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Digestive and Liver D
isease
49 S1
EL
SEV
IER
Vol . 49 / S
1 ( 2017 ) e1 – e71
VOLUME 49 SUPPLEMENT 1 16 FEBRUARY 2017 ISSN 1590-8658
Abstracts of the 50th A.I.S.F. –Italian Association for the Study of the Liver –
Annual Meeting 2017Rome, 23–24 February 2017
An International Journal of Gastroenterology and Hepatology
Digestiveand Liver Disease
Italian Association for the Study of the Liver (AISF)Italian Association for the Study of the Pancreas (AISP) Italian Association for Digestive Endoscopy (SIED)Italian Society of Gastroenterology (SIGE)
Italian Society of Pediatric Gastroenterology and Hepatology (SIGENP)Italian Group for the Study of Infl ammatory Bowel Disease (IG-IBD)Fédération Francophone de Cancérologie Digestive (FFCD)
SECTION EDITORS
Basic ScienceGianfranco Alpini, Temple, USA
Romina Mancinelli, Rome, Italy
Theresa T. Pizarro, Cleveland, USA
Digestive EndoscopyAndres Cardenas, Barcelona, Spain
Arnulf Ferlitsch, Vienna, Austria
Cesare Hassan, Rome, Italy
Helmut Neumann, Mainz, Germany
Emanuele Rondonotti, Como, Italy
Digestive OncologyThomas Aparicio, Paris, France
Côme Lepage, Dijon, France
General GastroenterologyMaura Corsetti, Leuven, Belgium
Nicola de Bortoli, Pisa, Italy
Edoardo Savarino, Padua, Italy
Radu Tutuian, Bern, Switzerland
Umberto Volta, Bologna, Italy
ImagingAnnalisa Berzigotti, Bern, Switzerland
Cristina Bezzio, Garbagnate Milanese, Italy
Federica Furfaro, Rozzano, Italy
Giovanni Maconi, Milan, Italy
Infectious DiseaseAntonella D’Arminio Monforte, Milan, Italy
Infl ammatory Bowel DiseaseAlessandro Armuzzi, Rome, Italy
Emma Calabrese, Rome, Italy
Stephen Collins, Hamilton, Canada
Laurent Peyrin-Biroulet, Vandoeuvre, France
Liver DiseaseTarik Asselah, Clichy, France
Jaime Bosch, Barcelona, Spain
Maurizia Brunetto, Pisa, Italy
Patrizia Burra, Padua, Italy
Alessia Ciancio, Turin, Italy
Alessandra Dell’Era, Milan, Italy
Rafael Esteban Mur, Barcelona, Spain
Silvia Fargion, Milan, Italy
Vincenzo La Mura, San Donato Milanese, Italy
Ana Lleo, Milan, Italy
Salvatore Petta, Palermo, Italy
Fabio Piscaglia, Bologna, Italy
Pancreatic DiseaseGabriele Capurso, Rome, Italy
Alberto Malesci, Milan, Italy
Pediatric GastroenterologySalvatore Cucchiara, Rome, Italy
SurgeryMassimo Falconi, Milan, Italy
Roberto Santambrogio, Milan, Italy
Statistical ConsultantFederico Ambrogi, Milan, Italy
Editors EmeritiGabriele Bianchi-Porro, Milan, Italy
Mario Angelico, Rome, Italy
Editor in ChiefRoberto de Franchis, Milan, Italy
Co-EditorsSavino Bruno, Milan, Italy
Maurizio Vecchi, San Donato Milanese, Italy
Managing EditorSilvia Malosio, Milan, Italy
Editorial AssistantBrenda Dionisi, Milan, Italy
EDITORIAL BOARD
Domenico Alvaro, Rome, Italy
Angelo Andriulli, Foggia, Italy
Paolo Angeli, Padua, Italy
Adolfo Francesco Attili, Rome, Italy
Gabrio Bassotti, Perugia, Italy
Laurent Beaugerie, Paris, France
Robert Benamouzig, Bobigny, France
Antonio Benedetti, Ancona, Italy
Marc Benninga, Amsterdam, Netherlands
Marina Berenguer, Valencia, Spain
Roman Bogorad, Cambridge, USA
Jean-Pierre Bronowicki, Vandoeuvre-Lès-Nancy, France
William R. Brugge, Boston, USA
Elisabetta Buscarini, Crema, Italy
Nicola Caporaso, Naples, Italy
Carlo Catassi, Ancona, Italy
Umberto Cillo, Padua, Italy
Agostino Colli, Lecco, Italy
Dario Conte, Milan, Italy
Gino Roberto Corazza, Pavia, Italy
Enrico Corazziari, Rome, Italy
Antonio Craxì, Palermo, Italy
Gianfranco Delle Fave, Rome, Italy
A. Jack Demetris, Pittsburgh, USA
Sharon DeMorrow, Temple, USA
Philippe Ducrotte, Rouen, France
Amal Dutta, Dallas, USA
Stefano Fagiuoli, Bergamo, Italy
Massimo Fantini, Messina, Italy
P. Marco Fisichella, Boston, USA
Heather Francis, Temple, USA
Mirella Fraquelli, Milan, Italy
Dennis Freshwater, Birmingham, UK
Giovanni Battista Gaeta, Naples, Italy
Antonio Gasbarrini, Rome, Italy
Eugenio Gaudio, Rome, Italy
Stefano Ginanni Corradini, Rome, Italy
Shannon Glaser, Temple, USA
Pietro Invernizzi, Milan, Italy
Robert Jensen, Baltimore, USA
Michel Kahaleh, New York, USA
David Laharie, Pessac, France
René Laugier, Marseille, France
Astrid Liévre, Saint-Cloud, France
Patrick Maisonneuve, Milan, Italy
Riccardo Marmo, Salerno, Italy
Marco Marzioni, Ancona, Italy
Carlo Merkel, Padua, Italy
David Mutimer, Birmingham, UK
Mattijs Numans, Leiden, Netherlands
Jean Marc Phelip, Saint Etienne, France
Paola Piccolo, Rome, Italy
Antonio Pinna, Bologna, Italy
Massimo Puoti, Milan, Italy
Franco Radaelli, Como, Italy
Alessandro Repici, Milan, Italy
Oliviero Riggio, Rome, Italy
Mario Rizzetto, Turin, Italy
Renato Romagnoli, Turin, Italy
Massimo Rugge, Padua, Italy
Tilman Sauerbruch, Bonn, Germany
Jean-Cristophe Saurin, Pierre-Benite, France
Vincenzo Savarino, Genoa, Italy
Laurent Siproudhis, Rennes, France
Etienne Sokal, Brussels, Belgium
Mario Strazzabosco, New Haven, USA
Giacomo Carlo Sturniolo, Padua, Italy
Pier Alberto Testoni, Milan, Italy
Guiseppe Tisone, Rome, Italy
Michael Trauner, Vienna, Austria
Vincenzo Villanacci, Brescia, Italy
Alrefai Waddah, Chicago, USA
Frank Zerbib, Bordeaux, France
Huiping Zhou, Richmond, USA
Official Journal of:
Vol. 49 Supplement 1 (2017)
Contents Vol . 49 Supplement 1 ( 16 February 2017 )
Index Medicus (MEDLINE), Current Contents/Clinical Practice,Science Citation Index and EMBASE/Excerpta Medica
Sociedad Iberoamericana de Información Cient ıfi ca (SIIC)
Associato alla Unione Stampa Periodica Italiana
Abstracts of the 50th A.I.S.F. - Italian Association for the Study of the Liver - Annual Meeting 2017 Rome, February 23rd-24th, 2017: Selected oral communications e1
Abstracts of the 50th A.I.S.F. - Italian Association for the Study of the Liver - Annual Meeting 2017 Rome, February 23rd-24th, 2017: Selected Posters Thursday e19
Abstracts of the 50th A.I.S.F. - Italian Association for the Study of the Liver - Annual Meeting 2017 Rome, February 23rd-24th, 2017: Selected Posters Friday e43
A.I.S.F. 2017: Abstracts Evaluation Procedure e71
Abstracts of the 50th A.I.S.F. – Italian Association for the Study of the Liver – Annual Meeting 2017
Rome, 23-24 February 2017
Digestive and Liver Disease 49S (2017) e1–e18
Contents lists available at ScienceDirect
Digestive and Liver Disease
journa l homepage: www.e lsev ier .com/ locate /d ld
Abstracts of the 50th A.I.S.F. – Italian Association for the Study of the
Liver – Annual Meeting 2017 Rome, February 23rd–24th, 2017:
Selected oral communications
OC-01
Increased hepatic glucose production andinsulin resistance are associated to increasedplasma concentrations of glucogenic aminoacids in subjects with NAFLD
M. Gaggini 1, C. Rosso 2, F. Carli 1, V. Della Latta 1,
D. Ciociaro 1, M. Marietti 2, E. Buzzigoli 1,
M.L. Abate 2, R. Gambino 2, M. Cassader 2,
A. Smedile 2, E. Bugianesi 2, A. Gastaldelli 1
1 Cardio-Metabolic Risk Laboratory, Institute of
Clinical Physiology, CNR, Pisa, Italy2 Division of Gastroenterology and Hepatology and
Lab. of Diabetology, Department of Medical Sciences,
University of Torino, Torino, Italy
Introduction: The liver plays a central role in the regulation
of glucose metabolism, being the major site of endogenous glu-
cose production (EGP) during fasting and of glucose storage (as
glycogen) during postprandial state. NAFLD subjects have increased
insulin resistance (mainly hepatic, Hep-IR) and are at higher risk of
hyperglycemia and type-2 diabetes (T2DM). However, the patho-
physiological mechanisms for increased EGP and Hep-IR are still
not known.
Aim: Since both amino-acids (AA) and lipids contributes
through gluconeogenesis to EGP, the goal was to evaluate if
concentrations of glucogenic AA (glutamate, alanine, branched
chain amino acids (BCAA), and aromatic amino acids (AAA)) were
increased and associated with EGP and Hep-IR in lean non-diabetic
NAFLD.
Materials and methods: We studied 44 non-diabetic subjects
with biopsy proven NAFLD (29 non-obese and 15 obese) and 20
non-obese controls (CT). We measured fasting EGP (by tracer infu-
sions), plasma AA and free fatty acid (FFA) concentrations by GCMS
and calculated Hep-IR (EGPxInsulin), HOMA and Adipo-IR (FFAxIn-
sulin).
Results: From CT to NAFLD non-obese to NAFLD obese
we observed the increase in EGP (584 ± 44 to 710 ± 23 to
839 ± 40 �mol/min, p < 0.0002) and Hep-IR (52 ± 6 to 96 ± 6
to 166 ± 23 �mol/kg/min × mU/l, p < 0.001). Both EGP and ln(Hep-
IR) increased proportionally to ln(ALT) (R = 0.47 and R = 0.55,
p < 0.0005), ln(AST) (R = 0.39 and R = 0.48, p < 0.003), and fibrosis
(R = 0.55 and R = 0.44, p < 0.001). EGP correlated positively with
ln(BCAA) (R = 0.35, p < 0.009), ln (AAA) (R = 0.48, p < 0.0002),
and ln(glutamate) (R = 0.29, p < 0.03); ln(Hep-IR) with ln (AAA)
(R = 0.33, p < 0.01), and ln(alanine) (R = 0.29, p < 0.03). Fibrosis
score was positively correlated to ln(AAA) (R = 0.34, p < 0.005),
ln(glutamate) (R = 0.38, p < 0.001), ln(BCAA) (R = 0.30, p < 0.01),
ln(alanine) (R = 0.29, p < 0.02).
Conclusions: In NAFLD, higher glucogenic AA concentrations
are positively associated to increased EGP, Hep-IR and fibrosis and
might explain, at least in part, the increased risk of hyperglycemia
and T2DM observed in NAFLD.
Funded by: FP7/2007-2013under grant agreement no. HEALTH-
F2-2009-241762, FLIP; PRIN2009ARYX4T; Horizon2020 under
grant agreement no. 634413, EPoS.
http://dx.doi.org/10.1016/j.dld.2017.01.005
OC-02
The hepatic expression of lysosomal acid lipase(LAL) is reduced in NAFLD patients, andassociated with features of geneticallydetermined LAL deficiency and NAFLD activityscore
U. Vespasiani-Gentilucci 1, F. Valentini 1,
S. Carotti 2, F. Vorini 1, M. Zingariello 2,
M. Francesconi 2, G. Galati 1, P. Gallo 1,
A. De Vincentis 1, C. Dell’Unto 1, S. Morini 2,
A. Picardi 1
1 Internal Medicine and Hepatology Unit, University
Campus Bio-Medico, Rome, Italy2 Laboratory of Microscopic and Ultrastructural
Anatomy, CIR, University Campus Bio-Medico, Rome,
Italy
Background: Lysosomal acid lipase (LAL) is responsible for
breakdown of neutral lipids in hepatocytes. Genetically deter-
mined LAL deficiency (Cholesteryl Ester Storage Disease – CESD-
and Wolman disease – WD) is characterized by lysosomal impair-
ment and consequent microvescicular steatosis. Recently, acquired
reductions of peripheral LAL activity were described in NAFLD
patients.
1590-8658/
e2 Abstracts / Digestive and Liver Disease 49S (2017) e1–e18
Aims: To determine hepatic LAL expression in a population of
NAFLD patients, and to verify its association with blood LAL activity
and hepatic phenotype.
Material and methods: Liver biopsy samples from 105 sub-
jects, 82 NAFLD patients and 23 controls (peritumoral healthy
liver), were studied. In a subgroup of 44 patients, blood LAL activ-
ity was determined also in dried-blood-spot (DBS). NAFLD grading
and staging were assessed according NAFLD activity score (NAS)
and Brunt’s criteria, respectively. Expression of LAL and LAMP1
(lysosomal marker) were analyzed by immunohistochemistry. LAL
expression was classified according to a specific score (LALs), while
LAMP1 positivity was used to recognize and count lipolysosomes
and lipid-loaded Kupffer cells (KCs).
Results: Hepatic LAL expression was reduced in NAFLD patients
with respect to controls [LALs 3 (1.8–3.1) Vs 3 (3.0–3.0), p < 0.001).
In the NAFLD group, hepatic LAL expression: – was reduced in
patients with blood LAL activity <0.8 nmol/spot/h compared to
those with activity ≥0.8 nmol/spot/h [2.4 (2.2–2.6) Vs 2.7 (2.5–2.8),
p = 0.03]; – was reduced in patients with ≥25% with respect to
those with <25% of microvescicular steatosis [2.4 (2.3–2.5) Vs 2.7
(2.6–2.8), p < 0.01];); – was inversely correlated with lipolyso-
somes and lipid-loaded KCs (r = −0.35; p = 0.01; r = −0.41; p < 0.01,
respectively); – was inversely correlated with NAS (r = −0.52;
p < 0.001 – was not significantly associated with fibrosis (r = −0.15,
p = 0.2).
Conclusion: The present results are the first to suggest that
hepatic LAL expression reduced in NAFLD patients and associ-
ated with blood LAL activity, some features of CESD and WD
(microvescicular steatosis, lipolysosomes, lipid-loaded KCs), and
NAFLD activity (NAS).
http://dx.doi.org/10.1016/j.dld.2017.01.006
OC-03
Serial combination of noninvasive toolsimproves the diagnostic accuracy of severe liverfibrosis in patients with nonalcoholic fatty liverdisease
S. Petta 1, V.W.-S. Wong 2,3, C. Cammà 1,
J.-B. Hiriart 4, G.L.-H. Wong 2,3, J. Vergniol 4,
A.W.-H. Chan 5, V. Di Marco 1, W. Merrouche 4,
H.L.-Y. Chan 2,3, F. Marra 6, B. Le-Bail 7,8,
U. Arena 6, A. Craxì 1, V. de Ledinghen 4,7
1 Sezione di Gastroenterologia, Di.Bi.M.I.S.,
University of Palermo, Italy2 Department of Medicine and Therapeutics, The
Chinese University of Hong Kong, Hong Kong3 State Key Laboratory of Digestive Disease, The
Chinese University of Hong Kong, Hong Kong4 Centre d’Investigation de la Fibrose hépatique,
Hôpital Haut-Lévêque, Bordeaux University Hospital,
Pessac, France5 Department of Anatomical and Cellular Pathology,
The Chinese University of Hong Kong, Hong Kong6 Dipartimento di Medicina Sperimentale e Clinica,
Università degli Studi di Firenze, Italy7 INSERM U1053, Bordeaux University, Bordeaux,
France8 Service de Pathologie, Hôpital Pellegrin, Bordeaux
University Hospital, Bordeaux, France
Background/aims: The accuracy of available noninvasive tools
for staging severe fibrosis in patients with nonalcoholic fatty
liver disease(NAFLD) is still limited. We assessed the diagnostic
performance of paired or serial combination of noninvasive tools
in NAFLD patients.
