirrhosis

Bledar Kraja1,2, Anisa Dhana3, Adriana Babameto1, Nerida Dhigoi1, Indrit Këlliçi1, Skerdi Prifti1 1University Clinic of Gastrohepatology, University Hospital Center Mother Theresa, Tirana, Albania 2Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands 3University Clinic of Family Medicine, University Hospital Center Mother Theresa, Tirana, Albania

Introduction: Predicting the presence of esophageal varices (EV) through non-invasive markers may reduce considerably the number of avoidable endoscopies. Our aim was to assess the non-invasive markers that could predict the presence of EV.

Methods: Our prospective study included all consecutive patients newly diagnosed with liver cirrhosis without variceal bleeding, hospitalized at our clinic during 2009–2012. Model for End-Stage Liver Disease (MELD), AST to platelet ratio index (APRI), platelet count to spleen diameter (PC/SD) and AST-to-ALT ratio (AST/ALT) were calculated for each patient. The diagnostic performance of these markers for the absence or presence of EV was evaluated by sensitivity and specificity and area under the curve (AUC).

Results: A total of 139 patients (109 men [mean age: 51.5] and 39 women [mean age: 51.3] were studied. The etiology of cirrhosis among all patients were: alcohol (48%), viral (22%), and other (30%). One hundred and thirteen patients (81%) had EV; of whom, 44 (39%) had small varices, 39 (35%) had medium varices and 30 (26%) had large varices. APRI (cut-off = 1.53), MELD (cut-off = 15) and PC/SD (cut-off = 1167) were good predictors for the presence of EV (AUC 0.652, 0.639 and 0.638, respectively). In contrast, AST/ALT (cut-off = 1.66) was poor predictor AUC 0.56 for presence of EV. Compared to APRI and MELD, PC/SD had the highest sensitivity (69%), specificity (69%) and negative predictive value (91%). However, the positive predicted value (34%) of PC/SD was the lowest.

Discussion/Conclusion: Our findings shown that APRI, MELD and PC/SD may become a first line tools to screen the presence of esophageal varices in cirrhotic patients. However, none of these non-invasive markers can replace the upper endoscopy for diagnoses of the esophageal varices.

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A national Wilson’s disease registry for Scotland

Dr Neil Lachlan, Hepatology Registrar, University of Edinburgh & Royal Infirmary of Edinburgh, Scotland, UK Dr Stewart Campbell, Consultant Gastroenterologist, Hairmyres Hospital, Scotland, UK Dr Andrew Duncan, Department of Biochemistry, Glasgow Royal Infirmary, Scotland, UK

Introduction: The care of patients with rare diseases such as Wilson’s disease (WD) can be improved by the use of disease registries, because these allow case identification, standardisation of diagnosis and treatment, and epidemiological assessment. WD was last assessed in Scotland 23 years ago, 33 cases were identified and a number of patients had incomplete follow-up.

Methods: Under the auspices of the Scottish Society of Gastroenterology, a national registry is being established for Scotland (population 5.2 million). WD is being identified using ehealth and laboratory computer records, and communication with Consultant Gastroenterologists. The initial pilot within Lanarkshire health board (population 560,000) is complete.

Results: 6 WD cases identified within Lanarkshire. 3 were asymptomatic, 2 had complications of cirrhosis and 1 had neuro-psychiatric disturbance. All initially received penicillamine, 1 with additional zinc, 2 were subsequently changed to trientine. 2 were clinically well under regular follow-up though 1 of them had developed abnormal liver biochemistry in conjunction with poor compliance. 3 were lost to follow-up. 1 developed neurological disability due to initial non-compliance but then a copper deficiency myelopathy and subsequently died of sepsis.

Discussion/Conclusion: Difficulties with treatment compliance, inadequate follow-up and treatment-induced copper deficiency were identified in this pilot cohort. These difficulties are similar to those identified in the 1989 Scotland-wide audit by Dr Park et al. Compared with 1989 we now have published clinical guidelines (EASL and AASLD) with which to set the standard of care to. Once case identification has been complete for Scotland we hope the registry will improve patient care.

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Serum neuron-specific enolase (NSE) in chronic liver diseases

B. Levitan, A. Astakhin, G. Levitan Medical Academy, Astrakhan, Russia

Objective: to determine the concentration of neuron-specific enolase (NSE) in serum of patients with various forms of liver disease.

Material and Methods: 9 patients with acute alcoholic hepatitis (AAH), 70 – with chronic hepatitis (CH), 60 – with liver cirrhosis (LC), 5 – with hepatocellular carcinoma (HCC) was surveyed. Control group – 30 healthy donors. Serum NSE concentration was determined by ELISA using commercial test kits (449-5830 DSL MBP).

Results: The most significant increase in the level of NSE was noted in patients with HCC and OAS in comparison with the control group (respectively 14.3 ± 4.5 ng/ml and 17.8 ± 0.6 ng/ml to 4.1 ± 0.9 ng/ml, p < 0.05). In LC and CH patients, average NSE concentration was not significantly higher than normal level and was significantly lower than in the AAH and HCC. Average values of NSE in patients with CH and LC did not significantly differ, however, a significant increase in its serum level in LC was observed only in 23% of patients, while in LC patients – 53%. There were no significant differences in NSE level in CH and LC patients with moderate or high activity of the process. We observed a trend to an increase in the average values of serum HCE in the progression of decompensation LC Child-Pugh class from "A" to "C". "C" level of NSE in LC patients was significantly higher than in "A "and also in the control group (p < 0.05).

Conclusion: The increased level of serum NSE concentration was observed in severe forms of liver disease, accompanied by expressed signs of liver failure (AAH, HCC, LC Child-Pugh class "C"). The investigation of serum concentration of NSE in liver pathology as predictor of hepatic encephalopathy may have important diagnostic and prognostic value.

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35*

Cdk5 inhibition improves HCC responsiveness to sorafenib treatment

Johanna Liebl, Max Ardelt, Sandra M. Ehrlich, Stefan Zahler, Angelika M. Vollmar Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, Munich, Germany

Introduction: The multi tyrosine kinase inhibitor (TKI) sorafenib represents the only approved therapy for advanced stage HCC. Although sorafenib currently is the best available option for systemic HCC treatment, therapeutic efficacy is limited with a survival advantage of 2–3 months and a response rate of 2%. Thus, prognosis for patients with advanced stage HCC is poor. This urgently demands for new systemic strategies for HCC therapy. Unfortunately, several clinical trials that investigated novel targeted approaches have not been successful so far. Combination therapy of sorafenib and targeting atypical signaling pathways might represent a promising option. Along this line, we provide evidence for combining Cdk5 inhibition with sorafenib administration as promising novel strategy for HCC treatment. Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase with essential and well-established functions in CNS development, function, and disease. In contrast, knowledge about Cdk5 in peripheral tissues is limited. We previously elucidated functions of Cdk5 in the endothelium and angiogenesis, i.e. endothelial Cdk5 was implicated in lymphatic vessel development, regulated endothelial cell migration and Cdk5 inhibition led to anti-angiogenic effects. Moreover, we recently elucidated Cdk5 as drugable target for HCC treatment. Cdk5 blockade reduced HCC growth in vitro and in vivo and synergistically enhanced effects of DNA damage inducing chemotherapeutics. The aim of the present study was to investigate whether blockade of Cdk5 can improve HCC responsiveness to treatment with sorafenib.

Methods: We analysed the functional effects of combined Cdk5 inhibition and sorafenib treatment on HCC cell lines (HUH7 and HepG2) by applying various functional assays. To block Cdk5 we used genetic knockdown with siRNA and shRNA and pharmacologic inhibition by small molecule Cdk5 inhibitors. Our mechanistic studies included immunoblot analysis and radioactive kinase assays.

Results: Simultaneous Cdk5 inhibition and sorafenib treatment synergistically inhibited HCC proliferation and clonogenic growth. Furthermore, Cdk5 blockade abrogated sorafenib-induced cell migration. Analyzing the underlying signaling mechanism, we found that Cdk5 was activated by sorafenib. Moreover, Cdk5 inhibition abrogated sorafenib-mediated activation of ATM and AKT signaling.

Discussion/Conclusion: In summary, our results reveal that Cdk5 inhibition improves the anti-tumor effects of sorafenib in HCC. Therefore, the present study proposes the combination of Cdk5 inhibition and sorafenib as promising novel alternative approach for HCC therapy.

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36*

Use of beta-blockers is associated with improved 30 day survival in patients with spontaneous bacterial peritonitis

Philipp Lutz1,3, Hans-Dieter Nischalke1,3, Benjamin Krämer1,3, Bettina Langhans1, Stefan Schlabe1, Jacob Nattermann1,3, Achim Hoerauf2,3, Christian P. Strassburg1,3, Ulrich Spengler1 3 1Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany 2Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany 3German Center for Infection Research

Introduction: Use of beta-blockers after spontaneous bacterial peritonitis (SBP) leads to increased long-term mortality. However, the effect on survival of the infection is unclear. In a murine peritonitis model, inhibition of the neuroadrenergic system even increased survival. Thus, we studied the role of beta-blockers for short-term survival in patients with SBP.

Methods: We determined transplant-free 30-day survival in cirrhotic patients who developed SBP between March 2012 and April 2014 in our department.

Results: The study population comprised 55 patients with SBP (32 [58%] male, median age 59 years). Cirrhosis was due to alcohol in 36 (66%) patients, to viral hepatitis in 11 (20%) patients. Seven (13%) patients had hepatocellular carcinoma (HCC). Median MELD score was 21, and 42 (76%) patients were classified as Child-Pugh stage C. SBP was nosocomial in 35 (64%) patients. 34 (62%) and 21 (38%) patients were without and with beta-blockers at time of SBP, respectively: 14 (67%) with propranolol, the rest with metoprolol, bisoprolol or nebivolol. Clinical and laboratory data did not differ between patients with and without beta-blockers. 30-day survival was 58% (n = 32): 16/21 (76%) in patients on beta-blockers versus 16/34 (41%) in patients without (p = 0.049). Poor survival was associated with the presence of HCC (1/7 [14%] vs. 31/48 [65%]; p = 0.017) and MELD score > 22 (6/25 [24%] vs. 26/30 [87%], p < 0.001). A forward conditional Cox logistic regression analysis confirmed MELD score ≤ 22 (p < 0.001) and use of beta-blockers (p=0.049) as prognostic factors of 30-day survival. During SBP, patients on beta-blockers had higher fractions of mononuclear cells among ascites leucocytes than patients without (median 31% vs. 19%; p = 0.036).

Discussion/Conclusion: Patients taking beta-blockers during SBP had slightly better survival, maybe owing to a more balanced peritoneal inflammation. Increased mortality reported for beta-blockers after SBP is probably not related to the infection itself.

Correspondence to: Philipp Lutz, Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany, E-Mail: [email protected]; Telephone: +49 228 287-15507, Fax: +49 228 287-51419

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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.G. Karamanolis Evangelismos General Hospital, Athens, Greece

Introduction: Diagnosis of oesophageal varices in patients with liver cirrhosis is essential for the primary prophylaxis of variceal haemorrhage. Ideally, screening of these patients should involve a non-invasive method with sparing of endoscopy unit resources and eliminating possible complications. Liver and spleen stiffness are reported to correlate with the presence of oesophageal varices (OV) and cut-off levels are being proposed.

Methods: The aim of the study was to determine the performance of liver (LSM) and spleen (SSM) stiffness measurement in the diagnosis of OV in compensated liver cirrhosis patients. Patients with compensated liver cirrhosis (based on clinical and ultrasound findings) were prospectively enrolled. All patients underwent LSM and SSM using transient elastography probe size M and within a month, elective upper gastrointestinal endoscopy. The LSM and SSM mean values between patients with or without OV were compared and the diagnostic performance of LSM and SSM cut-off values for predicting OV was assessed.