Methods: We analyzed data from 741 patients (287 training
cohort, and 474 validation cohort) with a histological diagnosis
of NAFLD. Severe fibrosis was defined as fibrosis ≥F3 according to
Kleiner classification. The GGT/PLT, APRI, AST/ALT, BARD, FIB-4, and
NFS scores were calculated according to published algorithms. Liver
stiffness measurement (LSM) was performed by FibroScan.
Results: In the entire cohort LSM, NFS and FIB-4 were the best
noninvasive tools for staging F3–F4 fibrosis (AUC 0.863, 0.774, and
0.792, respectively), with LSM having the highest sensitivity (90%),
and the highest NPV (94%), and NFS and FIB-4 the highest speci-
ficity (97% and 93%, respectively), and the highest PPV (73% and 79%,
respectively). The paired combination of LSM with FIB-4 strongly
reduced the likelihood of wrongly classified patients (2.7%), at the
price of a high uncertainty area (54.1%), and of a low overall accu-
racy (43%). Otherwise, the serial combination with the second test
used in patients in the grey area of the first test and in those with
high LSM values (>9.6 KPa) or low NFS or FIB-4 values (<−1.455 and
<1.30, respectively) overall increased the diagnostic performance
generating an accuracy ranging from 69.8% to 70.1%, an uncertainty
area ranging from 18.9% to 20.4% and a rate of wrong classification
ranging from 9.2% to 11.3%.
Conclusions: The serial combination of LSM with FIB-4 has a
good diagnostic accuracy for the noninvasive diagnosis of severe
fibrosis in NAFLD.
http://dx.doi.org/10.1016/j.dld.2017.01.007
OC-04
The combination of mucus-degradinggram-negative bacteria and reducedantimicrobial peptides drives adipose tissueinflammation and NAFLD progression in micelacking NLRP3-inflammasome
I. Pierantonelli 1, C. Rychlicki 1, D. Giordano 1,
A. Giordano 2, S. Uzzau 3,4, A. Gastaldelli 5,
L. Sartini 2, L. Trozzi 1, A. Benedetti 1,
M. Marzioni 1, S. Cinti 2,6, G. Svegliati-Baroni 1,6
1 Department of Gastroenterology, Università
Politecnica delle Marche, Ancona, Italy2 Department of Experimental and Clinical Medicine,
Università Politecnica delle Marche, Ancona, Italy3 Porto Conte Ricerche, Parco Scientifico e
Tecnologico della Sardegna, Alghero, Italy4 Department of Biomedical Sciences, Università di
Sassari, Sassari, Italy5 Cardiometabolic Risk Lab, Institute of Clinical
Physiology, National Council of Research (CNR), Pisa,
Italy6 Obesity Center, Università Politecnica delle Marche,
Ancona, Italy
Introduction and aims: Lack of NLRP3-inflammasome, a sen-
sor of altered homeostasis, is associated with Non-Alcoholic Fatty
Liver Disease (NAFLD) progression. Aim of the present study was
to evaluate the mechanisms of this effect that are still unknown.
Methods: Nlrp3−/− and wild-type (WT) mice were fed a high-fat
diet with fructose in drinking water (HFHC) or a chow diet, for 12
weeks.
Results: Nlrp3−/−-HFHC showed higher body weight, fat mass,
hepatic PPAR�2 expression (that regulates lipid uptake and stor-
age) and triglyceride content in the liver compared to WT-HFHC,
associated with increased hepatic oxidative stress, TNFa and MCP1
Abstracts / Digestive and Liver Disease 49S (2017) e1–e18 e3
expression and NAS score. Nlrp3−/−-HFHC showed greater adi-
pose tissue inflammation evaluated by immunohistochemistry
for MAC-2 positive crown-like-structures and TNFa and MCP1
expression. Steatosis was unrelated to different intestinal lipid
absorption, since HFHC diet reduced fecal triglyceride content
independently from the genotype. A pathogenetic microbiota was
observed in Nlrp3−/−-HFHC characterized by increased levels of
mucus-degrading bacteria Akkermansia and LPS-producing Pro-
teobacteria, such as Desulfovibrio. Bacterial translocation was
higher in Nlrp3−/−-HFHC but occurred without significant dif-
ferences in Zonulin-1 and E-cadherin protein expression. The
evaluation of immune response against intestinal microorganisms
(anti-microbial pathway, AMPs) showed a genotype-independent
reduction of RELM�, which regulates mucus synthesis, whereas
the expression of the antibacterial peptide Ang-4 was signifi-
cantly lower in Nlrp3−/−-HFHC, thus favoring bacterial penetration
susceptibility. Bacterial translocation induced higher hepatic
expression of TLR4 (as LPS receptor) and TLR9 (as receptor for
double-strand bacterial DNA). Most of the effects observed in
Nlrp3−/−-HFHC were restored by antibiotic treatment that reduced
gut bacterial load and gram-negative species.
Conclusions: The combination of mucus-degrading gram-
negative bacteria and impaired AMPs efficiency drives adipose
tissue inflammation and NAFLD progression mediated by increased
bacterial translocation. This study identifies in the AMPs-
microbiota cross-talk a specific target for NAFLD therapy.
http://dx.doi.org/10.1016/j.dld.2017.01.008
OC-05
Steatohepatitis and type 2 diabetes mellitus areinfluenced by genetic susceptibility to increasedintestinal permeability in patients withnon-alcoholic fatty liver disease
V. Giorgio 1, L. Miele 1, S. Petta 2, A. Liguori 1,
R. Pastorino 3, G. Marrone 1, M. Biolato 1,
C. Araneo 1, F.G. Vaccaro 1, C. Cefalo 1, D. Arzani 3,
G.L. Rapaccini 1, A. Gasbarrini 1, S. Boccia 3,
A. Craxì 2, A. Grieco 1
1 Internal Medicine and Gastroenterology Area,
Fondazione Policlinico Universitario A. Gemelli,
Catholic University of Rome, Rome, Italy2 Sezione di Gastroenterologia, Dipartimento
Biomedico di Medicina Interna e Specialistica,
University of Palermo, Palermo, Italy3 Institute of Public Health Section of Hygiene,
Catholic University of Rome, Rome, Italy
Introduction and aim: Individual susceptibility to increased
intestinal permeability (IP) has now been considered as a key fac-
tor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD)
and type 2 diabetes mellitus (T2DM).
The aim of our study was to assess whether a single nucleotide
polymorphisms (SNP) (rs2542151 G→T) of Protein Tyrosine Phos-
phatase Non-Receptor Type 2 (PTPN2), known to be involved in
regulation of IP, is associated with type 2 diabetes mellitus and
non-alcoholic steatohepatitis (NASH).
Material and methods: We recruited a prospective consecu-
tive cohort of NAFLD cases and healthy controls among Caucasian
patients from two Italian tertiary care centers. Zonulin serum lev-
els were used to assess IP in the study population. Unconditional
multiple logistic regression models were used to investigate the
association between selected SNP (PTPN2 rs2542151 G→T), comor-
bidities and histological severity of liver disease.
Results: We enrolled 416 cases (males 69.2%, mean age
45.1 ± 13.8 ys) and 377 controls (males 67.1%, mean age
41.3 ± 3.1 ys). Serum zonulin levels were significantly higher in
NAFLD subjects (7.0 ± 3.5 vs 0.9 ± 0.6 pg/ml, p < 0.05). Liver biopsy
was available for 307 patients (65.8%); 151/307 (49.2%) had NASH.
In patients’ population the analysis showed that PTPN2 rs2542151
G→T is associated with the presence of T2DM (OR 1.63 95% CI
1.03–2.59 p < 0.05). At a subgroup analysis of patients who under-
went liver biopsy, rs2542151 G→T of PTPN2 was associated with
the presence of NASH (OR 2.85 95% CI 1.15–7.07 p < 0.05).
Conclusions: Our study shows that rs2542151 G→Tof PTPN2
is associated with the presence of NASH and higher prevalence of
T2DM in patients affected by NAFLD. These results further suggest
that individual genetic susceptibility to an impaired IP is linked
to a higher severity of fatty liver disease and the presence of type
2-diabetes mellitus in NAFLD patients.
http://dx.doi.org/10.1016/j.dld.2017.01.009
OC-06
Down-regulation of hepatic MBOAT7 byhyperinsulinemia favors steatosis development
M. Meroni 1, P. Dongiovanni 2, R. Rametta 2,
G.A. Bassani 3, S. Badiali 4, S. Romeo 5, S. Gatti 3,
L. Valenti 1,2
1 Department of Pathophysiology and
Transplantation, Università degli Studi di Milano,
Milano, Italy2 Internal Medicine, Fondazione IRCCS Ca’ Granda
Ospedale Maggiore Policlinico, Milano, Italy3 Center for Surgical Research, Fondazione IRCCS Ca’
Granda Ospedale Policlinico Milano, Milan, Italy4 Surgery, Fondazione IRCCS Ca’ Granda Ospedale
Policlinico Milano, Milan, Italy5 Department of Molecular and Clinical Medicine,
University of Gothenburg, Sweden
Introduction: We have recently shown that the rs641738 C>T
variant in Membrane bound O-acyltransferase domain-containing
7 gene (MBOAT7), involved in phosphatidylinositol acyl-chain
remodeling, increases the risk of developing nonalcoholic fatty liver
disease (NAFLD), inflammation and fibrosis due to lower protein
expression.
Aim: To evaluate the regulation of hepatic MBOAT7 and the
impact on hepatic fat accumulation.
Methods: We examined hepatic MBOAT7 in 119 obese patients,
and in experimental models. We silenced hepatic MBOAT7 by i.v.
administration of Morpholino antisense oligonucleotides (MPO) for
4 consecutive days in C57Bl/6 male mice (n = 5 per group).
Results: In obese patients, hepatic MBOAT7 mRNA levels
progressively decreased from normal liver to simple steatosis and
NASH (p < 0.05). At multivariate analysis, type 2 diabetes (p < 0.05),
necroinflammation (p < 0.01) and MBOAT7 genotype (p < 0.01)
were independently associated with MBOAT7 downregulation.
MBOAT7 expression was reduced in experimental models of
NAFLD, such as the methionine-choline deficient diet, but more so
in genetically obese ob/ob mice, and in insulin resistant mice with
Insulin receptor haplo-insufficiency, characterized by development
of hyperinsulinemia (p < 0.05). Furthermore, in wild-type male
mice MBOAT7 was downregulated by refeeding concomitantly
with the rise of insulin levels and activation of hepatic insulin
signaling through PI3 K and AKT. In keeping, insulin (330 nM)
downregulated MBOAT7 in primary mouse hepatocytes in a
PI3Kinase-depedent manner. Finally, MPO induced a 45% silencing
e4 Abstracts / Digestive and Liver Disease 49S (2017) e1–e18
of hepatic MBOAT7 comparable to that associated with the
genetic risk variant, resulting in a 80% increase in hepatic triglyc-
eride content (p < 0.05 vs scramble) and in microvesicular steatosis
development, without altering circulating glucose, insulin and lipid
levels.
Conclusion: These data suggest that hyperinsulinemia causes
downregulation of hepatic MBOAT7, which both genetic and
experimental data indicate is causally implicated in steatosis
development. Further studies are necessary to investigate the
mechanisms linking reduced phosphatidyl-inositol desaturation by
MBOAT7 with the development of steatosis and hepatic inflamma-
tion.
http://dx.doi.org/10.1016/j.dld.2017.01.010
OC-07
External validation of the ITA.LI.CA prognosticsystem for patients with hepatocellularcarcinoma: A multicenter cohort study
E. Dionigi 1, M. Borzio 1, A. Rossini 2,
M. Marignani 3, R. Sacco 4, I. De sio 5, E. Bertolini 6,
G. Francica 7, A. Giacomin 8, G. Parisi 9, S. Vicari 10,
A. Toldi 11, A. Salmi 12, S. Boccia 13,
A. Maringhini 14, F. Fornari 15
1 UOC Gastroenterologia ed Endoscopia Digestiva,
ASST Melegnano e della Martesana, Italy2 Dipartimento di Medicina, SSVD di Epatologia,
ASST Spedali Civili di Brescia, Italy3 UOS Malattie delle vie Biliari e del Fegato, UOC
Malattie dell’Apparato Digerente e del Fegato, AO
S.Andrea, Università “Sapienza” Roma, Italy4 UO Gastroenterologia e Malattie del Ricambio,
Azienda Ospedaliero Universitaria Pisana, Ospedale
Cisanello, Pisa, Italy5 Unità di Gastroenterologia. Ospedale Policlinico,
Napoli, Italy6 U.O. Medicina VI Epatologia e Gastroenterologia,
Ospedale San Paolo, Università degli Studi di Milano,
Italy7 Presidio Ospedaliero Pineta Grande – Unità di
Ecointerventistica – Castelvolturno, Italy8 Dipartimento di Scienze Chirurgiche e
Gastroenterologiche Ospedale Policlinico Padova,
Italy9 Dipartimento di Medicina, Ospedale Santa Maria
del Prato, Feltre, Italy10 UOS Gastroenterologia Ospedale di Bentivoglio,
Bologna, Italy11 UO Gastroenterologia Ospedale Valduce, Como,
Italy12 Dipartimento Medicina, Università di Verona, Italy13 UOC Gastroenterologia, Ospedale S.Anna, Ferrara,
Italy14 UO Medicina Interna I, Ospedale “Civico e
Benfratelli”, Palermo, Italy15 Unità di Gastroenterologia ed Epatologia,
Ospedale G. da Saliceto, Piacenza, Italy
Several staging systems for HCC patients have been developed.
BCLC classification is still considered the best in predicting survival,
but few limitations have emerged. Recently the Italian Liver Cancer
(ITA.LI.CA) new prognostic score, showing strong ability to predict
individual survival was proposed. Aim of our study is to provide an
external validation of the ITA.LI.CA system in an independent and
large Western cohort.
Methods: From September 2008 to April 2016, 1508 cirrhotics
with incident HCC were consecutively enrolled in 27 Italian insti-
tutions (EpaHCC cohort). Clinical, tumor and treatment-related
variables were collected, patients stratified according to BCLC,
ITA.LI.CA staging and prognostic score, HKLC, CLIP, JIS, and MESIAH
scores. Harrel’s C-index, Akaike Information Criterion and likeli-
hood ratio test were used to compare predictive ability of different
systems. A subgroup analysis for treatment category (curative vs
palliative) was performed.
Results: Median follow-up was 44 months (IQ 23–63) and
median overall survival was 34 (IQ 13–82). Patients enrolled had
a median age of 71 years, and were mainly males and hepatitis C
carriers. According to ITA.LI.CA stage 246 patients were in stage
0, 472 in stage A; 657 in the stages B1-3; 133 in stage-C. The
ITA.LI.CA prognostic system showed the best discriminatory ability
(C-index = 0.77) and monotonicity of gradients, compared to other
prognostic systems. The superiority of the score was also confirmed
after stratification of the population for treatment strategy.
Conclusions: This is the first study that externally validated
the ITA.LI.CA prognostic system for HCC in a large cohort of West-
ern patients with incident HCCs. ITA.LI.CA score system performed
better than other available systems, including BCLC, even after
stratification by curative or palliative treatment. This new system
including both a tumor staging and an integrated prognostic score
appears to be particularly useful in clinical practice to predict indi-
vidual HCC prognosis.
http://dx.doi.org/10.1016/j.dld.2017.01.011
OC-08
The concept of therapeutic hierarchy forpatients with hepatocellular carcinoma: Amulticentre cohort study
A. Vitale 1, F. Farinati 1, T.L. Huo 2, F. Trevisani 3,
E.G. Giannini 4, F. Piscaglia 5, U. Cillo 1
1 Department of Surgery, Oncology and
Gastroenterology, University of Padua, Italy2 Department of Medicine, Taipei Veterans General
Hospital, Taipei, Taiwan3 Division of Semeiotics, Alma Mater Studiorum –
University of Bologna, Bologna, Italy4 Gastroenterology Unit, Department, University of
Genoa, Genoa, Italy5 Division of Internal Medicine, Alma Mater
Studiorum – University of Bologna, Italy
Background/aim: The ITA.LI.CA prognostic system for patients
with hepatocellular carcinoma (HCC) has been recently developed
and validated. Strict HCC treatment algorithms (i.e. BCLC or HKLC)
are poorly followed in clinical practice. We sought to develop
and validate ITA.LI.CA indications for treatment guidance in HCC
patients.
Methods: Prospective collected databases from 2002 to 2015 in
Italy (n = 4,627), and Taiwan (validation cohort, n = 2651) were used
for the analysis. Multivariable regression models including vari-
ables from the ITA.LI.CA prognostic system were used to calculate
the propensity score (PS, calculated by logistic regression), and the
predicted median survival (MS, calculated by parametric survival
model with stabilized inverse probability weight) for each therapy
(liver transplantation = LT, liver resection = LR, ablation = ABL, intra-
arterial therapy = IAT, Sorafenib = SOR, best supportive care = BSC).
Abstracts / Digestive and Liver Disease 49S (2017) e1–e18 e5
Results: Multivariable logistic regressions showed that the PS
of loco-regional therapies (LR, ABL, IAT) was negligible (PS ≤ 1◦
quintile) in patients with impaired ITA.LI.CA functional score
(Child C, or PST > 2, or Child 8–9 + PST 1–2: only LT or BSC
available) or advanced tumor stage (extra-hepatic HCC dis-
ease, stage C: only SOR or BSC available). In all other ITA.LI.CA
tumor stages (0, A, B1, B2, and B3) with preserved liver func-
tion (functional score ≤ 2) survival benefit estimations showed
a fixed therapeutic hierarchy (i.e. LT [MS ≥ 120 months] > LR
[MS 24–102 months] > ABL [MS 40–77 months] > IAT [MS
18–64 months] > SOR [MS 15–25 months] > BSC [MS 5–7 months]).
All multivariable parametric models proved to give accurate
survival estimations (C-index > 0.7).
The concept of therapeutic hierarchy within ITA.LI.CA stages was
validated also in the Taiwanese cohort.
Conclusions: Based on weighted survival benefit estimations
the concept of therapeutic hierarchy was established within each
ITA.LI.CA stage in a large Italian population and validated in a large
Taiwanese cohort.
http://dx.doi.org/10.1016/j.dld.2017.01.012
OC-09
Oncostatin M induces increased invasivenessand angiogenesis in hepatic cancer cellsthrough HIF1�-related release of VEGF-A
B. Foglia 1, S. Cannito 1, E. Morello 1, C. Turato 2,
G. Di Maira 3, E. Novo 1, S. Colombatto 4,
P. Pontisso 2, F. Marra 3, M. Parola 1
1 Department Clinical and Biological Sciences,
University of Torino, Turin, Italy2 Dept of Medicine, University of Padova, Padua, Italy3 Department Experimental and Clinical Medicine,
University of Firenze, Florence, Italy4 Dept of Oncology, University of Torino, Turin, Italy
Introduction: Oncostatin M (OSM) is overexpressed in cirrhotic
liver and can modulate hypoxia-dependent liver processes (devel-
opment, regeneration and angiogenesis) contributing to chronic
liver disease progression and hepatocellular carcinoma (HCC)
development. Recent data suggest that both hypoxia and OSM may
induce epithelial-to-mesenchymal transition (EMT) in cancer cells
by operating through hypoxia-inducible factors (HIFs).
Aim: In this study we investigated in vivo and in vitro the
relationships between OSM, vascular endothelial growth factor A
(VEGF-A) expression, and increased invasiveness.
Methods: EMT, invasiveness, angiogenesis and signal transduc-
tion pathways were investigated by integrating morphological,
molecular and cell biology techniques in: (a) HCC human spec-
imens, (b) HepG2 cells exposed to human recombinant OSM
(hrOSM) or stably transfected in order to overexpress OSM; (c)
murine xenografts.
Results: OSM was expressed in HCC specimens in areas positive
for HIFs and VEGF-A, with OSM expression correlating with early
recurrence in HCC patients. HepG2 cells exposed to hrOSM or OSM
overexpressing HepG2 cells show EMT-related changes, increased
invasiveness and metallo-proteinase-2 activity. OSM-dependent
invasiveness is due to the release of VEGF and involves activation
of PI-3 K, ERK1/2, and p38MAPK since: (1) OSM leads to an increase
of HIF1� and VEGF-A mRNA levels as well as release of VEGF-A in
culture medium; (2) the use of specific pharmacological inhibitors
against PI-3K, ERK1/2, p38MAPK signaling pathways, neutralizing
antibodies for Flk-1(VEGF receptor type 2) or specific inhibitors of
Flk-1 results in decrease of invasiveness induced by conditioned
medium collected by HepG2 cells treated with hrOSM for 48 h; (3)
OSM affects cell proliferation by blocking HepG2 cells in G0/G1
phase; (4) OSM promotes angiogenesis in vivo (xenograft model)
and in vitro (sprouting spheroid assay).
Conclusions: OSM, expressed in human HCC, can induce EMT
and increased invasiveness in human hepatic cancer cells through
a mechanism involving HIF1�-dependent release of VEGF-A.
http://dx.doi.org/10.1016/j.dld.2017.01.013
OC-10
Impact of natural killer (NK) cells receptorsgene haplotypes on the development ofhepatocarcinoma in cirrhotic patients
S. Onali 1, R. Littera 4, M. Casale 1, F. Capraro 1,
C. Balestrieri 2, F. Figorilli 1, G. Serra 2,
E. Congeddu 3, P. Ragatzu 3, R. Maddi 3, M. Serra 3,
V. Loi 3, M. Trucas 4, C. Carcassi 3, L. Chessa 1,2
1 Dipartment of Medical Sciences and Public Health,
University of Cagliari, Cagliari, Italy2 Liver Unit, Department of Internal Medicine,
Azienda Ospedaliera-Universitaria di Cagliari,
Cagliari, Italy3 Medical Genetics, Department of Medical Sciences
“M. Aresu”, University of Cagliari, Cagliari, Italy4 Bone Marrow Transplantation Centre, Binaghi
Hospital, Cagliari, Italy
Introduction: Killer immunoglobulin-like receptors (KIRs) are
key regulators of NK-mediated immune responses and their
expression is regulated by different aplotypes.
Aim: to analyse the genetic pattern of KIRs and their human
leukocyte antigen (HLA) ligands in cirrhotic patients with and with-
out HCC in order to identify a correlation between the expression
of inhibitory/activating KIRs and presence of HCC.
Methods: Cirrhotic patients with and without HCC were
included. Their immunogenetic characteristics were compared to
healthy individuals extracted from the Sardinian bone marrow
donor registry. High resolution (4 digits) typing of HLA A, B, C and 14
KIRs gene loci was performed. Subjects were divided into 2 groups:
homozygosity for KIR haplotype A, heterozygosity or homozygos-
ity for KIR haplotype B (Bx). They were also stratified according to
the numbers of activating/inhibitory KIRs, the type of KIRs related
HLA-ligands and the combinations with their receptors.
Results: 113 patients were included:68% had HCC. Compared
to controls, cirrhotic patients showed higher frequency of HLA-
C*05 allele (27%vs17.5% p = 0.001), while HLA-A*02 allele was more
common among HCC patients compared to non-HCC (30%vs18%
p = 0.05). No difference was observed in the frequency of activat-
ing/inhibitory KIR genes and KIR aplotypes between patients and
controls. Conversely, non-HCC patients showed a higher frequency
of the inhibitory KIR gene 3DL1 compared to HCC patients (100%
vs 87% p = 0.03). The frequency of KIR2DS4, the only activating KIR
gene of aplotype A, was comparable between HCC and non-HCC.
However, homozygosis for the deletion variant of KIR2DS4 was
more common in HCC group (17% vs 3% p = 0.03) indicating that
a higher proportion of HCC patients with KIRs haplotype A did
not express any activating KIR genes compared to only 1 non-HCC
patient.
Conclusions: Loss of activating KIR2DS4 is more frequent
among HCC patients, suggesting a decreased cytotoxic function of
NK-cells and therefore a negative impact on immunosurveillance
and tumour control.
http://dx.doi.org/10.1016/j.dld.2017.01.014
e6 Abstracts / Digestive and Liver Disease 49S (2017) e1–e18
OC-11
Efficacy of oral direct acting antivirals fortreatment of advanced chronic hepatitis orcompensated cirrhosis due to hepatitis C virusinfection: The real-life experience of the Sicilyregistry
I. Cacciola, S. Petta, M. Distefano, M.R. Cannavò,
A. Davì, S. Madonia, V. Calvaruso, L. Larocca,
F. Di Lorenzo, A. Digiacomo, G. Bertino, A. Licata,
F. Latteri, F. Benanti, R. Volpes, L. Guarneri,
A. Averna, I. Scalisi, C. Iacobello, P. Colletti,
F. Cartabellotta, V. Portelli, M. Russello, G. Scifo,
G. Squadrito, G. Raimondo, A. Craxì, V. Di Marco,
on behalf of RESIST-HCV (Rete Sicilia Selezione
Terapia – HCV)
RESIST-HCV (Rete Sicilia Selezione Terapia – HCV),
Italy
Background and aims: The RESIST-HCV (Rete Sicilia Selezione
Terapia – HCV) is a network that registered patients with Hepatitis C
Virus (HCV) infection evaluated for Direct Acting Antivirals (DAAs).
We reported real-life effectiveness of DAAs in genotypes (G) 1b, 2
and 3 patients with F3 fibrosis (F3) or Child-A cirrhosis
Methods: We analyzed 2,106 patients who reached post-
treatment week 12 at October 2016. A rate of SVR12 by
intention-to-treat analysis higher than 90% was defined as
optimal. Evaluated regimens were Sofosbuvir plus Simepre-
vir (SOF + SIM) ± Ribavirin (RBV); Sofosbuvir plus Daclatasvir
(SOF + DCL) ± RBV; Sofosbuvir plus Ledipasvir (SOF + LDV) ± RBV;
Ombitasvir/Paritaprevir/Ritonavir (OBV/PTV/r) ± Dasabuvir
(DSV) ± RBV.
Results: SOF + LDV was optimal in G1b Child-A cirrhosis treated
for 24 weeks (208/230, 92%) or for 12 weeks plus RBV (100/107,
93.4%), while was suboptimal in G1b F3 (41/46, 89.1%) and Child-A
cirrhosis (33/42, 78.5%) treated for 12 weeks without RBV.
OBV/PTV/r/DSV for 12 weeks was optimal in G1b F3 (105/109,
96.4%), as well as in G1b Child-A cirrhosis treated with (196/211,
92.8%) or without (82/85, 96.4%) RBV.
SOF + DCL was optimal in G1b F3 treated for 12 weeks (10/10,
100%) and in G1b Child-A cirrhosis treated for 12/24 weeks with
RBV (49/51, 96.1%), while was sub-optimal in G1b Child-A cirrhosis
treated for 24 weeks without RBV (43/52, 82.7%).
SOF + DCL was also optimal in G2 Child-A cirrhosis treated for
12 weeks (20/22, 90.2%) and in G3 Child-A cirrhosis treated for 24
weeks with RBV (39/43, 90.6%), while was sub-optimal in G3 Child-
A cirrhosis treated for 24 weeks without RBV (27/32, 84.3%). Finally,
SOF + SIM was optimal in G1b Child-A cirrhosis treated for 12 weeks
with RBV (230/246, 93.5%), while was sub-optimal in G1b F3 (12/16,
75%) and G1b Child-A cirrhosis (34/46, 73.9%) treated for 12 weeks
without RBV.
Conclusions: Real-life data confirmed the efficacy of DAAs in
HCV advanced fibrosis or cirrhosis using carefully therapy time and
the addiction of RBV.
http://dx.doi.org/10.1016/j.dld.2017.01.015
OC–12
Role of SerpinB3 in the stimulation ofmacrophage activation marker sCD163 in HCVinfected patients
A. Martini, A. Cappon, A. Biasiolo, C. Turato,
P. Pontisso
Clinica Medica 5, Department of Medicine,
University of Padua, Padua, Italy
Introduction: In chronic HCV infection, disease progression is
maintained by sustained necroinflammation and fibrosis in the
liver. Upon macrophage activation, the soluble marker CD163
(sCD163) is released in serum and its levels correlate with fibro-
sis and NASH in the liver. The serin protease inhibitor SerpinB3
(or SCCA1), has been shown to be involved in liver fibrogenesis and
the circulating SCCA-IgM complex has been depicted as a marker of
liver disease progression and of NASH in patients with chronic hep-
atitis C. Preliminary data suggest that SerpinB3 activates primary
monocytes through the Wnt canonical pathway.
Aim: The purpose of this study was to evaluate the relationship
between SCCA-IgM and sCD163 in serum and the possible effect of
SerpinB3 on sCD163 production in primary monocytes.
Materials and methods: In 91 patients with biopsy proven
chronic hepatitis C, serum samples were tested for sCD163 (ng/ml)
and SCCA-IgM (AU/ml) by ELISA. The results were analyzed in
relation with clinical and histological parameters. Primary mono-
cytes were isolated from healthy donors, treated with recombinant
SerpinB3 (200 ng/ml) and supernatants analyzed after 7 days.
Expression of sCD163 secreted in the supernatant was evaluated
by ELISA.
Results: In patients with chronic hepatitis C sCD163 was
found correlated with inflammatory and metabolic alterations
(AST, ALT, GGT, HOMA-IR, triglycerides), and was significantly
elevated in patients with more advanced histological fibrosis
stage (F1-F2 vs. F3–F4 s. Metavir: p < 0.04). Patients with levels of
SCCA-IgM > 200 AU/ml had more elevated serum levels of sCD163
(p < 0.05). When primary monocytes were stimulated with recom-
binant SerpinB3 “in vitro”, sCD163 expression increased of 2.5
times.
Conclusions: In chronic hepatitis C SerpinB3 is involved in
monocyte activation, leading to the release of sCD163. These results
support the correlation of these two molecules in serum of patients
with more severe liver fibrosis and metabolic alterations.
http://dx.doi.org/10.1016/j.dld.2017.01.016
Abstracts / Digestive and Liver Disease 49S (2017) e1–e18 e7
OC-13
Peripheral and intrahepatic virologicalphenotyping in HBeAg negative ChronicHepatitis B to evaluate risk of diseaseprogression and HCC in the “grey-zone” viralload cohort: Can grey-zone patients becandidate to treatment?
R. Salpini 1, L. Colagrossi 1, A. Battisti 1, N. Hansi 2,
C.F. Perno 1, U.S. Gill 2, P.T.F. Kennedy 2,
V. Svicher 1
1 Department of Experimental Medicine and Surgery,
Tor Vergata University, Rome, Italy2 Hepatology, Centre for Immunobiology, Blizard
Institute, Barts and The London SMD, QMUL, London,
United Kingdom
Introduction: HBsAg persistence is associated with an
increased risk for HCC-development in chronic hepatitis B (CHB)
and quantitative HBsAg (qHBsAg) has been proposed as a tool to
risk stratify patients for disease progression and HCC-development.
Limited data exist on the intrahepatic compartment and how accu-
rately qHBsAg reflects intrahepatic total HBV-DNA and cccDNA. We
studied liver tissue from eAg negative (eAg-) CHB patients, with 3
distinct disease profiles based on serum HBV-DNA: low-replicative
(LR) disease, “grey-zone” (moderate) and high viral-loads (VL).
Methods: To detect virological differences between periph-
eral and intrahepatic compartments, we quantified HBV-DNA and
HBsAg in serum and intrahepatic total HBV-DNA (itHBV-DNA)
along with cccDNA in biopsy specimens (n = 64). Patients were
divided as follows: low-replicative disease, HBV-DNA < 2000 IU/ml
(n = 22): Group 1; grey-zone VL, HBV-DNA 2000–20,000 IU/ml
(n = 18): Group 2; and high VL, HBV-DNA > 20,000 IU/ml (n = 24):
Group 3. Data on longitudinal ALT, Ishak fibrosis stage and
necroinflammatory (NI) scores were documented to establish
clinical correlations and determine any difference between the
groups.