Results: Twenty eight patients were included. Men 18; women 10; mean age 60 years. Twenty patients (71%) were diagnosed with OV. Of the 28 patients, 2 patients (0.07%) had inconclusive and unreliable LSM and another 3 patients (0.1%) had no valid SSM. Among the remaining patients, mean LSM without OV was 29.87 Kpa and for OV was 33.6 Kpa (p > 0.05). Mean SSM without OV was 36.73 Kpa and mean SSM with OV was 55.31 Kpa, the difference being statistically significant (p < 0.05). Using SSM of 46.45 Kpa as a cut-off, the presence of OV is anticipated with sensitivity 61.1%, specificity 85.7%, positive predictive value 64.67% and negative predictive value 83.71%.

Discussion/Conclusion: Transient elastography of the spleen may predict the presence of oesophageal varices in compensated cirrhotic patients. SSM cut-off values with good diagnostic performance should be further evaluated. This is an interim analysis and enrolment of patients is ongoing.

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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 University Clinic of Gastroenterohepatology, Skopje, Macedonia

Introduction: Various liver diseases may be associated with cholestasis. Urso-deoxycholic acid (UDCA) has been reported to be useful for patients with cholestatic liver diseases. In the present study we investigated the effects of long-term treatment UDCA in various cholestatic liver diseases.

Methods: 173 patients with biochemical, histological and radiological proven cholestatic liver disease were treated with UDCA (10–15 mg/kg/day) for a period of 36 months: 24 with chronic viral hepatitis (CVH), 33 with alcoholic liver disease (ALD), 21 with autoimmune hepatitis (AIH), 29 with primary biliary cirrhosis (PBC), 23 with secondary biliary cirrhosis (SBC), 17 with primary sclerosing cholangitis (PSC), 3 with Caroli's disease (CD) with cholestasis and 19 with drug-induced hepatitis (DIH). Clinical, biochemical and histological parameters were followed for a period of 4 years.

Results: UDCA improved clinical (jaundice, pruritus, fatigue) and biochemical markers of cholestasis and hepatocellular damage (aminotransferases, alkaline phosphatase, and serum bilirubin level) in 25 out of 29 patients with PBC, in 20 out of 23 patients with SBC, all patients with PSC, CD and DIH, in 16 out of 24 pts. with CVH, 25 out of 33 with ALD and 13 out of 21 with AIH. The beneficial effect of UDCA on the liver histology was assessed in 135 out of 173 patients after minimum period of 12 months of therapy. Improvement was found only in 5/24 pts. with CVH, 8/33 pts. with ALD, in the 3 patients with CD and 14/19 pts. with DIH.

Discussion/Conclusion: Our results strongly suggest that long-term treatment with UDCA improves biochemical and clinical parameters in a number of cholestatic disorders. Histological improvement was partial and in minority of the patients. The use of UDCA in the treatment of chronic cholestatic liver diseases appears to be safe and without side effects in our patient's group.

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Determination of serum 3-hydroxyisobutyrate, a possible biomarker for the catabolism of branched-chain amino acids in skeletal muscles, in patients with liver cirrhosis

Teruo Miyazaki1, Akira Honda1,2, Tadashi Ikegami2, Yasushi Matsuzaki2 1Joint Research Center and 2Department of Gastroenterology, Tokyo Medical University Ibaraki Medical Center, Japan

Introduction: In patients with liver cirrhosis (LC), the catabolism of branched-chain amino acids (BCAAs) in skeletal muscles is upregulated to compensate energy production and ammonia detoxification, and consequently, muscle atrophy and its accompanied symptoms would appear. Therefore, evaluation of BCAA catabolism in skeletal muscles is important for management of the patients with LC. We developed a new method for the quantification of serum 3-hydroxyisobutyrate (3HIB), an intermediate in the pathway of valine catabolism, to monitor the catabolism of branched-chain amino acids in skeletal muscles.

Methods: After the addition of [13C4]3-hydroxybutyrate to 5 µL of serum, deprotein-ized supernatant was injected into HPLC-negative ESI-MS/MS system. Serum 3HIB concentrations were determined in 32 LC patients, 48 healthy controls, and patients with other gastrointestinal diseases (chronic hepatitis C, alcoholic and non-alcoholic steatohepatitis, Crohn's disease, ulcerative colitis, and primary biliary cirrhosis).

Results: Serum 3HIB could be easily quantified by HPLC-negative ESI-MS/MS method with high sensitivity and accuracy. Mean 3HIB concentration in LC patients was 27.7 µM which was significantly higher than those in healthy controls (12.6 µM) and in patients with other gastrointestinal diseases. In LC patients, serum 3HIB concentrations were not correlated with either serum albumin or total bilirubin concentrations.

Discussion/Conclusion: In humans, each BCAA is consistently catabolized to either acetyl-CoA or succinyl-CoA in the muscle mitochondrion. 3HIB is an intermediate in the catabolic pathway of valine and is thought to be leaking from the mitochondrion to serum. The highest concentration of 3HIB in LC patients lends support to the idea that 3HIB is a useful biomarker for the monitoring BCAA catabolism in skeletal muscles and for the management of LC patients.

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The role of fibrosis scores and transient elastography in NAFLD progression

Daniela Neagoe, Anca Amzolini, Mihaela Popescu, G. Ianosi, Larisa Sandulescu, Anca Farmazon, T. Ciurea University of Medicine and Pharmacy, Craiova, Romania

Assessment of liver fibrosis is very important in NAFLD to evaluate prognosis of disease. Aim of our study was to compare fibrosis scores based on serum markers with transient elastography Fibroscan (TE).

Methods: We included 152 patients with NAFLD, 40 males (26.31%) and 112 females with age from 23 to 79 years. 35 patients (23.02%) were overweight, 9 patients had normal weight and 24 (15.79%) had severe obesity. In all patients we calculated BMI and fibrosis scores: BARD, FIB-4 and NAFLD fibrosis score (NAFLD-FS). Blood samples were collected to determinate aminotransferases, glucose, albumin level, platelet count. The abdominal ultrasonography was performed by the same physician and steatosis was graded using a semi-quantitative scale of 1 (mild) to 3 (severe).TE was, also, performed by a single physician using conventional M probe or XL probe, with 10 valid acquisitions. We considered significant fibrosis (F2) when estimated cutoff of F2 was 7.1 kPa, severe fibrosis (F3) when cutoff value was 9.5 kPa, and cirrhosis (F4) with cutoff value ≥ 12.5 kPa.

Results: 86.84% patients had metabolic syndrome and 51.31% had diabetes mellitus.40 patients had mild steatosis, 59 had moderate and 53 had severe steatosis. After we performed TE 69.07% of patients had no significant fibrosis, 14.47% had F2, 9.86% had F3 and 7.23% had F4. The area under the receiver-operating characteristic curve (AUROC) of TE was 0.823 (95% CI: 0.252–0.394) (p < 0.0001). Sensibility and specificity for cutoff 7.1 kPa was 0.74 respectively 0.79 to exclude significant fibrosis. NAFLD-FS correlated statistic significant with TE (p < 0.0001). BARD score did not correlate with TE and NAFLD-FS for significant fibrosis.FIB-4 correlated with TE for high degree fibrosis (p = 0.004).

Conclusion: NAFLD-FS, FIB-4 and TE can be used together to evaluate the progression of fibrosis in NAFLD and to select the patients for liver biopsy. In our study BARD score was not useful in detection of high degree fibrosis.

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The relationship between osteoporosis and fibrosis in NAFLD patients

Daniela Neagoe, Mihaela Popescu, G. Ianosi, Anca Amzolini, Amelia Genunche, Anca Farmazon, T. Ciurea University of Medicine and Pharmacy, Craiova, Romania

Low bone mineral density (BMD) is associated in patients with NAFLD, but the mechanisms behind the reduced BMD in NAFLD are still not completely known. Several factors may influence bone mineralisation such as cytokines, vitamin D deficiency, limited physical activity. Aim of our study was to establish the relationship between osteoporosis and the degree of fibrosis in NAFLD patients estimated by transient elastography (TE).

Methods: We included 145 patients with NAFLD and we performed for all of them TE, abdominal ultrasonography and lumbar BMD was measured by DEXA. Abdominal ultrasound was performed by the same physician and steatosis was graded from 1 (mild) to 3 (severe). TE was, also, performed by a single physician and we considered F0/F1-no/mild fibrosis, F2-significant fibrosis, F3-severe fibrosis, F4-cirrhosis. Blood samples were collected to determinate hepatic enzymes, lipid profile, glucose, albumin, platelet count, vitamin D level.

Results: We divided the patients into two groups: group A (97 patients with F0, F1) and group B (48 patients with F2, F3, F4). Mean age was 46 ±13 years in group A and 52 ± 12 years in group B (p = 0.012). No significant differences between the two groups in waist circumference, BMI, lipid profile and the degree of steatosis. Vitamin D was significant lower in group B vs. group A (p < 0.001). In group A we found 54 patients (55.6%) with normal T score, 23 with osteopenia and 20 (20.6%) with osteoporosis. In group B we found 18 patients (37.5%) with normal T score, 16 with osteopenia and 14 with osteoporosis (29%).

Conclusions: In our study osteopenia and osteoporosis are more frequent in NAFLD patients with high degree fibrosis and no dependent of steatosis degree. Vitamin D level correlated negatively with the fibrosis.

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Features of correction of maldigestia syndrome at the patients with cirrhosis

O.B. Nepesova, H.E. Blum, K.B. Nepesova Turkmen State Medical University, Ashgabat, Turkmenistan; Department of Medicine II, University Hospital of Freiburg, Germany

Introduction: Signs and symptoms of liver cirrhosis in most cases do not depend on its etiology but on the degree of impairment of liver functions and intrahepatic blood flow. While advanced liver cirrhosis presents with typical clinical symptoms, it can remain asymptomatic over long periods of time. A special feature is gastroentero-logical symptoms such as maldigestion due to exocrine pancreatic insufficiency. Objectives include study and correction of exocrine insufficiency of the pancreas in patients with liver cirrhosis and signs of maldigestion, such as steatorrhea.

Methods: 39 patients with liver cirrhosis from different etiologies without (20) and with ascites (19) were followed. The diagnosis was based on clinical, laboratory and immunological examinations, ultrasonography and computer tomography. 15 patients were female and 24 were male aged between 17 and 65 years. Pancreatic insufficiency was diagnosed by steatorrhea. The patients were treated with pancre-atine 25,000 ME 3 x/day for 10 days.

Results: Marked improvement of was observed in reduction of neutral fat in stool from 1.4 ± 0.15 to 1.21 ± 0.10, of fatty acids from 1.79 ± 0.14 to 1.16 ± 0.09,and of cellulose from 1.58 ± 0.12 to 0.89 ± 0.15 and of starch from 1.47 ± 0.12 to 0.68 ± 009.

Discussion/Conclusion: Maldigestion in patients with liver cirrhosis improved after treatment with pancreatine 25,000 ME and was associated with a reduction of fat and carbohydrates in stool.

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Genetic and environmental risk factors for development of hepatic encephalopathy in cirrhotics

Nevin Oruc1, Cagdas Aktan2, Muharrem Keskin1, Nalan Gulsen Unal1, Ali Ozturk1, Hakan Aydin3, Handan Ak Celik3, Omer Ozutemiz1

Ege University Faculty of Medicine, Gastroenterology Department, Medical Biology Department, Medical Biochemistry Department, Izmir, Turkey

Introduction: Hepatic encephalopathy (HE) occurs in advanced liver disease. Different etiological factors including infections, bleeding, and medication could predispose to HE. Some patients with cirrhosis have several HE attacks while others have none. This led to the idea that beside liver failure and environmental factors genetic factors determine the risk of developing HE. We thought that serotonin as an important mediator that regulates personality, depression or functional disorders might effect HE risk.