Results: Patients in each group were age-matched; median
(IQR) age of 34(8–41); with no difference in ALT, Ishak fibrosis stage
and NI score. Overall, itHBV-DNA positively correlated with serum
HBV-DNA and qHBsAg (Rho = 0.53, p = <0.0001; Rho = 0.3, p = 0.02,
respectively). cccDNA positively correlated with serum HBV-DNA
(Rho = 0.39, p = 0.002), qHBsAg (Rho = 0.3, p = 0.02), and itHBV-DNA
(Rho = 0.56, p = <0.0001). We noted the amount of itHBV-DNA and
cccDNA progressively increased with increasing HBV-DNA, with
group 2 patients (grey-zone) displaying values more similar to the
high VL patients.
Conclusions: These data show that eAg-negative CHB patients
with HBV-DNA between 2000–20,000 IU/ml (grey-zone patients)
and those with HBV-DNA >20,000 IU/ml have a similar HBV
genomic reservoir; that is distinguishable from those with low-
replicative disease. Based on these data, a case could be made for
the earlier treatment of these grey-zone patients to avoid the devel-
opment of disease progression or HCC over the long-term.
http://dx.doi.org/10.1016/j.dld.2017.01.017
e8 Abstracts / Digestive and Liver Disease 49S (2017) e1–e18
OC-14
The challenge of HCV-retreatment afterDAA-failure: Italian real-life from VIRONET-Cnetwork
V. Cento 1, S. Barbaliscia 1, V.C. Di Maio 1,
C. Masetti 2, C. Minichini 3, C.F. Magni 4,
V. Micheli 5, S. Marenco 6, L.A. Nicolini 7,
B. Bruzzone 8, Y. Troshina 9, C. Baiguera 10,
C. Dentone 11, V. Calvaruso 12, S. Paolucci 13,
M. Melis 14, M. Aragri 1, A. Bertoli 1, I. Lenci 2,
S. Landonio 4, M. Schiavini 4, L. Sticchi 15,
T. Ruggiero 16, E. Polilli 17, V. Messina 18,
A. Pellicelli 19, L. Boglione 20, R. Cozzolongo 21,
M. Biolato 22, F. Morisco 23, M. Siciliano 24,
G. Parruti 17, G. Barbarini 25, A. Craxì 12,
S. Babudieri 14, M. Puoti 10, A. Ciancio 9,
G. Rizzardini 4, N. Coppola 3, M. Angelico 2,
C.F. Perno 1, F. Ceccherini-Silberstein 1, on behalf
of VIRONET-C
1 Department of Experimental Medicine and Surgery,
University of Rome Tor Vergata, Rome, Italy2 Hepatology Unit, Policlinic Foundation of Rome Tor
Vergata, Rome, Italy3 Infectious Diseases, Department of Mental and
Physical Health and Preventive Medicine, Second
University of Naples, Naples, Italy4 1st Division of Infectious Diseases, ASST
Fatebenefratelli Sacco, Milan, Italy5 Clinical Microbiology, Virology and Bioemergencies,
ASST Fatebenefratelli Sacco, Milan, Italy6 Division of Hepatology, University of Genoa-AOU
IRCCS San Martino-IST, Genova, Italy7 Infectious Diseases, Department of Health Sciences
(DISSAL), University of Genoa-AOU IRCCS San
Martino-IST, Genova, Italy8 Hygiene Unit, University of Genoa-AOU IRCCS San
Martino-IST, Genova, Italy9 Gastroepatology, Department of Medical Sciences,
City of Health and Science of Turin, University of
Turin, Turin, Italy10 Infectious Diseases, Hospital Niguarda Ca’ Granda,
Milan, Italy11 Infectious Diseases, Sanremo Hospital, Italy12 Gastroenterology, “P. Giaccone” University
Hospital, Palermo, Italy13 Molecular Virology, Policlinic Foundation San
Matteo, Pavia, Italy14 Infectious Diseases Unit, Department of Clinical
and Experimental Medicine, University of Sassari,
Italy15 Department of Health Sciences, University of
Genoa-AOU IRCCS San Martino-IST, Genova, Italy16 Infectious Diseases, “Amedeo di Savoia” Hospital,
Turin, Italy17 Infectious Disease Unit, “Spirito Santo” General
Hospital, Pescara, Italy18 Infectious Diseases Unit, A.O. S. Anna e S.
Sebastiano, Caserta, Italy19 Gastroenterology, San Camillo Hospital, Rome,
Italy20 Unit of Infectious Diseases, University of Turin,
Turin, Italy
21 Department of Gastroenterology, Scientific
Institute for Digestive Disease “Saverio de Bellis”
Hospital, Castellana Grotte, Bari, Italy22 Liver transplant unit, “Cattolica” University of
Rome, Rome, Italy23 Gastroenterology, University “Federico II”, Naples,
Italy24 Gastroenterology, “Cattolica” University of Rome,
Rome, Italy25 Division of Infectious and Tropical Diseases,
Policlinic Foundation San Matteo, Pavia, Italy
Background: In Italy, over 60,000 HCV-infected patients
received a direct-acting antiviral (DAA)-regimen. With a failure
rate of 5–10%, around 3000–6000 DAA-failures will need to be
retreated. Drug-class switch is generally recommended by inter-
national guidelines, as the performance of a reliable baseline (BL)
genotypic-resistance-testing (GRT). Few real-life data are available
on retreatment outcome.
Methods: Within the collaborative network VIRONET-C, we
analyzed patients retreated after failure of IFN-free regimens con-
taining a protease-inhibitor (PI, N = 23), and/or a NS5A-inhibitor
(N = 12), or only sofosbuvir (N = 55). GRT was performed by
population-sequencing.
Results: 84 patients infected with HCV GT1a/1b (N = 39), 2c
(N = 4), 3a (N = 31), and 4d (N = 10), 81.1% with compensated-
cirrhosis, were included. 74/84 (88.1%) patients performed a
BL-GRT, that disclosed resistance-associated-substitutions (RASs)
in 17/22 (77.3%) PI-failing, and in 8/11 (72.7%) NS5A-failing
patients.
75 patients were retreated with a NS5A-inhibitor (daclatasvir,
N = 42; ledipasvir, N = 29; ombitasvir, N = 4), including 5 NS5A-
experienced patients; 8 patients received simeprevir + sofosbuvir
after NS5A-failure. One GT4d patient was retreated with sofos-
buvir + ribavirin after simeprevir + daclatasvir failure. Ad interim
results on 40 patients showed a sustained-viral-response (SVR) in
27 (67.5%), including 3/4 (75%) receiving simeprevir + sofosbuvir,
11/18 (61.1%) receiving daclatasvir + sofosbuvir ± ribavirin, 12/15
(80%) receiving ledipasvir/sofosbuvir ± ribavirin and 1/2 (50%)
receiving paritaprevir/ombitasvir + dasabuvir + ribavirin.
SVR was low in GT3 (55.6%, N = 8) and GT2 (0/2), vs. 66.7% in GT4
(N = 6), 70% in GT1b (N = 10), 84.6% in GT1a (N = 13).
SVR to NS5A-retreatment was achieved in 18/21 (85.7%)
patients without BL NS5A-RASs, vs. 3/4 (75%) with 1 NS5A-RAS,
and 1/6 (16.7%) patients with >1 NS5A-RAS. Only 1/5 patients with
Y93H/C reached SVR.
13/11 patients who failed retreatment were cirrhotic; all 11
tested showed RASs, in 80.0% of cases on both NS3 and NS5A.
Conclusion: Preliminary results indicate that cirrhosis and pres-
ence of BL NS5A-RASs, especially Y93H, reduce retreatment efficacy
after DAA-failure in real-life. GRT-guided regimens may help to
select the natural candidates for future-generation DAAs, partic-
ularly for non-GT1.
http://dx.doi.org/10.1016/j.dld.2017.01.018
Abstracts / Digestive and Liver Disease 49S (2017) e1–e18 e9
OC-15
High rates of renal tubular damage in HBVmonoinfected patients long-term treated withtenofovir: A cross-sectional, single center,real-life study in 414 patients
G. Grossi 1, A. Loglio 1, F. Facchetti 1, E. Galmozzi 1,
M. Colombo 2, P. Lampertico 1
1 Division of Gastroenterology and Hepatology,
Fondazione IRCCS Cà Granda Ospedale Maggiore
Policlinico, Università degli Studi di Milano, Milan,
Italy2 Center for Translational Hepatology Research,
IRCCS Humanitas Hospital and University, Rozzano,
Italy
Background and aim: TDF is a popular treatment option for
patients with CHB, although a recent 48-week study showed sig-
nificant renal and bone toxicities in TDF but not in TAF-treated
patients. Aim of the study was to define the prevalence and risk
factors for such toxicities in HBV monoinfected patients long-term
treated with TDF.
Material and methods: All consecutive TDF treated patients
with CHB were enrolled in a cross-sectional single center, real-life
study. Renal safety was assessed by proteinuria, UPCR, UACR, UBCR,
and TmPO4/GFR ratio. Spine DEXA scans, FRAX, Vitamin D and PTH
levels were also recorded as well as the rs717620 of MRP2 (ABCC2
gene) by rtPCR.
Results: 414 patients (62 yr, 76% males, eGFRCG 69 mL/min)
treated with TDF for 82 (1–197) months were enrolled. Most
patients were Caucasians (94%), HBeAg negative (91%), GT D
(79%) undetectable HBV-DNA (90%) and normal ALT (92%), NUC-
experienced (60%). 45% had cirrhosis, 38% arterial hypertension
and 10% diabetes, 6% had Vit D levels <15 ng/ml, 20% had ele-
vated PTH. Fibroscan values were 5.4 Kpa (range 3–33). Osteopenia
and osteoporosis were observed in 42% and 14% patients at spine.
The 10-year probability of major and hip fractures by FRAX was
4.7% and 1.2%. As far as renal tubular safety, 37% of the patients
had low blood phosphate (<2.7 mg/dl), 59% had increased UBCR
(>300 mg/g), 66% hyperphosphaturia (<0.80 TmPO4/GFR ratio) and
53% hypercalciuria (>0.11 UCA/Cr ratio). By converse, significant
glomerular proteinuria was observed in few patients only. Overall,
41% of the patients had two markers of proximal tubular dam-
age. Patients with proximal tubular toxicity were older, previously
exposed to ADV, with lower eGFR, diabetes and arterial hyperten-
sion.
Conclusions: A significant proportion of CHB patients on
long-term TDF has proximal tubular damage associated with
hypercalciuria. These patients might benefit from a TDF to TAF
switch.
http://dx.doi.org/10.1016/j.dld.2017.01.019
OC-16
Prothrombotic microparticles and risk of portalvein thrombosis in patients with HCV-relatedliver cirrhosis who underwent DAA antiviraltherapy
A. Zanetto 1, E. Campello 2, C.M. Radu 2,
S. Shalaby 1, E. Franceschet 1, A.M. Frigo 3,
A. Ferrarese 1, I. Bortoluzzi 1, M. Gambato 1,
G. Germani 1, M. Senzolo 1, A. Floreani 1,
F. Farinati 1, P. Burra 1, P. Simioni 2, F.P. Russo 1
1 Multivisceral Transplant Unit, Gastroenterology,
Department of Surgery, Oncology and
Gastroenterology, Padua University Hospital, Italy2 Hemorrhagic and Thrombotic Diseases Unit,
Department of Medicine, Padua University Hospital,
Italy3 Department of Cardiac, Thoracic and Vascular
Sciences, Biostatistics, Epidemiology and Public
Health Unit, Padua University Hospital, Italy
Background and aim: Prothrombotic microparticles (MP) have
been reported in cirrhosis. Since their ability of inducing the activa-
tion of coagulation cascade, high levels of MP have been associated
with a higher risk of portal vein thrombosis (PVT). Aim of this study
was to investigate the presence of MP in patients with HCV related
cirrhosis treated with DAA therapy as well as to correlate the MP
profile change with risk of PVT.
Methods: Patients with HCV related cirrhosis treated with
DAA were prospectively enrolled. Plasma levels of Annexin V-MP,
endothelial (E)-MP, platelet (P)-MP and tissue factor (TF) MP were
measured by cytofluorimeter at baseline (B-), at the end of therapy
(EOT) and 12 weeks (12 W) after EOT. During follow-up, PVT onset
was recorded. Fifty healthy subjects were enrolled as controls.
Results: 60 patients were enrolled (Child A/B 50/10). All of
them reached EOT. Twenty patients (33%) reached 12 W after
EOT follow-up. B-levels of Annexin V-MP (6640 MP/�L) and TF
bearing MP (32 MP/�L) were significantly higher than EOT lev-
els (4280 MP/�L, p < 0.05; 24 MP/�L, p < 0.01] and 12 W after
EOT-levels (2747 MP/�L, p < 0.01; 21 MP/�L, p < 0.01), respectively.
B-levels of P-MP (164 MP/�L) were higher than 12 W after EOT-
levels (125 MP/�L), however the difference was not significant
(p = 0.15). A statistically significant increase in E-MP was observed
after therapy (12 W after EOT: 1269 MP/�L in comparison to B-
levels 395 MP/�L; p < 0.05). Median follow-up was 12 months
(4–16). During follow-up, 1 PVT was recorded (incidence 2%).
Conclusions: Eradication of HCV is associated with significant
change in MP profile, related to reduction of inflammatory systemic
condition and to improvement of liver function. This ameliora-
tion may partially correct the disequilibrium of the hemostatic
imbalance of cirrhosis, leading to a reduction in the risk of PVT
development. Further studies are needed to confirm these results.
http://dx.doi.org/10.1016/j.dld.2017.01.020
e10 Abstracts / Digestive and Liver Disease 49S (2017) e1–e18
OC-17
Abnormal microvasculature in chronic viralhepatitis
S. Sarcognato 1, F. Farinati 2, R. Cardin 2,
F.P. Russo 2, M. Piciocchi 2, V. Guzzardo 1,
L. Giacomelli 1, M. Guido 1
1 Department of Medicine–DIMED, University of
Padua, Padua, Italy2 Department of Surgery, Oncology and
Gastroenterology, University of Padua, Padua, Italy
Background: Histological abnormalities of intrahepatic
microvasculature have been well described in both non-cirrhotic
and cirrhotic portal hypertension, but very little is known about
the prevalence of such lesions outside these settings.
Aim: The aims of this study were to investigate the type
and prevalence of morphological abnormalities of intrahepatic
microvasculature in chronic viral hepatitis B (CHB) and C (CHC)
and to correlate microvascular changes with fibrosis stage, tissue
markers of fibrogenesis, sinusoidal capillarization/angiogenesis,
and oxidative DNA damage.
Methods: Liver biopsies from 74 consecutive treatment-naive
patients with CHB or CHC were studied. No one had clinical signs
of portal hypertension or extra hepatic vascular alterations. The
evaluated microvascular changes included (i) phlebosclerosis, (ii)
aberrant vessels, (iii) portal angiomatosis, (iv) sinusoidal dilata-
tion, (v) thrombosis of small intrahepatic portal veins, vi) abnormal
parenchymal draining veins. Sections were stained with anti-CD34,
anti-CD105, and anti-alpha-smooth muscle actin (ASMA). Tissue
quantification of 8-OHdG adducts was performed as a marker of
oxidative DNA damage.
Results: Portal angiomatosis was the most frequent microvas-
cular change (46/74 cases; 62.1%), and it strongly correlated with
the HAI (p = 0.003), the stage of fibrosis (p = 0.00), the extension of
CD34 expression (p = 0.04), and with ASMA expression in both zone
1 (p = 0.0005) and 2/3 (p = 0.03). Aberrant vessels were detected
in 21.6% (16/74) of cases and correlated with the stage of fibrosis
(p = 0.008) and with the extension of ASMA immunoreactivity in
zones 2/3. Microvascular density in portal tracts was significantly
related to the number of 8-OHdG adducts. At the multivariate anal-
ysis, portal angiomatosis was an independent predictor of fibrosis
stage (p = 0.02).
Conclusions: Histological microvascular abnormalities are
common in CHB and CHC. Their correlation with fibrosis stage, sinu-
soidal capillarization, neoangiogenesis, and ongoing fibrogenesis
supports a role in disease progression. Systematic assessment of
microvascular changes in liver biopsies of chronic viral hepatitis
might provide prognostic informations.
http://dx.doi.org/10.1016/j.dld.2017.01.021
OC-18
External validation of the HCC-MELD score forpatients with hepatocellular carcinoma waitingfor liver transplantation
A. Vitale 1, A.C. Frigo 2, P. Burra 1, P. Angeli 1,
G. Zanus 1, U. Cillo 1
1 Liver Transplant Center, Padua University, Padua,
Italy2 Biostatistic Unit, Padua University, Padua, Italy
Background and aims: We recently described a method for cal-
ibrating HCC and non-HCC patients according to survival benefit to
restore equity to the organ allocation system. The aim of this study
is to externally validate this method in a large cohort of US patients.
Methods: We modelled the post-transplantation survival of
adult, first-time liver transplant recipients with HCC (n. 9135) or
without (n. 25,890) from 2002 through 2013 using Cox propor-
tional hazards regression. We modelled waitlist survival of patients
listed for transplantation with HCC (n. 15,605) or without (n.
85,229) using competing risks analysis. MELD-related hazard ratios
obtained using these models were included in a Monte Carlo sim-
ulation and used to calculate 5-year survival benefit estimations
(i.e. the difference between post-transplantation and waitlist life
expectancy) in HCC and non-HCC populations.
Results: The 5-year survival benefit increased with actual MELD
score for patients with and without HCC, ranging from just a few
months in patients with low MELD scores (i.e., 6–8) to more than
48 months in patients with the highest MELD scores (i.e., 36–40).
As in the Italian study, the survival benefit of patients with
HCC was higher than that of patients without HCC who had the
same actual MELD score, irrespective of tumor burden or serum
level of a-fetoprotein. Median 5 year transplant benefit was 10.30
months (5.72–45.09) for the non-HCC patients, and 28.54 months
(10.66–44.88) for the HCC patients (p < 0.001).
Using our previously published method, we obtained the
equation “HCC-MELD US” = 1.73 * MELD − logAFP + 2.8 calculating a
numerical score for HCC patients, whereby their transplant benefit
is equal to that of non-HCC patients with the same numerical value
for MELD.
Conclusions: Our proposed method for calibrating HCC and
non-HCC patients according to survival benefit was validated in
a large US population.
http://dx.doi.org/10.1016/j.dld.2017.01.022
OC-19
Entecavir or tenofovir monotherapy preventsHBV recurrence in liver transplant recipients: A5-year follow-up study after hepatitis Bimmunoglobulin withdrawal
M.A. Manini 1,2, M. Bruce 1, I. Carey 1,
G. Whitehouse 1, B. Wang 1, E. Gonsalkorala 1,
A. Considine 1, P. Lampertico 2, K. Agarwal 1
1 Institute of Liver Studies, King’s College Hospital,
London, United Kingdom2 A.M. and A. Migliavacca Center for Liver Disease,
Division of Gastroenterology and Hepatology,
Fondazione IRCCS CA’ Granda Ospedale Maggiore
Policlinico, Università degli Studi di Milano, Milan,
Italy
Background/aims: Prophylaxis with HBIg + NUC remains the
standard-of-care to prevent HBV reinfection after LT. Recent data
suggest that 3rd generation NUC therapy may be effective as well.
We investigated the 5-year efficacy/safety of ETV or TDF monopro-
phylaxis after HBIG withdrawal.
Methods: Between 01/2010 and 01/2012, all HBV and HDV
transplanted patients followed in our centre withdrew HBIg + NUC
and started ETV or TDF monotherapy. Patients were followed every
3–6 months until 10/2016. HBsAg and HBV-DNA were monitored
at each follow-up visit.
Result: 77 patients with a post-transplant follow-up of 68
(range 6–237) months were included (55% TDF, 45% ETV). Group
A included 69 HBV monoinfected patients (80% male, 59 years, 58%
Caucasian) who underwent LT due to fulminant hepatitis (16%),
ESLD (38%), acute-on-chronic liver disease (6%) and HCC (40%).
Abstracts / Digestive and Liver Disease 49S (2017) e1–e18 e11
Table 1
LTindication
HBVDNA atLT(IU/mL)
HBsAg atLT(IU/mL)
HBeAgat LT
HBIG + NUCpre-switch(mos)
NUC beforeHBIGwithdrawal
NUC afterHBIGwithdrawal
HBsAgrecurrence(mos)
AoCLF 800 3589 neg 31 LAM ETV 56HCC <12 43 neg 28 LAM ETV 19HCC 309 11391 pos 69 LAM TDF 22HCC 269 2281 neg 34 LAM ETV 47HCC <20 316 neg 8 TDF TDF 21
Group B included 8 HBV/HDV coinfected patients (50% male, 54
years, 75% Caucasian, ESLD in 88%, HCC in 12%).
Group A and B patients received oral therapy for a median of 69
(range 12–80) months and 61 (range 31–78) months, respectively.
No Group B patients had HBsAg or HBV DNA recurrence, while 5
(7%) Group A patients became HBsAg-positive, (see Table 1). The
cumulative 1-, 3- and 5-year rates of HBsAg recurrence were 0, 5%
and 8%. All 5 patients demonstrated undetectable HBV-DNA levels
and stable graft function at HBsAg seroreversion as well as during
follow-up. None experienced clinically relevant events.
Overall, 3 deaths occurred (1 for HCV recurrence and 2 for sep-
sis). The cumulative 5-year survival was 96%.
Conclusion: HBIG can be safely discontinued in HBsAg-positive
LT recipients and replaced by ETV or TDF monotherapy.
http://dx.doi.org/10.1016/j.dld.2017.01.023
OC-20
A new strategy to improve the liverengraftment efficiency of transplanted humanbiliary tree stem/progenitor cells (hBTSCs): Cellcoating with hyaluronic acid
L. Nevi 1, G. Carpino 2, D. Costantini 1,
V. Cardinale 1, O. Riccioni 3, S. Di Matteo 1,
F. Melandro 4, P.B. Berloco 4, L. Reid 5, E. Gaudio 3,
D. Alvaro 1
1 Department of Medico-Surgical Sciences and
Biotechnologies, Sapienza University of Rome, Rome,
Italy2 Department of Movement, Human and Health
Sciences, Division of Health Sciences, University of
Rome “Foro Italico”, Rome, Italy3 Department of Anatomical, Histological, Forensic
Medicine and Orthopedics Sciences, Sapienza
University of Rome, Rome, Italy4 Department of General Surgery and Organ
Transplantation, University of Rome “Sapienza”,
Rome, Italy5 Department of Cell Biology and Physiology and
Program in Molecular Biology and Biotechnology,
University of North Carolina, Chapel Hill, NC, United
States
Human biliary tree stem/progenitor cells (hBTSCs) have been
used for cell therapy of patients with advanced liver cirrhosis.
Strategies to improve the liver engraftment of transplanted cells
are currently under evaluation. We aimed to investigate whether
coating hBTSCs with clinical-grade Hyaluronic Acid (HA) may
influence their liver engraftment efficiency, proliferation and
hepatocyte differentiation.hBTSCs were isolated, by EpCAM-
immunoselection, from the extrahepatic biliary tree of adult
liver donors and incubated with 0.1% HA. In vitro, HA-coated and
uncoated hBTSCs were analyzed for cell viability, colony formation,
proliferation and mRNA expression of CD44,ITG�1,ITG�4,CDH1.
In vivo, HA-coated and uncoated hBTSCs were injected into the
spleen of SCID mice. After 30 days, the liver engraftment and
ectopic distribution in distant organs were evaluated by immuno-
histochemistry. The human albumin mRNA into the mice liver
was measured by a de novo developed RT-qPCR method and the
human albumin concentration in the mice serum was evaluated by
ELISA.
Immunofluorescence analysis showed that HA homogeneously
coated more than 90% of hBTSCs. HA-coated hBTSCs showed
increased colony formation (p < 0.001), increased cell viability
(79.24 vs 70.06%; p < 0.05) and, increased proliferation rate (Pop-
ulation Doubling 2.03 vs 0.77 times/week; p < 0.05) with respect to
uncoated hBTSCs. HA-coating resulted into a significant increase
(p < 0.05) in gene expression of the adhesion molecules ITG�1 and
ITG�4 while, CDH1 and CD44 resulted into a significant decrease
(p < 0.05) genes expression was unchanged than uncoated cells. In
vivo, the engraftment efficiency of HA-coated hBTSCs was markedly
enhanced with respect to uncoated cells (11.02 vs 2.62%; p < 0.01).
HA improved the proliferation and hepatocyte differentiation of
hBTSCs engrafted into the mice liver. In keeping, the gene expres-
sion of human albumin in the liver and the human albumin serum
levels (117.62 vs 64.94 ng/dl; p < 0.05) were markedly higher in
mice transplanted with HA-coated than uncoated hBTSCs. Insignif-
icant or minimal ectopic distribution of transplanted hBTSCs in
distant organs was observed.
In conclusion, the easy and cheap procedure of HA-coating
markedly improved the effects of hBTSC transplantation and could
be rapidly turned in the clinical use.
http://dx.doi.org/10.1016/j.dld.2017.01.024
OC-21
Parenchymal sparing vs. anatomic resection forhcc: A propensity score analysis
S. Famularo 1,3, A. Giani 1,3, S. Di Sandro 2,
M. Sandini 1,3, A. Giacomoni 2, E. Pinotti 1,3,
L. Nespoli 1,3, L. Gianotti 1,3, L. De Carlis 1,2,
F. Romano 1,3
1 School of Medicine and Surgery, University of
Milano-Bicocca, Milan, Italy2 Department of General Surgery and
Transplantation, Niguarda Ca’ Granda Hospital,
Milan, Italy3 San Gerardo Hospital, Department of Surgery,
Monza, Italy
Background: Although anatomic resection (AR) for hepatocel-
lular carcinoma (HCC) is advocated as the optimal approach for
curative intent, its superiority over parenchyma-sparing resection
(PSR) has not been consistently proven. The purpose of this study
was to compare the impact of AR vs. PSR on disease recurrence and
patient survival.
Methods: We retrospectively analyzed patients suffering from
HCC who underwent liver resection from January 2001 to August
2015 in two hospitals. Patients receiving AR or PSR were directly
compared by a propensity score analysis (caliper of 0.1) using 9
variables. Thus, patients were stratified also for number of nod-
ules, presence of cirrhosis, size of the nodule, and ALBI grade. The
primary outcome measures were disease-free (DFS) and overall
survival (OS) rates. The secondary outcome was to identify vari-
ables related to disease recurrence.
Results: 455 consecutive patients were retrospectively ana-
lyzed. Propensity score matching was run on: age, cirrhosis, HCV
infection, number and size of nodules, bilobar disease, extension
of hepatectomy, radical resection, microvascular invasion, pres-
ence of satellitosis and ALBI grade. After matching 354 patient were
enrolled, 177 pairs for both groups. The median follow-up was 30
e12 Abstracts / Digestive and Liver Disease 49S (2017) e1–e18
months. Median OS was 47.5 months (95% CI: 30.03–65.9) for AR
group and 56.48 months (95% CI: 33.2–79.6) for PSR (p: 0.169).
Median DFS was 29.2 months (95% CI: 17.6–40.8) for AR and 24.8
months (95% CI: 15.2–34.2) for PSR (p: 0.337). At univariate and
multivariate analyses PSR was not associated with an higher risk of
intra-hepatic or extra-hepatic recurrence or tumor-related death.
Microvascular invasion and satellitosis were the predominant risk
factors for recurrence.
Conclusions: Overall survival and disease recurrence seem to
be independent from the type of resection. PSR may be safely used
to preserve liver function and reduce the impact of hepatectomy.
http://dx.doi.org/10.1016/j.dld.2017.01.025
OC-22
The survival benefit of laparoscopic ablationover trans-arterial chemoembolization inpatients with hepatocellular carcinomaineligible for liver resection or percutaneousablation
A. Bertacco 1, A. Marchini 1, A. Vitale 1, C. Ungaro 1,
F. D’Amico 1, E. Gringeri 1, D. Neri 1, D. Bassi 1,
G. Zanus 1, R. Carandina 2, C. Aliberti 2, U. Cillo 1
1 Department of Surgery, Oncology and
Gastroenterology, Hepatobiliary Surgery and Liver
Transplantation, Padua University, Padua, Italy2 Oncology Radiodiagnostics, Oncology Institute of
Veneto, Institute for the Research and Treatment of
Cancer (IRCCS), Padua University, Padua, Italy
Background: Different options are available for hepatocellular
carcinoma (HCC) treatment according to tumor characteristics and
patients liver function. Trans-arterial-chemioembolisation (TACE)
is the first-line treatment for patients ineligible for liver resection or
percutaneous ablation. Aim of our study was to compare outcome
of patients with HCC treated with laparoscopic ablation versus
patients treated with TACE.
Methods: Two HCC patients populations were used for the anal-
ysis: 485 patients treated with laparoscopic ablation (LA) as first
therapy in the period 2004–2015 and 410 patients that received
TACE as first treatment in the period 2008–2015. After propensy
score analysis we obtained two comparable groups (n = 175 for
each) to evaluate the overall survival. A simulation analysis was
also used to define survival benefit between the groups in different
BCLC stages.
Results: Laparoscopic ablation showed a significantly superior
long-term survival compared with TACE in unmatched patients
(median survival 47 vs 30 months, p < 0.05) but after sample size
reduction due to propensity score analysis (175 vs. 175 patients) the
difference between groups became not significant (median survival
46 vs. 32 months, p = 0.117). With the application of the median
survival simulation (995 patients undergoing LA vs. 995 undergo-
ing TACE) we showed a significant survival benefit of LA over TACE
in each BCLC stage (48 months in stage 0, 17 in stage A, 7 in stage B).
The variables that most influenced the survival benefit were MELD
score and patient age.
Conclusions: In HCC patients ineligible for percutaneous abla-
tion or liver resection, LA should be evaluated as potential
therapeutic strategy before considering TACE, whenever BLCL
stage.
http://dx.doi.org/10.1016/j.dld.2017.01.026
OC-23
Outcome of liver transplant recipients after thefirst episode of bacterial infection
A. Ferrarese 1, A. Zanetto 1, G. Germani 1,
M. Gambato 1, F.P. Russo 1, U. Cillo 2, P. Angeli 3,
P. Burra 1, M. Senzolo 1
1 Multivisceral Transplant Unit, Department of
Surgery, Oncology and Gastroenterology, Padua
University Hospital, Italy2 Hepatobiliary Surgery and Liver Transplant Center,
Padua University Hospital, Italy3 Internal Medicine, Padua University Hospital,
Padua, Italy
Introduction: Bacterial Infections (BI) represent a major cause
of decompensation and death in patients with cirrhosis. However,
the outcome during and after infection, and subsequently prioriti-
zation and drop-out from the waiting list for Liver Transplantation
(LT) remain still poorly understood.
Aim: To prospectively evaluate, in a single center cohort of
cirrhotic patients awaiting LT, the prevalence of BI; the 1-, and 12-
month outcome after the first episode of BI; the change of liver
function during and after resolution of BI, and the consequent pri-
oritization for LT.
Materials and methods: All patients who experienced BI while
in the WL for LT at Padua University Hospital since 2006–2014
were prospectively evaluated. MELD score, type of infection were
assessed before, during BI, and 1 and 12 months thereafter, together
with recipients’ outcome. Data were compared with a control group
matched for severity of liver disease without episodes of BI.
Results: 1794 patients were evaluated, of which 114 (6.4%)
were enrolled (M/F 79/35, age 57.2 ± 7.8 years, HCV 29.8%, HCC
19.3%). Spontaneous bacterial peritonitis was the prevalent BI(36%),
without any impact on short term mortality (p = 0.09). One month
mortality was significantly higher after BI than controls (p < 0.001);
indeed, considering survivors, there was a trend towards an
higher 12 month drop-out rate (p = 0.08). MELD score significantly
increased during BI in the whole cohort (20 ± 6 to 22 ± 6; p = 0.001),
and in those who survived (17.5 ± 5 vs 19.6 ± 5; p = 0.01). In the lat-
ter subgroup, MELD after resolution of BI was higher than before
(18.1 ± 4.9 vs 19.2 ± 5; p = 0.02).