Methods: We investigated the role of serotonin regulating gene mutations including HT1A gene G294A, TPH gene A218C by RFLP-PCR method and 5HT1A gene C(-1018)G polymorphism by real time SNP detection method in 140 cirrhotics and 193 healthy controls.

Results: All the patients and controls had wild type GG allele for HT1A G294A gene. This gene was not considered as a risk factor for HE. For TPH gene healthy controls had Adenin (A) (48.2%) and cytosine (C) (51.8%) allele frequency while cirrhotics had (A) (52.1%) and (C) (47.9%). The differences between genotypes and allele frequency was not significant (2 = 0.382, p > 0.05; 2 = 1.016, p > 0.05). When patients stratified according to history HE, there was no relation between HE attack or HE history in cirrhotics and TPH genotype. For 5HT1A C(-1018)G gene healthy controls had (C) (47.2%) and Guanin (G) (52.8%) while cirrhotics had (C) (52.1%) and (G) (47.9%) allele frequency. Patients with HE had (C) (53.4%) and (G) (46.6%) allele frequency. This ratio was similar to patients without HE. The risk for HE in cirrhotics were related to history of variceal bleeding, the degree of liver failure and the history of alcohol usage.

Discussion/Conclusion: In this study we found that SNPs in genes coding for proteins taking role in serotonin related pathways do not have any role in HE pathogenesis. However other cirrhosis related complications and advanced liver failure increases the probability of HE.

Key words: hepatic encephalopathy, serotonin, polymorphism, cirrhosis

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Hepatic stellate cells are the major source of collagen in murine models of liver fibrosis

Christoph H. Österreicher1, Ursula J. Lemberger1, Robert Mahon2, Thomas Rülicke3, Michael Trauner2, Emilio Casanova4 1Institute of Pharmacology, Medical University Vienna, Austria 2Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Austria 3Institute of Laboratory Animal Science, Biomodels Austria, University of Veterinary Medicine, Vienna. Austria 4Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

Introduction: Hepatic stellate cells (HSCs) are the major storage site for vitamin A in vertebrates and are the major source of collagen in toxic liver injury. Lecithin-retinol acyltransferase (LRAT) catalyzes the esterification of all-trans-retinol and is essential for storage of vitamin A in the liver. Other sources of myofibroblasts have been proposed in fibrotic livers including bone marrow derived cells and epithelial cells (hepatocytes and cholangiocytes). Portal fibroblasts appear to be of particular importance in cholestatic liver disease. This study addressed if Lrat is a specific marker for HSCs and evaluated the contribution of HSCs to the pool of collagen-producing cells in different mouse models of liver fibrosis.

Methods: BAC transgenic Lrat-Cre mice were generated by insertion of a codon optimized Cre recombinase at the translational start of the lrat gene by ET cloning. Lrat-Cre mice were crossed to reporter mice, which express tdTomato after removal of a loxP-flanked STOP cassette. Triple transgenic mice (Coll-GFP/Lrat-Cre/ROSA26 LSL tdTomato) were generated and subjected to BDL or CCl4 treatment. Immunofluorescence staining and confocal microscopy was employed to assess the relative contribution of individual cell types to the pool of collagen-producing cells.

Results: Immunofluorescence staining for desmin indicated that Lrat-Cre marks > 95% of HSCs. Co-localization analysis of triple transgenic mice indicated that > 90% of collagen-producing cells in mice subjected to CCl4 treatment or BDL are derived from HSCs. Neither collagen-producing cells nor HSC (desmin-positive cells/tdTomato-positive cells in Lrat-Cre ROSA26 LSL tdTomato) expressed markers of hepatocytes, cholangiocytes or endothelial cells.

Discussion/Conclusion: Our study suggests that 1) Lrat is a specific marker for HSCs, 2) Lrat-Cre mice are a valuable tool to study gene function in HSCs and 3) HSCs are the main source of collagen in mice undergoing BDL and CCl4 treatment.

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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 Gastroenterology Unit, Bolton NHS Foundation Trust, Bolton, UK

Introduction: It has been traditional clinical practice to give high doses of thiamine and B complex vitamins to patients admitted with alcohol withdrawal to reduce the risk of development of Wernicke’s encephalopathy. NICE (National Institute for Health & Care Excellence, UK) Clinical Guidance (CG100) [1] recommends high-dose prophylactic parenteral thiamine followed by oral thiamine to harmful or dependent drinkers when admitted to hospital. An audit was undertaken to assess if the use of vitamin B supplements in patients admitted to a Royal Bolton Hospital (District General Hospital) with acute alcohol withdrawal is appropriate and in accordance with NICE guidelines.

Methods: Data were collected prospectively on patients admitted with acute alcohol withdrawal to Royal Bolton Hospital between 18th November and 13th December 2013. The following data were collected: patient demographics, nutritional status, severity of co-existent liver disease (Child-Pugh score), dose and route of vitamin supplements given in each patient. Nutrition status was assessed and scored as low and high risk using a standardised nutritional assessment tool locally developed at Royal Bolton Hospital.

Results: There were 53 patients in total (32 male, 21 female). The mean age was 52 (range 20–83). The majority of patients i.e. 25 (47%) had a nutritional score of 0–3. Among this group 10 (19%) had a score of zero (low-risk group). 12 (22%) did not have their nutritional score documented. The severity of liver disease based on Child-Pugh Score [2] showed that 32 (60%) had mild or no liver disease (Child A). 51 patients were started on i.v. thiamine (Pabrinex) at a standard dose as per BNF of 2 ampoules 3 times a day. All patients on i.v. were subsequently switched to oral thiamine 50 mg 4 times a day and 4 tablets of B complex strong tablets a day. As per NICE criteria 2 out of 53 should have been given i.v. thiamine and 5 out of the 51 who received i.v. Pabrinex required only oral rather than i.v. thiamine

Discussion/Conclusion: I looked into the evidence based on which NICE came up with their recommendations. Their conclusions were derived on the results of 5 studies out of which only 2 were randomised controlled trials [3, 4] with Level 1 evidence. The other 3 included 1 non-randomised trial [5] and 2 case series [6, 7] with Level 2–3 evidence. The studies included small numbers of patients ranging from 25 to 107. In the absence of large and powerful studies, some of the NICE recommendations appear to be based on consensus and extrapolation of evidence from clinical and laboratory studies on thiamine absorption and metabolism. A full-fledged double-blind randomised study on thiamine replacement in alcohol withdrawal is unlikely to receive ethical approval because of the potential health risks on the control group.

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NICE was unable to find any study that answered the crucial question of which subset of patients were at risk of developing WE. They were unable to find evidence based answers on the optimal dose/route/duration of vitamin replacement. There was also lack of clarity on the definition of malnutrition.

In general Royal Bolton Hospital appears to be adhering to NICE guidelines in that all patients were started on either oral or i.v. thiamine supplements. However, they are contravening the guidelines in a small proportion of patients. Some patients who would have needed i.v. thiamine are receiving oral and vice versa. There should therefore be a greater emphasis on stratifying patients to high and low risk based on their nutritional status and co existent liver disease. Compared to oral thiamine tablets, i.v. Pabrinex is expensive. Any i.v. treatment involves nursing time to set up the drip, has risk of line infection, and is inconvenient to the patient. There appears to be a trend to over prescribe i.v. Pabrinex by clinicians to minimise the risk of any of their patients developing Wernicke’s encephalopathy (WE). Some would argue that the potential costs involved in looking after patients with WE, a devastating illness leaving the individual with permanent long term brain damage, can outweigh the expenses involved in over prescription of i.v. Pabrinex. I noticed that all patients were discharged on oral thiamine and vitamin B complex strong tablets. However, NICE does not recommend routine replacement of vitamin B complex. Not all patients had their nutritional status assessed and this may have affected the results of the audit. The sample size was small due to time constraints. Bolton hospital is not fully compliant with NICE guidelines and there is scope for improvement through the following interventions: 1. Clinicians need to be made aware of the importance of stratifying patients to high-

and low-risk category so that they receive the correct dose and route of thiaminesupplements.

2. Aim to undertake nutritional assessment in 100% of patients as this is an essentialelement of risk stratification.

3. Re-audit after implementation of above recommendations.

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Activity of MMP1, MMP13 and amino acid metabolism in patients with alcoholic liver cirrhosis

Andrzej Prystupa1, Maria Szpetnar2, Anna Boguszewska-Czubara2, Wojciech Załuska3

1Department of Internal Medicine, Medical University of Lublin, Poland 2Department of Medical Chemistry, Medical University of Lublin, Poland 3Department of Nephrology, Medical University of Lublin, Poland

Alcoholic liver disease remains one of the commonest causes of chronic liver disease worldwide. Its clinical classification is based on pathologic findings of fatty liver, alcoholic hepatitis and alcoholic cirrhosis.

The aim of the study was to assess the usefulness of MMP1 and MMP13 as diagnostic markers of alcoholic liver disease and to determine the changes in free amino acid profile in the patients with alcoholic liver cirrhosis.

Methods: Sixty patients with alcoholic liver cirrhosis treated in various hospitals of the Lublin region were randomly enrolled. The stage of cirrhosis was assessed according to the Child-Turcotte-Pugh scoring system. The control group consisted of 10 healthy individuals without liver disease, who did not drink alcohol. Additionally, the group of alcoholics without liver cirrhosis was included in the study. The activity of MMP1 and MMP13 in blood plasma of patients and controls was measured using the sandwich enzyme immunoassay technique with commercially available quantitative ELISA test kits. Amino acids were determined by automated ion-exchange chromatography.

Results: No significant differences were observed in the activity of MMP1 in alcoholics with or without liver cirrhosis and in controls. Increased serum MMP13 was found in patients with liver cirrhosis (stage A, B, C) compared to control group. Patients with alcoholic liver cirrhosis (stage A, B, C) demonstrated reduced concentrations of glutamic acid and glutamine compared to control group. Plasma levels of valine, isoleucine, leucine and tryptophan were significantly lower in patients with alcoholic liver cirrhosis (stage C) than in controls.

Conclusions: Our findings demonstrate that determinations of MMP-13 can be useful to confirm the diagnosis of alcoholic liver cirrhosis whereas levels of MMP-1 are not significantly increased in patients with liver cirrhosis compared to controls. Moreover, serum branched-chain amino acid (BCAA) is markedly reduced in patients with stage C alcoholic liver cirrhosis. BCAA supplementation seems essential in the advanced stage of alcoholic liver cirrhosis whereas in stages A and B it is likely to improve nitrogen balance, increase glutamine availability and improve prognosis.

Correspondence to: Dr. Andrzej Prystupa, Department of Internal Medicine, Medical University of Lublin, Lublin, Staszica 16 Street, Poland

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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

Andrzej Prystupa1, Anna Boguszewska-Czubara2 1Department of Internal Medicine, Medical University of Lublin, Poland 2Department of Medical Chemistry, Medical University of Lublin, Poland

Introduction: In alcoholic liver cirrhosis, normal liver cells are replaced by scar tissue (fibrosis). Liver fibrosis is a dynamic process in which activated hepatic stellate cells are involved in the synthesis of matrix proteins and the regulation of matrix degeneration. The aim of the present study was to assess the usefulness of MMP-2, MMP-8 and MMP-9 as diagnostic markers of alcoholic liver disease.

Methods: Sixty patients with alcoholic liver cirrhosis were randomly enrolled during hospitalization in departments of hospitals from Lublin region. The stage of cirrhosis was estimated according to Child-Turcotte-Pugh criteria (Child-Pugh score) as P-Ch A, P-Ch B, P-Ch C. Control group consist of 10 healthy persons without liver disease, who didn’t drink alcohol. Additionally, the group of alcoholics without liver cirrhosis was collected to the study. The blood samples were obtained, and after the centrifuge, the serum was collected for further analysis. The activity of MMP-2, MMP-8 and MMP-9 in the blood plasma of the patients and the control group were measured by using the sandwich enzyme immunoassay technique with commercially available quantitative ELISA test kits.

Results: Activity of MMP-2, MMP-8 and MMP-9 in patients with liver cirrhosis were increased gradually according to Child-Pugh stages. The activity of MMP-2, MMP-8, MMP-9 were the highest in patients with liver cirrhosis stage C. MMP-2, MMP-8, MMP-9 concentrations in the people with liver cirrhosis (stage C) were significantly increased compared to controls. A significant difference was observed between activity MMP-2 in control group, alcoholics without liver cirrhosis and people with liver cirrhosis (stage A, B, C according Child-Pugh score).

Discussion/Conclusion: MMP-2, MMP-8 and MMP-9 may be a markers of alcoholic liver cirrhosis in the alcoholics. Elevated levels of MMP-2, MMP-8 and MMP-9 in the alcoholic patients indicated that cirrhosis has developed. The most sensitive is MMP-2, because of activity of this parameter is increased in all liver cirrhosis stages. On the second place, MMP-8 and MMP-9 activity were significantly elevated only in serum patient with advanced liver cirrhosis compared to controls.

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Predictive factors for developing hepatocellular carcinoma in patients with liver cirrhosis

Manuela Pumnea1,2, Elena Cristina Rezi¹1Polisano Medical Clinic, Sibiu, Romania 2Faculty of Medicine, ”Lucian Blaga” University, Sibiu, Romania

Introduction: Some patients with liver cirrhosis develop hepatocellular carcinoma (HCC), but it is not clear yet if we can predict which patients are more exposed at this risk. Our aim was to study which parameters can indicate those cirrhotic patients who are more likely to develop HCC.

Methods: We have taken in consideration a group formed by 80 patients with liver cirrhosis of different etiologies who were hospitalized in the Internal Medicine and Gastroenterology Departments of the Clinical County Hospital from Sibiu, Romania, during one year. Among the 80 patients with liver cirrhosis, 9 patients developed HCC. We have compared some laboratory parameters and the liver fibrosis at both groups: a group formed by 71 patients with liver cirrhosis, but without HCC and a group formed by 9 patients with HCC, developed on liver cirrhosis. For evaluating the liver fibrosis we have used the FORNS index of liver fibrosis, which is based on: age, platelet count, gamma glutamyl transpeptidase (GGT) and cholesterol levels. A value higher than 6.9 of the Forns index is a predictive factor for significant liver fibrosis.

Results: The medium age of the whole group was 54.03 ± 12.45 years and at the patients with HCC was 62.11 ± 14.95 years. The relative risk of developing HCC at patients with liver cirrhosis over 65 years of age was 6. The Forns index of liver fibrosis was, in average, 8.3271 at the patients with HCC comparing with only 6.0832 at the patients with liver cirrhosis, the difference being statistically significant (p = 0.0125). The relative risk of developing HCC at cirrhotic patients with a Forns index higher than 6.9 was 2.87.

Discussion/Conclusion: Age is an important predictive factor for developing HCC at patients with liver cirrhosis, the patients older than 65 years of age being six times more likely to develop HCC. The patients with a high Forns index are almost three times more likely to develop HCC. Age and the Forns index of liver fibrosis may indicate those cirrhotic patients who are at higher risk of developing HCC.

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Calcitriol inhibits activation of hepatic stellate cells in vitro and ameliorates hepatic damage in vivo

Florian P. Reiter*, Simon Hohenester*, Jutta M. Nagel*, Ralf Wimmer*, Lena Wottke*,Michael Trauner§, Christian Rust#, and Gerald U. Denk*

*Department of Medicine II, Campus Grosshadern, Liver Center Munich, University ofMunich, Munich, Germany §Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology andHepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria #Department of Gastroenterology, Krankenhaus Barmherzige Brüder, Munich, Germany

Background: Chronic liver diseases are characterized by reduced vitamin D levels. Expression of the vitamin D receptor can be observed in hepatic stellate cells (HSCs). Furthermore, low vitamin D levels are associated with progredient liver fibrosis in patients suffering from chronic hepatitis C. Hence, administration of vitamin D has been proposed to be beneficial in liver fibrosis. To characterize its mechanism of action, we hypothesized that calctriol (active 1,25-(OH)2 vitamin D3) directly inhibits HSC activation and ameliorates liver damage and fibrosis in Mdr2-/- mice.

Methods: Murine HSCs were treated for 14 days with calcitriol. Markers relevant for fibrogenesis were assessed by polymerase chain reaction, immunoblot, and zymography. As in vivo model, Mdr2-/- and wildtype (wt) mice were treated with calcitriol for 4 weeks. Hepatic damage and fibrosis were determined by serum bio-chemistry, polymerase chain reaction and hydroxyproline content.

Results: Administration of cacitriol reduced activation of HSC in vitro as indicated by a decrease of αSma. In comparison with controls proliferation of murine HSC was lower when treated with calcitriol (BrdU and PicoGreen® DNA assay). In addition calcitriol induced expression of the antifibrogenic enzyme matrix metalloproteinase 13. In vivo calcitriol administration reduced serum ALT in Mdr2-/- mice. In accordance,mRNA expression of F4/80 and Tnf-receptor was reduced. In contrast no beneficial antibrotic effect was observed.

Conclusion: Calcitriol impedes HSC activation in vitro and reduces hepatic injury in vivo. However, no effect against development of liver fibrosis could be unravelled.

Correspondence to: Florian P. Reiter, Department of Medicine II, Campus Gross-hadern, University of Munich, Marchioninistr. 15, 81377 Munich, Germany, E-Mail: [email protected]; Tel.: +49 89 4400-73129, Fax: +49 89 4400-78864

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Effects of lovastatin and pentoxifylline treatment in patients with nonalcoholic steatohepatitis

Elena-Cristina Rezi1, Romeo–Gabriel Mihaila2, Laurentiu Nedelcu3, Ovidiu Fratila4, Carmen Domnariu5

1Polisano Medical Clinic, Sibiu, Romania 2Faculty of Medicine, ”Lucian Blaga” University, Sibiu, Romania 3Faculty of Medicine, Transilvania University, Brasov, Romania 4Faculty of Medicine, University from Oradea, Oradea, Romania 5Public Health Center, Sibiu, Romania

Introduction: Today, there is no ideal treatment for nonalcoholic steatohepatitis (NASH). We performed a multicentric prospective study in order to assess the lovastatin and pentoxifylline efficiency administrated in patients with NASH.

Methods: A number of 87 patients with NASH were included in the study, out of which 59 were with NASH and dyslipidemia and were treated with lovastatin (10 mg/day), and 28 patients were with NASH, but without dyslipidemia and were treated with pentoxifylline, 3 x 400 mg/day.

Results: Regarding the lovastatin-treated group, the following results were obtained: the level of aspartate aminotransferase (AST) decreased after the first and second month of treatment (p = 0.0196, p = 0.032); the level of alanine aminotransferase (ALT) decreased after the first and second month of treatment (p = 0.0335, p = 0.021). The gamma-glutamyl transferasis (GGT) level decreased during the two months of treatment (p = 0.079, respectively p = 0.253). The level of cholesterol decreased after the first and second month of treatment (p = 0.00029, respectively p = 0.00028). The APRI score of liver fibrosis in the 3 months of treatment, decreased from the average initial value of 0.188 to 0.142, respectively to 0.102 after the second month of treatment (p = 0.030). Regarding the pentoxifylline-treated group, the following results were obtained: the level of AST decreased after the first month and second month of treatment (p = 0.018, p = 0.16); the level of ALT significantly decreased after the first and second month of treatment (p = 0.033, p = 0.126). The GGT level decreased after the first and the second month of treatment (p = 0.107, respectively p = 0.123). The APRI score decreased from the average initial value of 0.1587 to 0.1135 after the first month of treatment and to 0.133 after the second month of treatment (p = 0.022).

Discussion/Conclusion: Both drugs significantly decreased the levels of trans-aminases in patients with NASH. Lovastatin reduced the cholesterolemia in the dyslipidemic patients. The decrease of the APRI score suggests that both drugs may have beneficial effects on the liver histology, too and may prevent the disease's evolution towards cirrhosis. Our research pleads for the individual treatment in patients with NASH, taking into account the present components of the metabolic syndrome.

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51*

Development of hepatitis B virus quasispecies in association with nucleos(t)ide analogue treatment determined by MALDI-TOF MS

Magda Rybicka1*, Piotr Stalke2, Anna Woziwodzka1, Dręczewski Marcin2, Tomasz Smiatacz2 and Krzysztof Piotr Bielawski1 1Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland, Kladki 24, 80-822 Gdansk, Poland 2Department of Infectious Diseases, Medical University of Gdansk, Smoluchowskiego 18, 80-214 Gdansk, Poland *presenting author: [email protected]

Introduction: Minor drug-resistant variants may pre-exist in every patient infected with HBV. However, understanding the dynamic of genotypic evolution within HBV population requires the ability to accurately follow allele frequencies through time. In this study we used MALDI-TOF mass spectrometry (MS) for localization and quantitative allele frequency detection to investigate pre-existing HBV quasispecies and the genotypic evolution of drug-resistant variants during NA therapy.

Methods: Serum samples obtained from 42 chronic HBV-patients treated with lamivudine (24), entecavir (13) and tenofovir (5) monotherapy were analyzed by MALDI-TOF MS. The 37 selected HBV variants were determined in 4 separate iPLEX reactions upon initiation of treatment, at week 12, 24 and 48. The study group consisted of treatment-experienced (21) and naïve-patients (21).

Results: Resistant mutations in lamivudine-group were detected upon the treatment in 72% (13/18) of naïve and in all experienced-patients (6) with the allelic frequency of 1.2–44% and 1.2–100%, respectively. In entecavir-group resistant HBV-variants were identified in both groups (1.8–20%). All patients treated with tenofovir were experienced. We observed changes occurring in the HBV quasispecies within 48 weeks of NA-treatment. The percentages of resistant-variants notably increased relative to the baseline in the nonresponder patients, as well as new mutations appeared during NA-therapy (p = 0.00058). In the case of responder group drug-resistant mutants disappeared in time.

Discussion/Conclusion: These studies showed that there is a significant difference between the genotypic evolution of drug-resistant variants depending on the response to NA-therapy. The pre-existence of natural resistance mutations in treat-ment-naïve patients is common.

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Surgical treatment results of HCC in Mongolia

Sanduijav Ruvjir Department of Oncology, Mongolian National University of Medical Sciences (MNUMS), National Cancer Center of Mongolia, Ulaanbaatar, Mongolia

Background: Hepatocellular carcinoma (HCC) is very widespread among the Mongolian people, and it seems to have a tendency to increase.

Aim: To estimate of results of current surgical treatment of HCC in Mongolia.

Patients and Methods: We have observed 158 patients with HCC (M/F ratio 63/37% and from 29 of age 78 from years, a mean age of 55.1 years). 102 of them undergone surgical treatment. In this study there was compared the liver resection conducted by anatomical and non-anatomical methods.