Conclusions: BI represents a common cause of decompensation
and death in patients awaiting LT, determining a poorer outcome.
BI was associated with a significant short-term worsening of liver
function according to MELD score, also in those LT recipients who
recovered from BI. Thus, in this specific window time, personalized
scores for prioritization of patients awaiting LT should be advisable.
http://dx.doi.org/10.1016/j.dld.2017.01.027
Abstracts / Digestive and Liver Disease 49S (2017) e1–e18 e13
OC-24
Identification of Twinfilin-1 as a key regulatorof cholangiocyte biological response to injury:Evidence for a possible role of ageing in theprogression of cholangiopathies
L. Maroni 1, C. Pinto 1, D.M. Giordano 1,
S. Saccomanno 1, C. Rychlicki 1, L. Trozzi 1,
M.C. Albertini 2, F. Orlando 3, E. Melum 4,
J. Banales 5, A. Benedetti 1, G. Svegliati Baroni 1,
M. Marzioni 1
1 Dipartimento di Gastroenterologia e Epatologia,
Università Politecnica delle Marche, Ancona, Italy2 Dipartimento Scienze Biomolecolari, Università
degli Studi di Urbino “Carlo Bo”, Urbino, Italy3 Servizio di Allevamento Sperimentazione
Animale, Polo Scientifico Tecnologico, Falconara,
Italy4 Norwegian PSC Research Center, Division of
Surgery, Inflammatory Medicine and
Transplantation, Oslo University Hospital,
Rikshospitalet, Oslo, Norway5 Department of Liver and Gastrointestinal Diseases,
Biodonostia Health Research Institute – Donostia
University Hospital, Ikerbasque, CIBERehd,
University of the Basque Country (UPV/EHU), San
Sebastian, Spain
Introduction: Disorders of the biliary tree such as PBC, PSC or
cholangiocarcinoma develop and progress differently according to
the patient age. Similarly, biliary injury after liver transplantation
is affected by donor age. It is not known yet whether the ageing
process plays any role in the pathophysiology of biliary disorders.
The aim of the study was to identify molecular pathways associ-
ated to the ageing process and to verify their role in cholangiocyte
response to injury.
Materials and methods: Expression of a number of age-related
microRNAs (miRs) were evaluated in cholangiocytes of 2-month
old (young) and 22-month old (old) mice, either subjected or not
to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-treatment, a
model of sclerosing cholangitis. Common intracellular pathways
and molecular targets of elevated miRs were identified by in silico
analysis. Proliferation was assessed by sulforhodamine B (SRB)
assay; senescence and senescence-associated secretory phenotype
(SASP) markers (p16INK4a, p21WAF1/Cip1, Il-1, Il-6, Igf-1, Pai-1) were
evaluated in vitro by qPCR.
Results: Ageing-related miR-1a, miR-30e, miR-93, miR-34a,
miR-146b and miR-20a were up-regulated in cholangiocytes from
DDC-treated mice compared to controls. In silico analysis identi-
fied Twinfilin-1 (Twf1) as a common target of the up-regulated
miR-1a, miR-30e and miR-20a. Young mice subjected to DDC and
old-untreated mice showed similar expression of Twf1 and related
miRs in cholangiocytes, which was markedly increased as com-
pared to young untreated ones. Twf1 and miRs expression was
further increased in DDC-treated old mice. By immunofluores-
cence, intrahepatic cholangiocytes of PSC patients were positive
for Twf1 expression. Knock-down of Twf1 by siRNAs in cultured
cholangiocytes significantly reduced cell proliferation. In parallel,
senescence and SASP markers were increased in Twf1-deficient
cholangiocytes.
Conclusions: Twf1 is as an important mediator of both cholan-
giocyte adaptation to ageing processes and response to injury. Our
data suggest that disease and ageing might share common path-
ways, which may unveil novel markers of disease progression.
http://dx.doi.org/10.1016/j.dld.2017.01.028
OC-25
Metformin reduces cell migration anddown-regulates epithelial to mesenchymaltransition (EMT) by AMPK/Foxo3a pathway inhuman intrahepatic cholangiocarcinoma (CCA)
S. Di Matteo 1, D. Costantini 1, L. Nevi 1, A. Lustri 1,
C. Napoletano 3, J. Faccioli 1, F. Giulitti 1,
E. Manzi 2, A.M. DeRose 4, M.C. Bragazzi 1,
G. Grazi 2, P.B. Berloco 5, F. Giuliante 4,
V. Cardinale 1, G. Carpino 6, D. Alvaro 1
1 Medico-Surgical Sciences and Biotechnologies,
Sapienza University of Rome, Rome, Italy2 Gastroenterology Unit, Regina Elena National
Cancer Institute, Rome, Italy3 Department of Experimental Medicine, Sapienza
University of Rome, Rome, Italy4 Hepatobiliary Unit, Catholic University of the
Sacred Heart School of Medicine, Rome, Italy5 Department of General Surgery and Organ
Transplantation, Sapienza University of Rome, Rome,
Italy6 Department of Health Science, University of Rome
“Foro Italico”, Rome, Italy
CCA is an aggressive cancer resistance to chemotherapeutics.
We demonstrated that CCA is enriched of cancer stem cells express-
ing EMT traits associated with aggressiveness and drug resistance.
We established primary cell cultures from human IHCCA sub-
types (mucin and mixed). Treatment with the anti-diabetic drug
metformin has been associated with reduced cancer incidence. In
immortalized cancer cell lines, metformin showed EMT inhibitory
effects by up-regulating Foxo3a signaling.
We aimed evaluating the effects of metformin on proliferation,
apoptosis, cell migration and expression of EMT traits in primary
cultures of CCA subtypes.
CCA were treated with acute increasing metformin concentra-
tions (5–1000 �M, 1–4 days) and chronically at 10 �M Metformin.
We evaluated proliferation by MTS assay; apoptosis by Flow
cytometry analysis of Annexin V-FITC/Propidium Iodide; and cell
migration by wound-healing assay. The expression of Vimentin,
E-Cadherin, SNAIL1/2, TWIST1, Cytokeratin19, FOXO3a and AMPK
genes were analyzed by RT-qPCR, whereas FOXO3a, Cytokeratin19
and Vimentin were analyzed by Immunofluorescence Assay.
Metformin significantly inhibited cell proliferation and induced
apoptosis in primary cultures ofmucin- and mixed-IHCCA; the
effects were dose- and time-dependent. The migration of IHCCA
cells, from both mucin and mixed CCA subtypes, was also signifi-
cantly reduced by acute treatment. The effects of metformin were
associated with enhanced gene expression of the epithelial marker
E-Cadherin and decreased expression of Vimentin and EMT specific
genes, SNAIL1/2 and TWIST1. Metformin also increased the AMPK
and FOXO3a mRNA levels. FOXO3a gene expression was negatively
correlated with the expression of SNAIL1 and Vimentin genes. The
FOXO3a protein migrates from cytoplasm to nucleus in metformin
treated cells. After chronic treatments the Mucin-IHCCA showed
a high expression of Cytocheratin19 and a very low expression of
Vimentin.
In conclusion, we demonstrated that metformin inhibits cell
proliferation, enhances apoptosis and impairs EMT traits by activat-
ing Foxo3a in primary cultures of human CCA. Therefore, metformin
could play anticancer effects against human CCAs with relevant
therapeutic implications.
http://dx.doi.org/10.1016/j.dld.2017.01.029
e14 Abstracts / Digestive and Liver Disease 49S (2017) e1–e18
OC-26
Microgravity maintains stemness and enhanceglycolytic metabolism in human hepatic andbiliary tree stem/progenitor cells
D. Costantini 1, V. Cardinale 1, L. Casadei 2,
G. Carpino 3, L. Nevi 1, S. Di Matteo 1, A.M. Lustri 1,
S. Safarikia 1, F. Melandro 4, P. Berloco 4,
C. Manetti 2, D. Alvaro 1
1 Department of Medico-Surgical Sciences and
Biotechnologies, Sapienza University of Rome, Rome,
Italy2 Department of Chemistry, Sapienza University of
Rome, Rome, Italy3 Department of Health Science, University of Rome
“Foro Italico”, Rome, Italy4 Department of General Surgery and Organ
Transplantation, Sapienza University of Rome, Rome,
Italy
Gravity plays a key role in regulating cell processes such as pro-
liferation, differentiation and cell function.
The aim of the study was to evaluate the effects of microgravity
on differentiation and exo-metabolome profile of human hepatic
and biliary tree stem/progenitor cells.
Simulated weightless conditions were obtained by the RCCS
(Synthecon). Primary cultures of human biliary tree stem cells
(hBTSCs) and immortalized human hepatic cell line (HepG2)
were cultured in microgravity or in normogravity conditions.
Self-replication and differentiation toward mature cells were
determined, respectively, by culturing in Kubota’s Medium and
hormonally defined medium tailored for hepatocyte differentia-
tion. RT-qPCR was used to evaluate gene expression and NMR to
analyze the cell exo-metabolome profile.
Microgravity determined an increase of stemness genes (OCT4,
SOX17, PDX1) in hBTSCs (p < 0.05 vs normogravity). hBTSCs cul-
tured in microgravity showed an impaired capacity to differentiate
toward mature hepatocytes, since the expression of hepatocyte
lineage genes (ALB, ASBT and CYP3A4) was significantly lower
with respect to normogravity (p < 0.05). In HepG2, the microgravity
caused a lower (p < 0.05 vs normogravity) expression of CYP3A4,
a terminal differentiation gene expressed in lobular zone 3. The
NMR PCA of the exo-metabolome cell profile evidenced that, in
microgravity, both cell lines presented higher glucose consumption
and lower consumption of pyruvate and glutamate with respect
to normogravity (p < 0.05), with formation of fermentation and
ketogenesis products. Interestingly, while in normogravity the
differentiation of hBTSCs toward mature hepatocytes was associ-
ated with increased oxidative phosphorylation (p < 0.05), this was
prevented by microgravity in association with the impaired cell
differentiation.
Our results demonstrated significant combined biologic and
metabolomic effects of microgravity on hepatic stem/progenitor
cells with several implications. From one side, these effects of
microgravity should be taken into consideration for space medicine
programs but, from the other side, they could be interesting for the
generation of devices based on stem/progenitor cells.
http://dx.doi.org/10.1016/j.dld.2017.01.030
OC-27
Epidemiology of primary biliary cholangitis inItaly: evidences from a real world database
M. Marzioni 1, C. Bassanelli 2, B. Marini 2,
C. Ripellino 3, D. Urbinati 3, D. Alvaro 4
1 Clinic of Gastroenterology and Hepatology,
Università Politecnica delle Marche, Ancona, Italy2 Intercept Pharmaceuticals, Milan, Italy3 IMS Health, Milan, Italy4 Department of Medical-Surgical Sciences and
Biotechnologies, “La Sapienza” Rome University,
Rome, Italy
Introduction and aim: Primary biliary cholangitis (PBC) is a
rare chronic autoimmune liver disease. Orphanet estimates that
the global prevalence of PBC is 21.0/100,000 with an incidence
of 3.0/100,000/year. The only available data concerning PBC epi-
demiology in Italy, specifically in the Lombardy region, report a
prevalence of 29.5/100,000 and an incidence of 1.6/100,000/year
based on administrative databases. The aim of this analysis was to
investigate the epidemiology of PBC in Italy and describe the main
characteristics of this patient population.
Materials and methods: IMS Health analyzed longitudinal
databases of 900 General Practitioners and selected patients with
a 571.6 diagnosis code (ICD9, Biliary Cirrhosis) from 1/2014 to
12/2015. Demographics and treatment were registered at the time
of first evidence of PBC diagnosis. Comorbidities were collected up
to twelve months prior to diagnosis.
Results: 1,204,216 inhabitants >14 years old, homogenously
distributed throughout Italy were analyzed: 412 patients had
a diagnosis of PBC according to the ICD9 code 571.6. In
2015, the prevalence was 28.0/100,000 while the incidence was
5.3/100,000/year. The female to male ratio was 4:1. The most
common comorbidities were osteoporosis (21.5%), and diabetes
(12.7%). Diseases of the connective tissue, rheumatoid arthritis and
thyroiditis primarily affected female patients. 13 patients had cir-
rhosis and 3 patients had primary liver cancer. 364 patients (88.4%)
received a pharmacologic treatment for PBC, 92% of whom received
UDCA. Within six months of follow up, 1 (0.24%) patient underwent
liver transplantation and 5 (1.20%) patients died.
Conclusions: The estimated prevalence of PBC based on a real
world database analysis was consistent with a previous Italian
study based on administrative databases and with Orphanet data,
while the incidence was slightly higher. Despite limitations, data
collected through the IMS longitudinal database provides unique
and valuable insight into the current epidemiology of PBC in Italy,
key PBC patient’s characteristics and medications.
http://dx.doi.org/10.1016/j.dld.2017.01.031
Abstracts / Digestive and Liver Disease 49S (2017) e1–e18 e15
OC-28
Characterisation of the immune response inpatients with drug induced liver injury
C. Bergamo 1, G. Germani 1, D. Bizzaro 1,
C. Frasson 2,3, G. Basso 2, A. Ferrarese 1,
A. Zanetto 1, S. Shalaby 1, I. Bortoluzzi 1,
M. Gambato 1, M. Senzolo 1, F.P. Russo 1, P. Burra 1
1 Multivisceral Transplant Unit, Department of
Surgery, Oncology and Gastroenterology, Padova
University Hospital, Padova, Italy2 Haemato-Oncology Laboratory, Department of
Woman and Child Health, University of Padova,
Padova, Italy3 Fondazione Città della Speranza, Istituto di Ricerca
Pediatrica, Padova, Italy
Introduction and aim: Drug Induced Liver Injury (DILI)
represents the leading cause of acute liver failure and liver trans-
plantation in Western countries. The aim of the study was to assess
the clinical presentation, outcome and modification of the immune
pattern in patients with DILI.
Methods: Patients admitted at Multivisceral Transplant Unit of
Padova University Hospital for suspected DILI from 2013 to 2016
were included. Demographic and clinic characteristics and trans-
plant free survival were evaluated in all patients.
In a subgroup of patients with DILI, isolated mononuclear cells
from peripheral blood were analyzed by flow cytometry for: mono-
cytes, B-lymphocytes, T-helper and T-cytotoxic lymphocytes. Data
were compared with healthy controls.
Results: 31 DILI patients were evaluated, 55% women with a
median age of 46.7 years (range 33–70). The most frequent drugs
involved in DILI were antimicrobials (42%). Transplant free sur-
vival rate at 1 year was 73%, with 16% patients who underwent
liver transplantation. The cytofluorimetric analysis performed in 7
DILI patients compared to 4 healthy controls showed a significant
decrease of B-lymphocytes in DILI patients (2.4% ± 0.9 vs. 7.9 ± 0.5%,
p = 0.01). Patients with DILI due to antimicrobials, compared to con-
trols, showed a more evident decrease of B-lymphocytes (0.6 ± 0.4%
vs. 7.9 ± 0.4%; p = 0.004), of T-Helper lymphocytes (8.3 ± 7.7% vs.
20.9 ± 12.2%; p = 0.05) and a significant decrease of T-Helper
compared to the other DILI patients (8.3 ± 7.7% vs. 26.6 ± 12.2%,
p = 0.04). Male patients showed a higher percentage of immature
(12.9 ± 3.3% vs. 2.7 ± 2.7%, p = 0.007), early monocytes with pro-
inflammatory properties (9.7 ± 1.6% vs. 3.0 ± 2.9%, p = 0.03) and a
higher percentage of memory T-cells (22.5 ± 2.8% vs. 3.8 ± 1.7%,
p < 0.001) compared with female patients.
Conclusions: The most frequent agents involved in DILI were
antimicrobials, which seem to induce a marked immunodeficiency,
especially towards B-lymphocytes, suggesting a possible cytotoxic
T-cell-mediated damage. Despite the incidence of DILI was higher
in women, males seem to have a more enhanced pro-inflammatory
status.
http://dx.doi.org/10.1016/j.dld.2017.01.032
OC-29
In-hospital mortality and length of stay incirrhotic patients with sepsis treated withnon-selective beta-blockers
A. Facciorusso, R. Villani, F. Bellanti, R. Bruno,
G. Fioravanti, G. Vendemiale, G. Serviddio
Department of Internal Medicine, University of
Foggia, Foggia, Italy
Introduction: Non-selective beta-blockers (NSBBs) have been
suggested to be associated with decreased rate of bacterial infection
and reduced severity of systemic inflammation in cirrhotic patients.