Results and Discussion: After the anatomical liver resection, the average bleeding was 599.5 ml, complications were 5.4%, death after liver resection is 1.0%. In comparison, with the traditional liver resection method which was used before in our clinic the complications were reduced by the following percentage: 16.6% from 28.1–66.75% (p < 0.002) for expanded hepatectomy, 0% from 11.2% for left lobectomy and 10.7 from 20.0–46.7% for lobectomy. After expanded liver resection the mortality rate was reduced to 5.2% from 33.3%, the bleeding was decreased to 710.0 ml from 2067.7 ml. There was 68.4% of the patients whom the resection was done at early stage have a 5 years or more survival rate. The survival rate was for 85% of the 102 patients who had the liver resection was one year, for 70.3% of them it was 3 years, for 39.5% of them it was a 5 year or more survival rate.

Conclusions: In Mongolia, the anatomical liver resection for HCC is effective and increased of results treatment, improved for quality of life and survival rate of patients.

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Differential expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX) in the development of hepatic fibrosis

Amal Santra, Bidhan Chandra Chakraborty, Debasree Bishnu, Suman Santra, Gopal K Dhali, Abhijit Chowdhury Center for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education & Research, 244, Acharya J.C. Bose Road, Kolkata 700020, India

Background and Aims: Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a multicomponent enzyme and has an important role for the activation of the hepatic stellate cell (HSCs) which ultimately leads to fibrosis development. However, different isoforms of NOX express in different cell types in the liver during the process of hepatic fibrosis is still lacking. The aim of this study is to identify the expression NOX homologues in different hepatic cells during the development of fibrotic liver.

Materials and Methods: Using Carbone tetrachloride (CCl4) model of hepatic fibrosis in C57BL/6 mice, we studied the expression of different isoforms of NOX in liver tissues as well as different liver cells like hepatocytes, Kupffer cells (KC) and HSCs isolated at the end of 1st, 3rd, 6th and 9th week of CCl4 injection. Expression of NOX homologues was correlated with hepatic fibrosis. Some experiments were carried out using diphenylene iodonium (DPI), an inhibitor of NOX.

Results: The NADPH oxidase activity in the liver tissue was highly increased after 1st week of CCl4 injection associated with up-regulation of both phagocytic NOX (NOX2) and nonphagocytic NOX1 and NOX4 expression. NOX1 was only expressed in HSCs, while NOX2 was expressed in both KC and HSCs and NOX4 in only hepatocytes. Hepatic up-regulation of NOX homologues was associated with up-regulation of mRNA expression of proinflammatory cytokines (IFN-gamma, IL-12, IL-6 and TNF-alpha) which was significantly reduced by pretreatment the mice with DPI, a NOX inhibitor. Continuation of CCl4 injection lead to gradually increased of NOX4 expression in HSCs from 3rd weeks onwards and was associated with the development of liver fibrosis. The increased expression of NOX4 in HSCs was found to be correlated with hepatic fibrosis.

Conclusions: This study demonstrates the contributory role of NOX4 in HSCs in the development of hepatic fibrosis.

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Cellular mechanism of hepatic stellate cells activation with conditioned medium derived from isoniazid treated cytochrome P450 2E1 overexpressing hepatocytes

Suman Santra, Abhijit Chowdhury, Debasree Bishnu, Gopal K Dhali, Amal Santra Centre for Liver Research, School of Digestive and liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, India

Background and Aims: Isoniazide (INH), administered for prolonged periods, can lead to liver fibrosis. The present in vitro study was designed to look for evidence with regards to answer 1. Whether soluble mediators released from INH exposed hepatocytes can activate

hepatic stellate cells (HSC)2. Molecular mechanism of HSC activation and fibrogenesis by mediators, released

from hepatocytes during INH treatment.

Methods: HepG2 cells that constitutively express CYP2E1 (E47 cells) were treated with INH (5 μM) in serum-free media (DMEM). Supernatant was harvested after 18 hours of incubation and was used as conditioned medium for culture of human HSC LX-2 cells. Intracellular ROS, NOX activity and collagen production were evaluated. Isoforms of NOX, phenotypic markers of HSC activation and fibrogenesis were assessed by real time PCR and Western blot analysis. Relevant signaling pathways were looked at using pharmacological inhibitors.

Results: Conditioned medium from INH treated E47 cells elicited a burst of reactive oxygen species in LX-2 cells and activated these cells into proliferative and collagen producing phenotype. The catalytic subunit of non-phagocytic NOX, NOX1/4 was overexpressed as evidenced by real-time PCR and Western blot analysis. ERK1/2 and PI3K/AKT pathways, downstream of NOX signaling, were found to be overexpressed and were involved in enhanced collagen synthesis as evident by using inhibitors of these signaling pathways. NOX inhibitor (DPI and apocynin) inhibited conditioned medium-induced activation of LX-2 cells and collagen synthesis by these cells in presence of conditioned medium.

Conclusion: Apart from cellular cross talk in the hepatocyte microenvironment, conditioned medium derived from INH treated hepatocytes is fibrogenic through its effect on HSC activation, proliferation and fibrogenesis through enhanced NOX1/4 upregulation, ROS generation and ERK1/2 and PI3K pathways.

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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 B2

Julia Schewe, Lisa Selzner, Ingrid Liss, Burkhard Goeke, Alexander L. Gerbes, Christian J. Steib Department of Medicine II, University of Munich, Campus Grosshadern, Munich, Germany

Introduction: We have already shown an important role of TLR-dependent formed thromboxane (TX) for portal hypertension in cirrhosis in previous work (including Steib CJ, et al., Hepatology. 2010). Aim of the present study was to determine, which liver cells play a relevant role for TX-production and which TLR are involved in this process.

Methods: KC and SEC were isolated from mouse livers (male C57/Bl6) and stimulated over 24 h with various TLR-agonists (Pam3CSK4 [TLR 1/2] 0.1 g/ml; HKLM [TLR 2] 10e8 cells/ml; Poly (I:C) [TLR 3] 10 ng/ml; LPS-EK [TLR 4] 10 ng/ml; ST-FLA [TLR 5] 10 ng/ml; FSL-1 [TLR 6/2] 1 ng/ml; ssRNA40 [TLR 7] 0.25 µg/ml; ODN1826 [TLR 9] 5 µM; n = 6 each). Thromboxane B2 (TXB2) efflux before and after stimulation into the cell media was measured by ELISA (mean ± SD, *p < 0.05).

Results: TXB2-efflux (before stimulation vs. after stimulation in pg/ml) is shown in table 1.

Discussion/Conclusion: The activation of TLR 2, 4, 5, 2/6, and 9 on isolated KC of healthy livers lead to a significant production of vasoconstrictive effective TXB2, whereas the activation of SEC through TLR 1/2, 3, 4, 6, 7 and 9 led to a decrease of TXB2 production. Our findings provide an important basis to identify relevant early stage microbial products for the formation of TXB2 in the future and to develop targeted strategies to prevent complications of portal hypertension.

This study is supported by DFG STE 1022/2-3 and DFG STE 1022/4-1.

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Ischemic postconditioning (IPostC) in fibrotic livers following warm ischemia: A new strategy to protect the liver against ischemia-reperfusion injury

Julia Schewe, Ingrid Liss, Lisa Selzner, Marie-Christine Makeschin, Burkhard Goeke, Alexander L. Gerbes, Christian J. Steib Department of Medicine II, University of Munich, Campus Grosshadern, Munich, Germany Department of Pathology, University of Munich, Campus Grosshadern, Munich, Germany

Introduction: Decreased organ function following liver resection is a clinically relevant problem. The practical method of IPostC has been studied in heart diseases, but no data exist about fibrotic livers. Therefore we tested this procedure for different liver models focussing on TXB2, an important mediator of liver injury especially in fibrotic livers with portal hypertension.

Methods: Fibrosis was induced in male Sprague-Dawley rats by bile duct ligation (BDL, 4 weeks) or via thioacetamid (TAA, 18 weeks), healthy rats were used as controls. The livers were examined histologically using HE and EvG staining. Isolated liver perfusion was performed: 30 min. stabilization, 90 min. warm ischemia at 37°C and reperfusion for 90 min. at 37°C. In all liver models three groups (each n = 4) were investigated: A: reperfusion; B: IPostC 8 x 20 sec. + reperfusion; C: IPostC 4 x 60 sec. + reperfusion. Lactate dehydrogenase (LDH) and Thromboxane B2 (TXB2) in the perfusate and bile flow (healthy/TAA) were measured (mean ± SEM; *p < 0.05).

Results: Histologic evaluation is shown in table 1. LDH and TXB2 was reduced by IPostC (LDH-efflux [mU/min x g liver] healthy A: 13924 ± 1259 vs. B: 8298 ± 571* vs. C: 7786 ± 1546*; BDL A: 4241 ± 342 vs. B: 1588 ± 465* vs. C: 1766 ± 616*; TAA A: 3460 ± 526 vs. B: 2871 ± 142 vs. C: 1998 ± 258*; TXB2-efflux [pg/min x g liver] healthy A: 19028 ± 4629 vs. B: 6329 ± 1113* vs. C: 7254 ± 2336*; BDL A: 17332 ± 3886 vs. B: 13983 ± 4087 vs. C: 6197 ± 1173*; TAA A: 8843 ± 587 vs. B: 4625 ± 807* vs. C: 3431 ± 333*) and bile flow increased (bile flow [ml/min x g liver] healthy A: 0.38 ± 0.09 vs. B: 2.27 ± 0.31* vs. C: 1.63 ± 0.28*; TAA A: 1.3 ± 0.3 vs. B: 2.29 ± 0.55 vs. C: 2.35 ± 0.24*).

Discussion/Conclusion: IPostC following warm ischemia is protective in different liver models (healthy, BDL, TAA). Reduced efflux of TXB2 is one possible mechanism for this protective effect of IPostC, maybe because of a reduced portal pressure, which means less injury and improved organ function. Currently this hypothesis is investigated in an in vivo setting.

This study is supported by DFG STE 1022/2-3 and DFG STE 1022/4-1.

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DILI in 1-year analysis of 3rd Department of Medicine

Jozef Sedlacko1,*, Zuzana Sedlakova1, Martina Jakabovicova1, Maria Szantova1 3rd Department of Medicine, Medical Faculty of Comenius University, Bratislava, Slovakia

Introduction: Drug-induced liver injury (DILI) is the increasing cause of morbidity of older people of the past years.

Aims and Methods: The analysis of DILI in the 1-year follow up of all inpatients at 3rd Department of Medicine is given. The clinical approach was essential for determining of suspected drug. Type of lesion (hepatitic, cholestatic, mixed) according to the enzyme (ALT, AST, ALP, GMT) and bilirubin levels, time of onset, duration of medication, presence of jaundice were determined. RUCAM scale for objective valuation of diagnosis was rated and correlation with the clinical consideraton was done.

Results: Eleven cases of DILI from the total amount of 1509 inpatients were recorded. Using the clinical approach the diagnosis was done in all patients. Hepatitic type of DILI in 8 patients (73%), cholestatic in 2 (18%) and mixed in 1 patient (9%) was present. Hepatitic type was more often in younger, but cholestatic in older people. Jaundice was present in 54% of patients. Drugs responsible for DILI in our series were: analgesics (46%), contraceptives (27%), antibiotics (18%) and hypolipidemics (9%). According to the scoring system RUCAM scale the definitive diagnosis of DILI was done in 5 cases, probable in 4 and possible in 2 patients. Higher predominance in women was determined (91%). In 3 of them excessive physical training and in 2 energetic drinks and nutritional supplements were recorded. The incidence of DILI in our series was 0.73% to 100 inpatients. After drug cessation the liver function was completely restored in all patients.

Conclusion: Correlation between the clinical approach and RUCAM scale was poor. RUCAM scale is nowadays the only quantitative scale for DILI diagnosis determining. Accurate history taken on concomitant treatment, alcohol, drug and nutritional supplements, excessive physical training or massage procedures are needed. The consistent drug combination together with monitoring of liver and kidney function especially in patients over 60 with more than 4 drugs is needed for prevention of DILI.

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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 University Hospital Hradec Kralove, Czech Republic

Background: TIPS is endovascular radiologic method mainly used for management of complications of intrahepatic portal hypertension (usually caused by cirrhosis) such as acute variceal bleeding, refractory ascites and prevention of variceal rebleeding. The method is sometimes used as a bridge to liver transplantation. It is still difficult to predict surviving of patients either after TIPS and on waiting list before liver transplantation even when using new MELD score. There are emerging studies which consider nutritional status as possible predictor of surviving of patients with liver cirrhosis. Aim of this study is to evaluate if sarcopenia representing nutritional status is contributing factor effecting surviving patients after TIPS.

Methods: We enrolled all patients with liver cirrhosis who underwent TIPS in University Hospital Hradec Kralove between September 1992 and February 2014 and have available abdomen computed tomography in time before TIPS. We have measured a volume of psoas major muscle (as referential muscle) - the part between level of first pelvic bones appearing by craniocaudal move and level 5 cm above. Achieved volume was divided by body surface area (BSA). These values were used for Cox regression analysis. We have used statistical software “R”.

Results: We examined 148 patients, 102 males, 46 females, average age 57.2 years, average Child-Pugh score 8.6 points, average MELD score 14.6 points. The most often etiology of liver cirrhosis was alcohol abuse (105 patients, 71%), then cryptogenic cirrhosis (17 patients, 12%). The most common indication for TIPS was refractory ascites (87 patients, 59%), then prevention of variceal rebleeding (37 patients, 25%) and management of acute variceal bleeding refractory to standard therapy (so-called urgent TIPS) (14 patients, 10%). Average ratio of psoas muscle volume and body surface area was 42.2 cm³/m² (range 17.9–80.8), average for males and females was 48.6 and 36.9 cm³/m² respectively. According to indication for TIPS, average volume of psoas muscle differs only between group of patients indicated for TIPS because of refractory ascites and for prevention of variceal rebleeding. There were differences between group of patients with Child-Pugh score A vs. B, B vs. C. According to Cox-analysis volume of referential muscle divided by body surface area is predicting factor for surviving of patients after TIPS only for group of patients indicated to manage acute variceal bleeding refractory to standard therapy (p = 0.043, HR 0.853). The psoas muscle volume/BSA is not statistically significant associated with surviving of patients after TIPS at all patients, females, males, other then urgent TIPS indications. By comparing MELD score with psoas mucle volume/BSA it seams to be muscle volume more important predictor of surviving (p = 0.09, HR 0.87 vs. p = 0.48, HR 1.094).

Conclusion: In our study muscle volume is prediction factor of surviving at patients after TIPS for acute variceal bleeding.

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Optimization of the treatment of patients with liver cirrhosis and chronic hepatic encephalopathy

Skrypnyk Igor, Maslova Ganna Ukrainian Medical Stomatological Academy, Poltava, Ukraine

Urgency of the liver cirrhosis (LC) diagnosis and treatment in Ukraine is caused by its increasing prevalence of 51.4% (2010 vs. 2007 year). Ukraine is a country with medium-high level of alcohol consumption (12 liters per person annually) and it takes the 5th place in the world. High (5 points) indicator of disease risk associated with alcohol, typical for Ukraine and Russia. The aim of the present study was to increase the treatment effectiveness of patients with liver cirrhosis by incorporating a combination of hepatoprotectors and non-absorbable antibiotic rifaximin on the basic therapy background. Were examined 49 patients with LC, of which stage A by Child-Pugh in 40 (81.6%); stage B in 9 (18.4%), all patients with chronic hepatic encephalopathy (HE) I–III degrees. All patients were divided into three groups depending on the therapeutic complexes: I (n = 15) – ademethionine 1200 mg/day; II (n = 18) – ademethionine 1200 mg/day + L-ornithine L-aspartate (LOLA) 15 g/day; III (n = 16) – ademethionine 1200 mg/day + LOLA 15 g/day + rifaximin 800 mg/day.

The protein content in the diet of LC patients in the HE presence was 1.0–1.5 g/kg to maintain a positive nitrogen balance. The treatment effectiveness evaluation was carried out of the test number time, the nature of changes in handwriting, clinical and laboratory parameters. As a result, after 20 days of treatment the execution time reduction of "test number" was noted in group I patients by 25.4%, II – by 38.7%, group III – by 51.2%. The ammonia concentration in the blood on the therapy background decreases maximum in patients of group III – 59.3% versus 30.5% and 42.4% in groups I and II respectively. The most effective reduction of cytolysis and cholestasis enzymes activity achieved in patients of group III. ALT activity in patients of group III decreased in 3.2 times compared with 2.1 and 2.7 times in groups I and II, alkaline phosphatase activity – in 1.8 times compared with 1.3 and 1.5 times respectively. The blood argynase activity, reflecting liver detoxication function, increased in 1.4 times, 1.7 and 2.4 times, respectively in patients of I–III groups. The combined therapy of LC patients complicated by HE, the most effective when treatment complexes include the rifaximin on the background of ademethionine, L-ornithine L-aspartate and basic therapy.

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Who gets referred to a liver clinic and are we making best use of resources?

A. Tohani, M. Lander, A. Rochford, A. Dias Newham University Hospital, Barts Health NHS Trust, London, UK

Introduction: Chronic liver diseases are complex and can deteriorate without regular follow up. Our East London hospital serves a young and ethnically diverse population of 250,000. We converted an existing Gastroenterology clinic to focus on liver disease. We examined the demographics and caseload of this new clinic.

Methods: We retrospectively reviewed the notes and electronic records for all patients attending the Hepatology clinic for 12 months from October 2012.

Results: 596 patients attended the clinic, 278 were male and the mean age was 41 (range 17–81). 281 were new.

Table 1:

Referral Reason

HBV 362

HCV 72

ALD 28

Autoimmune hepatitis 9

PBC/PSC 2

Other 123

Referral Source

GP 367

Antenatal clinic 100

Other clinic 35

Genito-urinary clinic 34

Ex-inpatient 33

Other 27

Ethnicity Indian Subcontinent 203

Black African 169

Eastern European 92

White British 58

Far Eastern 30

Other 44

Follow Up <3 months 29

3 months 83

6 months 322

12 months 64

None 98

58 patients had cirrhosis. 113 Did not attend their follow up. Most had ALD (32), were ex-inpatients (27) and were from Eastern Europe (25). If a patient DNAs one appointment, another is given but only half re-attend.

Discussion/Conclusion: Specialist Hepatology clinics are in high demand. Ensuring proper follow-up and preventing DNAs ensures best use of resources. Strategies to prevent this are needed; reminding patients in their own language could help.

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Transient elastography in detecting minimal hepatic encephalopathy in cirrhotic patients

Tudora Adriana, Dragan-Teicu Emil, Dragan-Teicu Alina Medlife Genesys Hospital, Arad, Romania

Introduction: Minimal hepatic encephalopathy (MHE) represents a neurocognitive dysfunction that is present in the majority of patients with liver cirrhosis (LC). Currently, the psychometric hepatic encephalopathy score (PHES) is recommended for diagnosing MHE. It involves five paper-and-pencil tests: the digit symbol test, number connection test A, number connection test B, serial dotting test, and line tracing test. Transient elastography (TE) is an established non-invasive tool to determine severity of hepatic fibrosis.

Aim: To investigate the prevalence of minimal hepatic encephalopathy (MHE) and to assess relation with TE values.

Methods: 66 patients with LC (29 women [46.3%] and 37 males [57.3%]) with clinically, biologically and endoscopy established diagnosis and 50 healthy subjects were included. Subjects from both the control group and from the LC group completed the PHES. In all these patients transient elastography (TE) was performed the same day.

Results: The age and education years of the LC group were 57.9 ± 2.86 and 11 ± 4 years, respectively, and for the healthy subjects 44.45 ± 10.1 and 10.1 ± 3.8 years respectively. The PHES in the control group was -0.45 ± 2.88, (the normal range was thus set at > -5 points) and in the cirrhotic patients -4.04 ± 4.14 (significanyly higher p < 0.0001). Moreover, the results of NCT-A, NCT-B, LTT, SDT and DST in the LC group were 44.49 ± 17.69, 87.2 ± 21.29, 87.34 ± 31.49, 63.2 ± 21.06 and 39.1 ± 11.9, respectively (significantly higher from normals). Based on PHES, 42.54% (28/66) patients were considered as having MHE. LSM was significantly higher in those with MHE than in those without MHE (median 34.75 ± 8.6 kPa vs. 23.75 ± 9.1 kPa; p = 0.007).

Discussion/Conclusion: TE can be used identify patients for the presence of MHE. In our study we identified a cut-off of 22.5 kPa (sensitivity 81% and specificity of 72%) to detect MHE, and thus all patients with LSM> 22.5kPa should undergo PHES testing to rule out the presence of MHE.

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FibroTest and its correlation with other laboratory parameters of liver function in patients with Wilson’s disease

L. Turecký, V. Kupčová, E. Uhlíková, P. Ščigulinský Institute of Medical Biochemistry and Clinical Biochemistry and 3rd Department of Medicine, Medical School, Comenius University, Bratislava, Slovakia

Introduction: Wilson’s disease (WD) is an autosomal recessive genetic disorder which manifests as neurological or psychiatric symptoms and liver disease. The condition is due to mutations in ATP7B gene. Clinical features which are results from toxic accumulation of copper in the liver may include hepatic abnormalities such as chronic hepatitis and cirrhosis, culminating in progressive liver failure. Hepatic fibrosis is an important pathogenetic mechanism which ultimately leads to liver cirrhosis. FibroTest is a potential biomarker that uses results of six blood serum tests to generate a score that is correlated with the degree of liver damage in people with a variety of liver diseases. The aim of our study was to determine the FibroTest score in patients with WD and to correlate the results of FibroTest with other laboratory parameters of liver function.

Methods: Examined group consists of 18 patients with Wilson’s disease. We determine the FibroTest, serum levels of alpha-2-macroglobulin, apoprotein A1, haptoglobin, albumin, prealbumin, cholinesterase and total bile acids level.

Results: As showed results of our study, the levels of alpha-2-macroglobulin (AMG), potential fibromarker, were significantly increased in group of patients with WD (4534 mg/l vs. 2294 mg/l). The calculation of FibroTest score showed positive results in 50% of our patients, but the results were mainly only moderately increased (there was only 17% of results corresponding to F4 in METAVIR classification). The differences in albumin and prealbumin levels between FibroTest-positive and -negative patients were not significant. The most significant difference between Fibro Test positive and negative patients was in levels of total bile acids.

Discussion/Conclusion: The results showed that in the group of patients with Wilson’s disease despite of 50% positive FibroTest results the parameters of liver proteosynthetic function were changed only minimally.

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Oxidative stress and induction of cytochrome P450 in development of diabetic hepatopathy in experimental animals

L. Turecký, E. Uhlíková, V. Kupčová Institute of Medical Biochemistry & Clinical Biochemistry and 3rd Department of Medicine, Medical School, Comenius University, Bratislava, Slovakia

Introduction: NASH is increasingly recognized as a significant form of chronic liver disease. The clinical course of NASH is known to be variable ranging from one of indolence to one of progressive liver disease with cirrhosis. There is evidence that oxidative stress is strongly implicated in the pathogenesis of NASH. Important risk factors for NASH include obesity, type 2 diabetes, insulin resistance and hypertriacylglycerolemia. The possible source of reactive oxygen species (ROS) in liver tissue are mitochondria, monooxygenase system of cytochrome P450 and peroxisomes. The aim of our contribution was to study the oxidative stress and activity of cytochrome P450 in liver tissue of animals with streptozotocin diabetes induced in newborn rats which is accepted as a model for diabetes type 2.