Aim: To test whether low doses NSBBs ameliorate short-term
outcomes in cirrhotic patients with sepsis.
Methods: Out of 854 cirrhotics admitted to our hospital
between 2006 and 2016, 107 patients with sepsis were included
in the analysis and grouped into 2 cohorts: 48 patients under
NSBB treatment (Group 1) and 59 NSBB non-users (Group 2). Uni-
variate/multivariate logistic regression analysis was performed to
identify the factors influencing in-hospital mortality, and results
were expressed as odds ratios (OR) and 95% confidence intervals
(CI). Duration of hospital stay, severity of septic events, and tem-
poral trend of MELD score were analyzed too.
Results: The two cohorts resulted balanced for clinical and
demographical characteristics. NSBB-users experienced milder
septic events, although not significantly (72.9% of septic events reg-
istered in group 1 were not severe vs 54.2% in group 2, p = 0.12). This
trend was paralleled by inflammatory lab markers [white blood cell
count: 9.2 (3.4–16.3) in NSBB-users vs 12.1 (4.2–19.8) in NSBB non-
users (p = 0.004); and plasma C-reactive protein: 47.4 (1.55–172)
and 65.5 (2.3–248) in the two groups, respectively (p = 0.24)]. In-
hospital mortality was significantly lower in group 1 (18.7% versus
42.3%, p = 0.01) and duration of hospital stay was shorter among
NSBB users (15 days, range 2–37 versus 18.5, 2–60; p = 0.03).
Comorbidity index (OR: 4.14, p = 0.03) and NSBB use (OR: 0.29,
p = 0.02) resulted significantly associated with in-hospital mortal-
ity in multivariate analysis. MELD score resulted significant higher
in group 2 from the sixth day since sepsis occurrence onwards.
Conclusions: Our study is the first report on the efficacy of low
doses of NSBB in reducing mortality and hospital stay in cirrhotics
with sepsis. NSBB may exert these effects through the modulation
of systemic inflammatory responses.
http://dx.doi.org/10.1016/j.dld.2017.01.033
e16 Abstracts / Digestive and Liver Disease 49S (2017) e1–e18
OC-30
Local prothrombotic state in portal venoussystem in cirrhosis
S. Shalaby 1, P. Simioni 3, E. Campello 3,
S. Gavasso 3, A. Zanetto 1, F. D’Amico 2,
E. Gringeri 2, U. Cillo 2, M. Battistel 4, P. Burra 1,
M. Senzolo 1
1 Multivisceral Transplant Unit, Department of
Surgery, Oncology and Gastroenterology, Padua
University Hospital, Padua, Italy2 Hepatobiliary Surgery and Liver Transplantation
Unit, Department of Surgery, Oncology and
Gastroenterology, Padua University Hospital, Padua,
Italy3 Hemorrhagic and Thrombotic Diseases Unit,
Department of Medicine (DIMED), University of
Padua Medical School, Padua, Italy4 University Radiology, Department of Medicine,
University Hospital of Padua, Padua, Italy
Introduction: Cirrhosis is characterized by both bleeding
and thrombotic complications due to underlying procoagulative
haemostatic imbalance. Among thrombotic-events, portal-vein
thrombosis (PVT) is the most common with annual incidence ran-
ging between 4.6% and 12.8%. Demonstrated associated risk-factors
are severity of portal-hypertension and slowed portal-flow. How-
ever, data regarding haemostasis in the portal venous-system of
cirrhotics are lacking.
Aims and methods: To evaluate peripheral and portal
venous haemocoagulative-state in patients with cirrhosis in
comparison with controls, through thrombin generation-test
(TGT), rotational-thrombelastometry (ROTEM) along with evalu-
ation of endothelial-dysfunction by quantification of circulating
endothelial-microparticles (MP). Correlate these results with
activity-levels of local pro and anticoagulant factors. Compare
peripheral and portal venous districts in cirrhotics in terms of
haemostatic-balance.
We consecutively enrolled cirrhotic patients undergoing liver-
transplantation (LT) or TIPS. Non-cirrhotic patients awaiting
liver-surgery or deceased liver-donors were enrolled as controls.
On citrated peripheral and portal venous blood we performed: TGT
with/without thrombomodulin (TM), ROTEM, dosage of pro and
anticoagulant factors and endothelial-MP.
Results: 25 cirrhotics (15 LT and 10 TIPS) and 6 controls
(2 undergoing hepatic-resection for benign liver-lesions and 4
liver-donors) were enrolled. Peripheral-blood in cirrhotics showed
resistance to activation of PC-pathway at TGT (ETP with/without
TM 0.89 (0.78–0.92) vs 0.6 (0.3–0.74), p < 0.001), lower clot sta-
bility at ROTEM (MCF-NATEM mm: 43.5 (36–51) vs 63 (53–69),
p = 0.042), and significant increase of endothelial-MP (CD62E-
MP/�L: 1391 (651–2301) vs 582 (380–1161), p = 0.046), indicative
of higher endothelial-damage compared to controls. Similar results
were obtained comparing portal-blood of cirrhotics and controls
(ETP with/without TM 0.89 (0.78–0.92) vs 0.63 (0.33–0.75),
p = 0.001; MCF-NATEM mm: 46 (39–51) vs 62 (49–66), p = 0.056;
CD62E-MP/�L: 1606.5 (680–1885) vs 529.5 (266–781), p = 0.069).
There was a significant correlation between diminished levels of
PC, PS, AT-III, FII and either TGT or ROTEM parameters. Comparing
portal and peripheral blood of cirrhotics, we detected endogenous
heparinoids in portal blood (ɑ-angle NATEM 51◦ (46–57) vs HEP-
TEM 57◦ (50–59), p = 0.05). This finding, together with a decreased
concentration of endothelial-MP carrying TM (TM-MP/�L:
232 (190–287) vs 377 (218–493), p = 0.002) and endothelial-PC
receptor (EPCR/CD65E-MP/�L: 16 (14–25) vs 37 (24–70), p < 0.001),
demonstrated a local greater endothelial damage in cirrhotics.
Conclusion: In cirrhotics, venous hypercoagulability and por-
tal site-specific endothelial damage, associated with hampered
antithrombotic properties, may be important local risk-factors in
the pathogenesis of PVT along with the documented venous stasis.
http://dx.doi.org/10.1016/j.dld.2017.01.034
OC-31
In experimental ascitic cirrhosis reduction ofadrenergic function by means of �2Aadrenergic receptor agonists has considerableaquaretic effects
G. Sansoè 1, M. Aragno 2, R. Mastrocola 2,
M. Ayoubi 1, M. Parola 2
1 Division of Gastroenterology, Humanitas Gradenigo
Hospital, Torino, Italy2 Department of Clinical and Biological Sciences,
University of Torino, Italy
Introduction: Catecholamines trigger proximal tubular fluid
retention and decrease Na+ and water delivery to the diluting
segment of the Henle’s loop, thereby reducing renal excretion
of solute-free water. In advanced cirrhosis, non-osmotic hyper-
secretion of vasopressin (ADH) has a role in causing dilutional
hyponatremia, but the advantage of ADH V2 receptor antagonists
is somewhat controversial in the treatment of ascites.
Aims: By means of the use of sympatholytic agents (�2A adren-
ergic receptor agonists), we assessed the hypothesis that adrenergic
hyperfunction might contribute to water retention in experimental
ascitic cirrhosis.
Methods: Hormonal status, renal function ad tubular free-water
reabsorption (TFWR) were evaluated in six groups of rats with
ascitic cirrhosis: rats with cirrhosis due to 13 weeks of CCl4 (group
G1); cirrhotic rats receiving, from 11th to 13th CCl4 week, daily
diuretics alone (0.5 mg/kg furosemide plus 2 mg/kg K+-canrenoate)
(G2), or diuretics plus guanfacine oral prodrug (�2A adrener-
gic receptor agonist and sympatholytic agent) 2 (G3), 7 (G4), or
10 mg/kg (G5). Group G6 received diuretics plus SSP-004240F1 (V2
receptor antagonist) 1 mg/kg.
Results: Compared to G2, low-dose guanfacine plus diuret-
ics (G3) reduced serum norepinephrine from 423 ± 22 to
211 ± 41 ng/mL and plasma renin activity from 35 ± 8 to
9 ± 2 ng/mL/h (all P < 0.03). Compared to G1 and G2, TFWR was
significantly reduced, and to the same extent, with low-dose guan-
facine plus diuretics (G3) and with V2 antagonist plus diuretics (G6)
(all P < 0.03). TFWR correlated with plasma aldosterone (r = 0.51,
P < 0.01) and urinary potassium excretion (r = 0.90, P < 0.001).
Conclusions: In ascitic cirrhosis, reduced volaemia and adren-
ergic hyperfunction, especially when exacerbated by potassium-
depleting diuretics (furosemide), contribute to tubular retention of
water and dilutional hyponatremia. In this case, suitable doses of
sympatholytic agents are as effective as V2 antagonists when the
aquaretic effect is needed.
http://dx.doi.org/10.1016/j.dld.2017.01.035
Abstracts / Digestive and Liver Disease 49S (2017) e1–e18 e17
OC-32
Extracellular vesicles induce renal tubular cellsapoptosis, oxidative stress and functionalabnormalities in patients with an acutedecompensation of cirrhosis
A. Brocca 1, D. Medica 2, S. Piano 1, A. Romano 1,
A. Sticca 1, V. Cantaluppi 3, P. Angeli 1
1 Unit of Internal Medicine and Hepatology,
Department of Medicine – DIMED, University of
Padua, Padua, Italy2 Department of Medical Sciences, University of
Torino, Azienda Ospedaliera “Città della Salute e
della Scienza-Molinette”, Torino, Italy3 Nephrology and Kidney Transplant Unit,
Department of Translational Medicine, University of
Eastern Piedmont, Novara, Italy
Introduction: Extracellular vesicles (EVs) are involved in bio-
logical processes as well as in disease pathogenesis. The origin and
the role of EVs in the pathogenesis of liver disease is poorly recog-
nized. The aims of this study were to: (a) characterize plasma EVs
isolated from patients with compensated cirrhosis (CC), AD, ACLF
and healthy subjects (CTRL), (b) study the in vitro effects of EVs on
renal tubular cells (RTCs).
Methods: 12 CC, 13 AD, 11 ACLF patients and 12 CTRL were
enrolled. Plasma EVs were characterized by Nanosight analysis.
Detection of EVs surface proteins, ROS productions in RTCs, pro-
tein expression in RTCs was performed by FACS analysis. Cytotoxic
effects of plasma EVs on RTCs were assayed.
Results: Plasma EVs isolated from ACLF patients were more
concentrated and bigger compared to CTRL (p = 0.002). Plasma
EVs were mainly derived from platelets activated endothelium, as
shown by the expression of CD62E. CD62E levels were significantly
higher in ACLF patients compare to CC patients and CTRL (p = 0.011
and p = 0.004, respectively). Platelet derived and monocytes derived
EVs, as assessed by CD41, CD42b and CD14, were not found. CD40L
levels, a receptor involved in lymphocytes T activation, were sig-
nificantly higher in CC, AD and ACLF groups than in CTRL (p < 0.02).
Plasma EVs from patients with AD and ACLF exerted a higher cyto-
toxic effects than EVs from CTRL and CC patients on RTCs (p < 0.001).
Cells incubated with EVs from AD and ACLF patients showed an
increase in apoptosis (p < 0.001) and ROS production (p < 0.001),
loss of albumin intake capabilities (p < 0.001) and reduction of ZO-1
expression (p = 0.017) compared to CTRL and CC patients.
Conclusions: EVs derived from activated endothelium may
exerts an important role in the pathogenesis of acute kidney injury
in patients with AD of cirrhosis and ACLF.
http://dx.doi.org/10.1016/j.dld.2017.01.036
OC-33
Non-invasive tools to ruling out large varices:RESIST-HCV vs Baveno VI criteria in a largecohort of patients with HCV cirrhosis
V. Calvaruso, I. Cacciola, A. Licata, S. Madonia,
R. Benigno, F. Bronte, S. Petta, G. Malizia,
G. Bertino, M. Distefano, R. Volpes, A. Montineri,
A. Digiacomo, G. Alaimo, B. Cacopardo, A. Davì,
L. Guarneri, I. Scalisi, G. Mazzola, F. Cartabellotta,
V. Portelli, M. Russello, G. Squadrito,
G. Raimondo, A. Craxì, C. Cammà, V. Di Marco, On
behalf of RESIST-HCV (Rete Sicilia Selezione
Terapia-HCV)
RESIST-HCV (Rete Sicilia Selezione Terapia-HCV),
Italy
Background: Patients with cirrhosis should undergo to endo-
scopic variceal screening to identify large esophageal varices
(LEV-F2/F3) requiring primary prophylaxis. Recently, Baveno
VI consensus suggested criteria to avoid esophagogastroduo-
denoscopy (EGD) in patients with liver stiffness by Transient
elastography (TE) 150,000/mm3.
Aims: To validate the performance of Baveno VI criteria and to
assess the ability of RESIST-HCV (REte SIcilia Selezione Terapia-
HCV) criteria in predicting LEV in patients with HCV cirrhosis
included in a single-centre cohort (Palermo – training cohort) and
from the other 21 centres of the RESIST-HCV (validation cohort).
Methods: We evaluated 1381 patients with HCV cirrhosis who
had endoscopy within 1 year of TE. By multivariate logistic analy-
sis we selected laboratory variables independently associated with
LEV to create RESIST-HCV criteria.
Results: PLT and Albumin were independently related with LEV.
Best-cut off values were >120000 mmc (sensitivity: 87.4%, negative
predictive value (NPV) 97.2%) for PLT and >3.6 g/dl (sensitivity: 65%,
NPV: 94.7%) for albumin and together define RESIST-HCV criteria.
Patients of the training cohort were 326 (100% of EGD according
to guidelines), only 53 (16.2%) met Baveno VI criteria and among
them 1 patient had LEV. Thus Baveno VI allow to reduce the rate
of EGD to 83.8% (273 patients) with a false negative rate (FNR) of
1.9% (NPV: 98.1%). 119 patients (36.5%) met RESIST-HCV criteria
and among them 1 patients had LEV (FNR: 0.8%, NPV: 99.2%) allow-
ing a reduction of EDS to 63.5% (207 patients). In the validation
cohort (1055 patients), 169 (16%) and 315 (29.9%) met BAVENO VI
and RESIST HCV criteria respectively and among them 5 (FNR: 3.0%,
NPV: 97.0%) and 6 (FNR: 1.9%, NPV: 98.1%) had LEV. According to
BAVENO VI and RESIST-HCV criteria the rates of EDS to perform are
84% and 70.1% respectively.
Conclusions: RESIST-HCV criteria include only routine labora-
tory data and allow to avoid endoscopies in more of 30% of patients
in comparison of 16% of saved EDS by Baveno VI criteria, further
improving the negative predictive value.
http://dx.doi.org/10.1016/j.dld.2017.01.037
e18 Abstracts / Digestive and Liver Disease 49S (2017) e1–e18
OC-34
Assessment of Sepsis-3 criteria in patients withcirrhosis and bacterial infections
S. Piano, G. Chies, M. Tonon, A. Romano,
E. Vettore, M. Stanco, C. Pilutti, A. Brocca,
S. Fasolato, P. Angeli
Unit of Internal Medicine and Hepatology,
Department of Medicine – DIMED, University of
Padua, Padua, Italy
Introduction: Patients with cirrhosis have a high risk of sepsis,
which confers a poor prognosis. SIRS criteria has several limitations
in cirrhosis. Recently, new criteria for sepsis have been suggested
in general population. Sepsis was defined an increase of Sequen-
tial Organ Failure Assessment(SOFA) ≥2 points from baseline in
patients with infections (Sepsis-3). Outside the ICU, the Qsofa (at
least 2 among: alteration in mental status, systolic blood pres-
sure ≤100 mmHg, or respiratory rate ≥22/min) was suggested to
screen sepsis. These criteria have never been evaluated in cirrhotic
patients. The aim of our study was to assess the ability of sepsis-3
criteria in predicting in hospital mortality in patients with cirrhosis
and bacterial infections.