Methods: Newborn male Wistar rats were used in experiment. Diabetes was induced by repeated i.p. administration of STZ on 2nd and 9th day after birth. 12 weeks after birth the animals were killed. In the liver tissue we determined the concentration of malondialdehyde (MDA), the activity of non-stimulated and stimulated lipoperoxi-dation, enzymatic activity of cytochrome P450 and the level of reduced glutathione.

Results: The results of our study showed increased levels of MDA in liver tissue of diabetic animals (21 vs. 12 ng/g). The activity of lipoperoxidation was significantly increased in diabetic animals in comparison with control group. The enzymatic activity of cytochrome P450 was significantly increased and the level of reduced glutathione was decreased in liver of diabetic animals. There was significant positive correlation between the activity of lipoperoxidation and the activity of cytochrome P450.

Discussion/Conclusion: According to these results is supposed, that oxidative stress may play an role in pathogenesis of diabetic hepatopathy and that important source of ROS in liver of diabetic animals is induction of cytochrome P450.

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Alpha-2-macroglobulin and laboratory parameters of oxidative stress in patients with Wilson’s disease

E. Uhlíková, V. Kupčová, P. Ščigulinský, L. Turecký Institute of Medical Biochemistry & Clinical Biochemistry and 3rd Medical Clinic, Medical School, Comenius University, Bratislava, Slovakia

Introduction: Fibrogenesis is an important pathobiochemical factor which participates in the pathogenesis of chronic liver diseases. Alpha-2-macroglobulin (AMG) is one of potential non-invasive biochemical fibromarkers. There are several informations about the role of oxidative stress in the pathogenesis of liver fibrosis. Wilson’s disease (WD) is an inherited metabolic disease characterized by toxic accumulation of copper, primarily in the liver and therefore may be associated with chronic liver damage (chronic hepatitis, cirrhosis). The aim of our study was to analyze the relationships between the level of alpha-2-macroglobulin and serum parameters of oxidative stress in patients with WD.

Methods: The study group included 18 patients with verified Wilson’s disease. We determined in the serum the levels of alpha-2-macroglobulin, malondialdehyde (MDA) and nitrotyrosine, the activities of polyphenoloxidase, ferroxidase and paraoxonase (PON) and the activity of erythrocyte superoxide dismutase (SOD) and total serum antioxidant capacity (TEAC).

Results: The serum levels of alpha-2-macroglobulin were significantly increased in patients with WD in comparison with control group of healthy people (4534 mg/l vs. 2294 mg/l). The regression analysis between the serum level of AMG and para-meters of oxidative stress (TEAC, MDA, PON, polyphenoloxidase, ferroxidase) showed no significant correlations. The only significant correlation was between serum AMG and erythrocyte SOD.

Discussion/Conclusion: The lack of more significant correlation between the level of fibromarker AMG and parameters of oxidative stress in serum of patients with WD could reflect the fact, that fibrogenesis in WD has more complex pathogenesis and that oxidative stress is not the main factor. On the other side, serum markers of oxidative stress may not reflect accurately the oxidative stress in the liver and the situation in liver tissue could be different to the situation in the blood.

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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 Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, Iasi, Romania

There has been shown an inverse relationship between insulin resistance, highly corelated with fatty liver disease, and blood 25-hydroxy-vitamin D (25(OH)D) levels.

The aim of the present study was to evaluate the association between the presence, stage of fatty liver disease and levels of vitamin D among non-obese subjects and to determine the effect of vitamin D status on the development of fatty liver disease.

Methods: We retrospectively reviewed 67 non-obese (body mass index < 30 kg/m²) 45 (67%) women and 22 (33%) men admitted to our clinic. Laboratory values, lipid profiles, liver function tests, C-reactive protein, fasting blood glucose, insulin, calcium and 25(OH)D levels were studied.

Results: Low vitamin D levels, higher alanine aminotransferase levels and higher triglyceride levels were found to be the significant determinants for non-alcoholic fatty liver disease. In the group of patients with low or normal vitamin D, the low levels of vitamin D was assesed as a risk factor for fatty liver disease.

Conclusions: Patients with low vitamin D status may have an increased risk for fatty liver disease. This issue may be suggestive of mechanisms promoting fat flow and accumulation in the liver. Molecular studies are warranted to elucidate the action of vitamin D on the liver with respect to fat metabolism.

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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. Więcek, H. Woś, B. Kordys-Darmolińska, U. Grzybowska-Chlebowczyk Department of Pediatrics, Medical University of Silesia, Katowice, Poland

SERPINA1 gene is present in about 2% of patients with cystic fibrosis, but more frequently, i.e. in approximately 5% of patients with cystic fibrosis and concomitant changes in the liver. SERPINA1 gene is responsible for the synthesis of serine protease inhibitor, and protein associated with the Z allele is accumulated within the endoplasmic reticulum of hepatocytes, resulting in their damage, inflammation and cirrhosis.

The aim of this study was to assess the impact of SERPINA gene mutation on the occurrence of liver damage and cholestasis in patients diagnosed with cystic fibrosis.

Patients and Methods: The analysis included 30 children, 13 girls (43.3%) and 17 boys (56.6%), aged from 6 months to 18 years (mean age 5.5 years), with diagnosed cystic fibrosis. All patients underwent genetic testing for SERPINA gene mutation. The analysis included age, sex, clinical symptoms, type of mutation of the CFTR protein, laboratory abnormalities (levels of transaminases, GGTP, FA, protein, acid steatocrit) and ultrasound examination of the abdomen.

Results: Elevated transaminases were found in 9/30 (30%), whereas elevated levels of gamma-glutamyl transferase in 6/30 (20%) children. In 5/30 patients the ultra-sound examination demonstrated liver enlargement with increased echogenicity. The mutation in SERPINA gene was found in 1/30 (3.3%) patient with cystic fibrosis. Currently, this patient has normal values of transaminases, GGTP and FA, whereas a significant worsening of respiratory symptoms is observed. There was no correlation between the occurrence of SERPINA gene mutation and clinical symptoms, type of CFTR protein mutation, results of laboratory tests of liver function and hepatocyte damage, and ultrasound examination of the abdomen.

Conclusions: There was no correlation between the occurrence of SERPINA gene mutation and the presence of features of liver damage and cholestasis in children diagnosed with cystic fibrosis.

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Influence of single-nucleotide polymorphisms in TFR2, TF and HFE genes on iron homeostasis and hepatic injury in chronic hepatitis C patients

A. Woziwodzkaa, A. Bernata, M. Rybickaa, J. Markiewiczb, K. Sikorskac, K.P. Bielawskia aIntercollegiate Faculty of Biotechnology, Laboratory of Molecular Diagnostics, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822 Gdansk, Poland bPomeranian Centre for Infectious Diseases and Tuberculosis, Smoluchowskiego 18, 80-214 Gdansk, Poland cDepartment of Infectious Diseases, Medical University of Gdansk, Smoluchowskiego 18, 80-214 Gdansk, Poland Correspondence to: [email protected]

Introduction: Clinical manifestation of iron overload includes iron storage in the liver, often leading to progressive fibrosis, cirrhosis, and hepatocellular carcinoma. Mild to moderate iron overload is common among patients with chronic hepatitis C (CHC) and may lead to poor clinical outcome. The most common genetic factor leading to iron overload is C282Y polymorphism in HFE gene. Moreover, polymorphisms in TF and TFR2 genes encoding transferrin and transferrin receptor, are supposed to affect iron homeostasis.

Methods: The aim of this study was to assess the impact of TFR2, TF and HFE genes polymorphisms on both serum iron parameters and histopathological markers of liver injury in 90 patients with confirmed CHC. Genetic polymorphisms were determined with MALDI-TOF mass spectrometry and correlated with clinical data.

Results: Increased levels of ALT activity (p = 0.027), serum iron (p = 0.006), transferrin saturation (p = 0.017), and ferritin (p = 0.01) were observed in HFE C282Y patients. Interestingly, HFE S65C heterozygotes showed a slightly reduced ALT activity. Elevated parameters of liver iron deposits were observed in HFE C282Y and S65C patients. No differences in serum iron markers and liver injury were detected among carriers of HFE H63D and S65C, TF and TFR2 variants. However, the 0.5 frequency of C allele in TFR2 gene (rs7385804) observed in this study was significantly higher than its 0.31 frequency in a general European population, suggesting its role as a potential risk factor in course of HCV-related disease.

Discussion/Conclusion: To conclude, this study provided evidence that HFE polymorphisms are genetic factors influencing iron homeostasis in CHC patients. Further studies on the impact of variations in genes possibly influencing iron status, on both disease progression and efficacy of CHC treatment occur to be of a substantial clinical significance.

Acknowledgement: This research was financed by Polish National Science Centre (grant no 2011/01/B/NZ6/00320).

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Bile duct stenting in teenagers with advanced primary sclerosing cholangitis

Małgorzata Woźniak1, Jan Pertkiewicz2, Katarzyna Zieniewska-Pingwara3, Marek Woynarowski1 1Children’s Memorial Health Institute, Warsaw, Poland 2ENDOTERAPIA, Warsaw, Poland 3Paediatric Hospital, Warsaw, Poland

The paper discusses the effects of endoscopic bile duct stenting in patients with PSC.

Introduction: Primary sclerosing cholangitis (PSC) is chronic liver disease progressing to liver cirrhosis and insufficiency. Endoscopic bile duct stenting may reduce cholestasis and delay the need for liver transplantation. The aim of this study was to analyse the endoscopic bile duct stenting procedures done in adolescents with PSC.

Methods: This is retrospective analysis of patients with PSC and severe cholestasis referred for endoscopic retrograde cholangiography (ERCP) with bile duct stenting between 2008 and 2013.

Results: ERCP was done in 11 patients (7M, 4F) with PSC diagnosed at the age of 3–19 years (mean 13.5). At the time of diagnosis mean bilirubin concentration was 4 mg% (1–12), GGTP was 370 U/l (12–1180) and ALT activity was 240 U/l (16–1075). PSC/AIH overlap syndrome was diagnosed in three patients and ulcerative colitis in two. In total 51 ERCP procedures were performed (1–9 per patient, mean: 5). The time between the procedures varied from 1 to 48 months (mean 5 months). Majority of patients had implementation of 8.5 or 10 Fr bile duct stent. Immediately after the procedure patients had reduction of total bilirubin concentration (from 3.9 to 2,6 mg%), reduction of ALT activity (from 107 to 67 U/l) and GGTP activity (from 260 to 203 U/l). Bile duct radiography showed progression of the liver disease in 5 patients and stable liver disease in the remaining 6 subjects. No important complications of ERCP were noted. Clinical status of patients remained stable without the progression requiring liver transplantation. 7 patients were transferred to adult centre for further treatment. 4 patients continue therapy in paediatric site and 3 of them continue endoscopic therapy.

Discussion/Conclusion: In the analysed group of adolescents with PSC, ERCP with bile duct stenting was safe and improved laboratory liver function.

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69

Role of hepatitis and other factors precursor to originating the liver cancer

A. Yusupbekov, M. Djuraev Tashkent City Cancer Center, Tashkent Pediatric Medical Institute, National Scientific Center of Oncology, Uzbekistan

The purpose: To learn influencing hepatitis A, B, C and some other factors in originating the liver cancer (LC). With this purpose the outcomes of 430 patients with the primary LC, which were in the department of abdominal surgery of clinic from 1996 to 2004 (264 men [61.4%] and 166 women [38.6%]). The age oscillated from 13 to 78 years. The methods of testing included: X-ray inspection of gastrointestinal tract, gastroscopy, ultrasonog-raphy, computed tomography, laparoscopy inspection with biopsy, morphological and clinical – biochemical researches. 305 (70.9%) patients among 430 before addressed in medical entity concerning this or that pathology of liver. The diagnosis histological was established in 408 (95%) patients. From them hepato-cellular cancer is established in 310 (76%) and cholangiocellular in 96 (24%) patients. T3N1M0 in 96 (22.%), T4N0-1M0 in 334 (77.7%) patients. Careful data acquisition on the transferred diseases, kind of work, nature of a feed, the ecological features showed that in 195 (45.%) patients in anamnesis took place the transferred different forms o hepatitis, from them hepatitis A in 65 (15.1%) patients, hepatitis B in 105 (24%), which one confirmed also by availability in a blood HBsAg. Hepatitis C in 14 (3.3%) patients. The small number observation hepatitis C is connected that identification of this virus started since 2000. Duration of transition of hepatitis in cancer gives from 8 till 26 years. The alcoholic cirrhosis of liver with transition to cancer is marked in 38 (8.8%) patients. The long and constant contact with agricultural chemicals is found at 42 (9.7%) patients with liver cancer. In 14 (3.2%) patients professional work was connected with manufacturing color products. 85 (19.7%) patients were hospitalized from an ecological ill-behaved zone – Aral sea coastal region, where the poor maintenance of water, reinforced contamination of water and soils by nitrogen-containing agricultural chemicals. Burdened a heredity is established in 8 (1.8%) patients and in 48 (11.2%) patients precursor factors were not established. Under the data of testing methods from 430 patients for 365 (84.8%) apart from a tumoral lesion in the rest segments are found cirrhotic changes 55.4% and in 44.6% phenomenon of chronic hepatitis, that eliminated a capability of surgical treatment. Only in 65 (15.1%) patients rest segments of liver were in a normal or rather normal condition permitting to execute this or that kind of surgical intervention.

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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.М. Zygalo# State Institution “Institute of Gastroenterology of National Academy of Medical Sciences of Ukraine", Dnipropetrovsk*, State Institution "National Scientific Center of Radiological Medicine of National Academy of Medical Sciences of Ukraine", Kyiv#,

Ukraine

Although the cause of the disease is unknown at this time, autoimmune processes is known to pay significant role in development and progresses of PBC. Moreover, most scientists consider that PBC is autoimmune, when pathogenesis of it bases on antigen-antibody reaction and other different immune disorders.

Materials and Methods: 15 patients with established diagnosis of PBC were studied. Humoral link of immunity, including of serum levels of immunoglobulins A (IgA), M (IgM), G (IgG), was determined by radial immunodiffusion technique of Mancini. Circulating immune complex (CIC) was studied by V. Haskova method.

Results: The absolute number of T lymphocytes was decreased patients with PBC. Quantitative deficiency and violation of functional activity of T-links of immune system is accompanied by change of a ratio of immunoregulatory T-lymphocyte subpop-ulations. Violations of T-links of immune system stayed in close connection with changes of B-links. There was different extent of increase relative and absolute quantity of B-cells.

The obtained data allow to draw a conclusion that the tendency to exhaustion of immune system is observed in patients with PBC. At the same time there remains a high expression of activation anti-genes that might point to violations in carrying out signals in cells of immune system.

Thus, insufficiency of an energy potential of lymphocytes, violations of maturing and differentiation of immune regulatory subpopulations is accompanied by sharp change of quantitative and functional indices of all immunocompetent cells that is the main link in pathogenesis of secondary immune deficiency at PBC.

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Author Index to Poster Abstracts(Name - Poster Number)

Aktan, C. 43Aleksiev, A. 7Alexiev, A. 29Amzolini, A. 40, 41Ananiev, Y. 30Anastasiou, J. 37Antipa, E. 37Antonov, K. 7Ardelt, M. 35Arena, S. 13Astakhin, A. 34Aydin, H. 43Aytemiz, E. 20

Baatarkhuu, O. 6Babameto, A. 32Babasheva, G. 26Bachmann, A. 1Badea, M.A. 2, 3Bahcecioglu, I.H. 4Bataga, S. 5Bayarmagnai, B. 6Bekhbold, D. 6Bernat, A. 67Bielawski, K.P. 19, 51, 67Bishnu, D. 53, 54Blackwell, R. 45Blaj, A. 2, 3, 10, 11, 12, 24,

25, 65Blum, H.E. 42Boguszewska-Czubara, A. 46, 47Bossi, P. 27Botianu, A.-M. 5Boyanova, Y. 7Bradley, A. 28Bueringer, K. 1

Calovska Ivanova, V. 38Campbell, S. 33Casanova, E. 44Cecere, R. 14Celik, H.A. 43Celinski, K. 9Chakraborty, B.C. 53Chioncel, C. 8Chiriva-Internati, M. 27Chovanec, V. 23, 58

Chowdhury, A. 53, 54Christidou, A. 37Cichoz-Lach, H. 9Cijevschi Prelipcean, C. 2, 3, 10, 11,

12, 24, 25, 65Ciorba, M. 5Ciurea, T. 40, 41Crompton, S. 45Cucos, A. 2, 3, 10, 11, 12

Dahgwahdorj, Y. 6de Mey, C. 7de Toni, E.N. 13Delle Monache, M. 14Demeshkina, L.V. 15, 70Denk, G.U. 49Dhali, G.K. 53, 54Dhana, A. 32Dhigoi, N. 32Di Biccari, S. 27Dias, A. 60Didenko, V.I. 15, 70Dillon, A. 16Dimitrova, N. 31Djuraev, M. 69Domnariu, C. 50Dragan-Teicu, A. 17, 18, 61Dragan-Teicu, E. 17, 18, 61Dragneva, S. 31Dranga, M. 3, 24, 65Dreczewski, M. 19Dülger, A.C. 20Duncan, A. 33

Ehrlich, S.M. 35El Aggan, H.A. 21, 22El Deeb, N. 22

Farcas, H. 5Farmazon, A. 40, 41Fawzy, M. 22Fejfar, T. 23, 58Ferrone, S. 27Franceschini, B. 27Francia, C. 14Fratila, O. 50

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Gallmeier, E. 13Galvin, Z. 16Gavrilescu, O. 24, 25, 65Genadieva-Dimitrova, M. 38Genunche-Dumitrescu, A. 41Georgiev, K. 30Gerbes, A.L. 13, 55, 56Geyvandova, N. 26Göke, B. 13, 55, 56Gönüllü, E. 20Grizzi, F. 27Grzybowska-Chlebowczyk, U. 66Gulubova, M. 30

Helmy, M. 22Heydtmann, M. 28Hoerauf, A. 36Hohenester, S. 49Honda, A. 39Hulek, P. 23, 58

Ianosi, G. 40, 41Ikegami, T. 39Ispiroglu, M. 4Ivanova, Radina 29Ivanova, Raya 29

Jakabovicova, M. 57Janevska, D. 38Jelev, D. 7Jirkovsky, V. 23, 58

Kal, I. 4Kalinova, K. 30Kaneti, E. 31Karadzova, A. 38Karamanolis, D. 37Kasztelan-Szczerbinska, B. 9Kellici, I. 32Keskin, M. 43Kolligs, F.T. 13Kordys-Darmolinska, B. 66Kosseva, O. 31Kowalik, A. 9Kraja, B. 32Krajina, A. 23, 58Krämer, B. 36Krastev, Z. 7, 31Kudryavtseva, V.E. 15, 70Kupcova, V. 62, 63, 64

Lachlan, N. 33Lander, M. 60Langhans, B. 36Lemberger, U.J. 44Levitan, B. 34Levitan, G. 34Liebl, J. 35Lipscomb, G. 45Lis, E. 9Liss, I. 55, 56Lojik, M. 23, 58Lowry, D. 16Lu, S. 13Lutz, P. 36

Macarie, M. 5Mahon, R. 44Makeschin, M.-C. 56Marcin, D. 51Markiewicz, J. 67Maslova, G. 59Mateva, L. 7, 29Matsuzaki, Y. 39Mela, M. 37Michl, A. 23Mihai, C. 2, 3, 10, 11, 12, 25Mihaila, R.G. 50Miloshevski, M. 38Miyazaki, T. 39Moldovan, A. 8Müller, S. 1

Nagel, J.M. 49Naranjargal, D. 6Nattermann, J. 36Neagoe, D. 40, 41Nedelciuc, O. 2, 3Nedelcu, L. 50Negovan, A. 5Nepesova, K.B. 42Nepesova, O.B. 42Nigiyan, Z. 26Nischalke, H.-D. 36Nüssler, A.K. 1

Oien, K. 28Oruc, N. 43Österreicher, C.H. 44Ottinger, S. 1Ozercan, I.H. 4Ozturk, A. 43

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Ozutemiz, O. 43

Padmakumar, K. 45Padmakumar, N. 45Peccerella, T. 1Pertkiewicz, J. 68Petkova, T. 31Popescu, A. 8Popescu, M. 40, 41Popova Jovanovska, R. 38Prifti, S. 32Prystupa, A. 46, 47Pumnea, M. 48

Raupach, J. 23, 58Reda, M.I. 21Reiter, F.P. 49Renc, O. 23, 58Rezi, E.-C. 48, 50Rheinländer, J. 1Rizk, M.M. 21Rizzani, A. 13Rochford, A. 60Rülicke, T. 44Rust, C. 49Rybicka, M. 19, 51, 67

Safka, V. 23, 58Sanduijav, R. 52Sandulescu, L. 40Santra, A.K. 53, 54Santra, S. 53, 54Saprikis, E. 37Schäffer, T.E. 1Schewe, J. 55, 56Schlabe, S. 36Scigulinsky, P. 62, 64Sedlacko, J. 57Sedlakova, Z. 57Selzner, L. 55, 56Sembera, S. 23, 58Serafimoski, V. 38Shihab, A. 8Sikorska, K. 19, 67Skrypnyk, I.N. 59Smiatacz, T. 19, 51

Spengler, U. 36Stalke, P. 19, 51Steib, C.J. 55, 56Stewart, S. 16Stoyanov, G. 30Strassburg, C.P. 36Szantova, M. 57Szpetnar, M. 46

Tilinca, M. 5Todorovska, B. 38Tohani, A. 60Torok, I. 5Trajkovska, M. 38Trauner, M. 44, 49Tudora, A. 17, 18, 61Turecky, L. 62, 63, 64

Uhlikova, E. 62, 63, 64Unal, N.G. 43Ungureanu, I. 2, 3, 10, 11, 12, 25,

65

Vanasek, T. 23, 58Viazis, N. 37Vollmar, A.M. 35

Wiecek, S. 66Wimmer, R. 49Wos, H. 66Wottke, L. 49Woynarowski, M. 68Woziwodzka, A. 51, 67Wozniak, M. 68

Yagoda, A. 26Yalniz, M. 4Yusupbekov, A. 69

Zahler, S. 35Zaluska, W. 46Zeid, A. 22Zieniewska-Pingwara, K. 68Zizka, J. 23, 58Zygalo, E.V. 15, 70Zygalo, V.N. 70

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AbstractsPoster Abstracts

Falk FoundationDr. Falk Pharma Falk Symposium 195

Challenges and Management ofLiver Cirrhosis

October 10 – 11, 2014Konzerthaus FreiburgFreiburg, Germany

112116_Falk_Freiburg_Symp195_Abstracts_US.indd 1 18.09.14 09:33


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