Methods: From 2012 to 2016 consecutive patients with cirrho-
sis and bacterial infections were included. Demographic, laboratory
and microbiological data were collected at diagnosis of infection.
Preadmission SOFA was assessed using preadmission data as pro-
vided for acute kidney injury criteria. Patients were followed-up
until death, liver transplantation or discharge.
Results: 259 patients were included (Age = 61 ± 12 years, MELD-
score = 20 ± 7). The most common infections were urinary tract
infection (33%), SBP (23%) and pneumonia (14%). SIRS, qSOFA
and Sepsis-3 criteria were found in 34, 23 and 76% of patients,
respectively. During the hospitalization 19% of patients died. In
multivariate analysis CLIF-AD score (OR = 1.06; p < 0.01), C-reactive
protein (OR = 1.64; p = 0.01), qSOFA (OR = 3.37; p < 0.01), Sepsis-3
criteria (OR = 5.81; p = 0.02) and nosocomial infections (OR = 2.16;
p = 0.05), but not SIRS, were found to be independent predictors of
mortality. Patients with Sepsis-3 criteria had a higher incidence of
onset of acute-on-chronic liver failure (50 vs 19%; p < 0.01), were
more likely to be transferred in ICU (14 vs 2%; p = 0.01) and to die
(22 vs 3%; p < 0.01) during the hospitalization than those without
Sepsis-3 criteria. Similar findings were found for qSOFA.
Conclusions: Sepsis-3 criteria are accurate in predicting the
severity of bacterial infections in patients with cirrhosis. qSOFA
is a useful bedside tool to assess risk for worse outcomes in these
patients. Patients with Sepsis-3 criteria and positive qSOFA deserve
more intensive management and a strict surveillance.
http://dx.doi.org/10.1016/j.dld.2017.01.038
Digestive and Liver Disease 49S (2017) e19–e42
Contents lists available at ScienceDirect
Digestive and Liver Disease
journa l homepage: www.e lsev ier .com/ locate /d ld
Abstracts of the 50th A.I.S.F. – Italian Association for the Study of the
Liver – Annual Meeting 2017 Rome, February 23rd–24th, 2017:
Selected Posters Thursday
T-01
Ang-2 polymorphisms in relation to outcome inadvanced HCC patients receiving sorafenib
G. Marisi 1, M. Scartozzi 2, L. Faloppi 2,
M. Iavarone 3, F.G. Foschi 4, G. Lauletta 5,
M. Valgiusti 6, S. Cascinu 7, G.L. Frassineti 1,
G. Ercolani 7,8, A. Dino 6, A. Casadei Gardini 6
1 Biosciences Laboratory, Istituto Scientifico
Romagnolo per lo Studio e la Cura dei Tumori (IRST)
IRCCS, Meldola, Italy2 University of Cagliari, Cagliari, Italy3 A.M.&A. Migliavacca Center for Liver Disease, 1st
Division of Gastroenterology, Fondazione IRCCS Ca’
Granda Maggiore Hospital, University of Milan,
Milan, Italy4 DPT Internal Medicine, Faenza Hospital, AUSL
Romagna, Faenza, Italy5 Department of Biomedical Sciences and Human
Oncology, Internal Medicine “G. Baccelli”, University
of Bari “A. Moro”, Bari, Italy6 Department of Medical Oncology, Istituto
Scientifico Romagnolo per lo Studio e la Cura dei
Tumori (IRST) IRCCS, Meldola, Italy7 University of Modena, Italy8 Department of General Surgery,
Morgagni-Pierantoni Hospiatal, AUSL Romagna,
Forli, Italy
Background: Sorafenib represents the standard care for
advanced hepatocellular carcinoma. Angiopoietin-2 (Ang-2) is a
crucial angiogenic factor. By binding to its receptor Tie2, Ang-2
cooperates with the VEGF pathway to maintain normal physi-
ological functions. In the presence of VEGF, Ang-2 destabilizes
blood vessels and promotes vascular sprouting. In cancers, Ang-2
is linked to not only angiogenesis but also invasive and metastatic
phenotypes. Although sorafenib exerts no significant activity
against Tie2, the predictive value of Ang-2 has been explored in 2
studies. Llovet et al conducted a large biomarker study based on
SHARP study. The authors found that a high baseline plasma Ang-2
level was an independent factor for poorer OS but not for reduced
sorafenib efficacy. Conversely, in a small retrospective study, a high
serum Ang-2 level was associated with a lower DCR and poorer
PFS. The actual role of Ang-2 in predicting sorafenib efficacy war-
rants further investigations. Polymorphism analysis seems to have
more advantages than protein or gene expression analysis. Gene
expression analysis is performed on biological material collected at
a specific time in the natural history of the disease. It is also subject
to the influence of a number of laboratory biases. In our study we
analysed the role of ANG-2 polymorphisms in relation to clinical
outcome in patients with hepatocellular carcinoma treated with
sorafenib.
Methods: We analyzed 135 patients with hepatocellular car-
cinoma treated with sorafenib. Peripheral blood samples were
available for DNA extraction and genotyping analysis. Nine Ang-
2 polymorphisms were analyzed by direct sequencing or Real Time
PCR method. With regard to Ang4rs55633437 was observed that
patients carrying the allele GG were associated with a better PFS
and OS. The variants GG were associated with a median OS of 16.9
months vs 6.5 months of variants GT and TT (p = 0.016). The vari-
ants GT and TT were associated with a median PFS of 2.94 months
vs 4.67 months of variants GG (p = 0.03). These data were confirmed
by multivariate analysis.
Conclusions: Ang4rs55633437 could represent prognostic
markers in patients with advanced hepatocellular carcinoma
treated with sorafenib.
http://dx.doi.org/10.1016/j.dld.2017.01.039
1590-8658/
e20 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
T-02
Impact of multidisciplinary team approach toliver tumors: 5-Years experience
S. Okolicsanyi 1,2, V. Pontecorvi 1, G. Bonato 1,
A. Ciaccio 1,2, R. Perego 3, F. Romano 1,2,
F. Uggeri 1, D. Leni 3, F. Vacirca 3, A. Gambini 3,
A. Mariani 3, M. Ratti 3, M. Acquati 4, N. Zucchini 5,
G. Bovo 5, R. Corso 3, M. Strazzabosco 1,2,6
1 Department of Surgery and Translational Medicine,
University of Milano-Bicocca, Milan, Italy2 International Centre for Digestive Health,
University of Milan-Bicocca, Milan, Italy3 Department of Radiology, San Gerardo Hospital,
Monza, Italy4 Oncology Unit, San Gerardo Hospital, Monza, Italy5 Department of Pathology, San Gerardo Hospital,
Monza, Italy6 Liver Center & Section of Digestive Diseases,
Department of Internal Medicine, Yale University
School of Medicine, New Haven, CT, USA
Background: Multidisciplinary team (MDT) approach is a major
requirement to guarantee a fair access to treatment to heteroge-
neous patients with liver neoplasms and to improve the quality
of care provided. This work retrospectively analyzes the impact of
MDT experience at our tertiary center.
Methods: Between 2011 and 2016, 490 consecutive patients
with a liver mass were discussed at standardized meetings involv-
ing hepatologists, radiologists, surgeons, pathologists, oncologists.
Patients with HCC were assigned a BCLC stage, treated accordingly
BCLC recommendation whenever possible and followed-up as per
AASLD/EASL guidelines (median f-up: 26 months).
Results: Out of 490 patients, 70% had a HCC diagnosis, 5% cholan-
giocarcinoma or metastasis and 25% benign liver nodules. Among
341 HCC patients, 55% were BCLC 0/A, 29% BCLC B and 15% BCLC
C. Of them, 80% received treatment after the first MDT discus-
sion. Patients with BCLC B stage had significantly more treatments
(2.5 ± 0.9 treatments per patient), compared to BCLC 0/A (1.3 ± 0.1)
and to BCLC C (1.2 ± 0.5, both p < 0.05). First-line BCLC recommen-
dations for therapy were followed in 67%, 59%, 32% of cases for
BCLC 0/A, B, C respectively. In 274 HCC patients managed until
February 2015 (median f-up: 30 months), median survival from
first MDT discussion was 37 months. Main predictors of outcomes
were BCLC stage (5-years survival in BCLC 0/A 54%, B 21%, C 23%,
p < 0.0001), CHILD score (5-years survival CHILD A 42%, B 20%, C 0%,
p < 0.0001) and first treatment applied (survival at 5 years from
OLT 90%, resection 49%, ablation 40%, TACE 28%, sorafenib 15%,
p < 0.0001)
Conclusions: A MDT approach to HCC patients allowed a ratio-
nal revision of treatments suggested by BCLC recommendations in
30% to 70% of cases; this discrepancy did not affect survival out-
comes, indicating that the difficulties related to the applicability of
the current guidelines in the clinical practice could be overcome by
a MDT approach.
http://dx.doi.org/10.1016/j.dld.2017.01.040
T-03
In experimental liver cirrhosis impairedsecretion of renalase into blood may lead toorgan damage and sympathetic overactivity
G. Sansoè 1, M. Aragno 2, R. Mastrocola 2,
M. Ayoubi 1, M. Parola 2
1 Division of Gastroenterology, Humanitas Gradenigo
Hospital, Torino, Italy2 Department of Clinical and Biological Sciences,
University of Torino, Torino, Italy
Introduction: Sympathetic overactivity and generation of per-
oxidant molecules are crucial in liver fibrogenesis and functional
renal failure of advanced cirrhosis. Renalase (REN), 38 kDa amine
oxidase with just 13% aminoacid identity with monoamine oxidase
A, is secreted into the blood and clears plasma from excess cat-
echolamines. Isomers of �-NAD(P)H are also substrates for tissue
REN, a reaction leading to H2O2 and �-NAD(P)+ production in liver
and kidney.
Aims: To study plasma and tissue content and function of REN
in experimental preascitic and ascitic cirrhosis.
Methods: In normal rats (group G1), rats with CCl4-dependent
liver cirrhosis without ascites (G2) and with ascites (G3) we eval-
uated: REN levels and activity in plasma, liver and kidney; REN
gene transcription and immunohistochemical localization in both
organs; liver histology and matrix deposition, hormonal status and
kidney function.
Results: In plasma, mature (38 kDa) REN and REN activity, well
detected in normal rats, were virtually absent in rats with com-
pensated or ascitic cirrhosis (P < 0.01 vs. G1). In G2 and G3 rats, but
not in G1, we found large amount of enzymatically active high-
molecular weight (78 kDa) REN and very little 38 kDa protein in
hepatocytes of regenerative nodules of the cirrhotic liver and in
kidney tubules. RT-PCR confirmed higher levels of REN gene tran-
scription in both liver and kidney of G2-3 (P < 0.03 vs. G1). Rats with
preascitic liver damage showed increased plasma catecholamines,
normal renin-angiotensin system activation and subtle sodium
retention, while ascitic rats had both secondary aldosteronism and
increased adrenergic activation.
Conclusions: Active 78 kDa REN accumulates in diseased liver
and kidney and generates H2O2 and other pro-oxidant molecules,
but release of mature (38 kDa) REN into the circulation is almost
absent, leading to increased levels of catecholamines and early
sodium retention in preascites.
http://dx.doi.org/10.1016/j.dld.2017.01.041
T-04
A novel role for heparanase in the onset of liverfibrosis
M.F. Secchi 1, M. Crescenzi 2, F.P. Russo 2,
M. Onisto 1, A. Floreani 2
1 Department of Biomedical Science, University of
Padua, Padua, Italy2 Department of Surgery, Oncology and
Gastroenterology, University of Padua, Padua, Italy
Introduction: Activation of both Kupffer cells and hepatic stel-
late cells (HSCs) plays a fundamental role in fibrosis process.
Heparanase (HPSE) is the only mammalian endoglucuronidase
capable of cleaving heparan sulfate (HS) chains of HS proteogly-
cans. The involvement of HPSE in chronic liver disease has not been
demonstrated so far.
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42 e21
Aims: (a) To investigate the HPSE expression in chronic liver
injury and (b) to study its effects on the fibrosis process.
Materials and methods: 1. Experimental design: CCl4 model
for fibrosis was utilized in 20 BALB/cJ mice. 2. In vitro studies: HPSE
expression was assayed on macrophages (U937 cell line) by real
time RT-PCR and western blot analyses. Furthermore, we evaluated
the HPSE activation of HSCs (LX-2 cell line). Finally, the migration
of macrophages (RAW 264.7 cell line) was assayed by treatment
with HPSE.
Results: HPSE expression in liver tissue of CCl4-treated mice
increased after 1 and 2 weeks of treatment but not after 8 and 12
weeks. Immunostaining analyses revealed that HPSE was restricted
in the centrilobular areas with both necro-inflammatory damage
and fibrosis, and co-localized with macrophage markers F4/80
and CD68. TNF-� treatment of U937 macrophages significantly
increased HPSE mRNA and protein expression, as well as HPSE
secretion. Using the conditioned medium of TNF-�-pre-treated
U937, we found that macrophage-secreted HPSE regulated the
expression of both �-SMA and fibronectin in LX-2 cells. Finally,
macrophages with latent HPSE significantly increased the cell
migration rate.
Conclusions: Overall, HPSE is involved in early stages of fibrosis
process. Inflammatory macrophages could be an important source
of HPSE. In this context, HPSE may play a role in the macrophage-
mediated activation of HSCs and in migration of macrophages
themselves.
http://dx.doi.org/10.1016/j.dld.2017.01.042
T-05
Local renin–angiotensin system in the kidney ofascitic cirrhosis: An innocent bystander or amajor protagonist?
G. Sansoè 1, M. Aragno 2, R. Mastrocola 2,
M. Ayoubi 1, M. Parola 2
1 Division of Gastroenterology, Humanitas Gradenigo
Hospital, Torino, Italy2 Department of Clinical and Biological Sciences,
University of Torino, Torino, Italy
Introduction: In liver cirrhosis, kidney local renin–angiotensin
system (RAS) deserves scrutiny and includes: conversion of
angiotensin I into angiotensin II (Ang-II) by ACE and chymase;
binding of renin and prorenin to their tissue receptor (RPRr),
and hence local generation of angiotensin I and Ang-II; conver-
sion of Ang-II by ACE2 into angiotensin1-7; degradation of the
latter to angiotensin1-4 by neprilysin. Changes in expression of
these enzymes and receptors affect renal levels of sodium-retentive
(Ang-II) and natriuretic (angiotensin1-7) peptides.
Aims: To assess, in ascitic rats’ kidney, expression and
immunolocation of major components of RAS and their hormonal
consequences.
Methods: Healthy rats (group G1) and rats with ascitic cirrho-
sis due to CCl4 (G2) were studied. Kidney content of ACE, chymase,
RPRr, ACE2, neprilysin, Ang-II, angiotensin1-7 and plasma levels of
Ang-II, direct renin (DR), plasma renin activity (PRA) were mea-
sured. DR is quantified through monoclonal antibodies that bind
both active renin and prorenin, and therefore plasma concentra-
tions of prorenin can be derived from the ratio DR/PRA.
Results: DR/PRA ratios were 3.3 ± 0.8 and 7.9 ± 1.6 in healthy
and ascitic rats, respectively (P < 0.03), showing more prorenin in
ascitic rats. In G2, Ang-II was higher than normal in plasma (P < 0.01)
but especially in renal tissue (1150 ± 199 vs. 78 ± 22 pg/mg kid-
ney protein, P < 0.001). Kidney content of ACE, chymase, ACE2 and
neprilysin was significantly higher, but RPRrs significantly lower,
in ascitic than in healthy rats. The ratio Ang-II/Angiotensin1-7 in
kidneys rose from 1.3 ± 0.2 in G1 to 5.3 ± 0.4 in G2 (P < 0.03).
Conclusions: In ascitic cirrhosis: (a) the contribution of ACE
and chymase to renal Ang-II synthesis seems stronger than that
of RPRrs, despite increased plasma prorenin; (b) the kidney shows
an imbalance in favour of the production of anti-natriuretic Ang-II
because overexpressed neprilysin finally degrades ACE2-generated
angiotensin1-7.
http://dx.doi.org/10.1016/j.dld.2017.01.043
T-06
Durable response in the markers of cholestasisthrough 24 months of open-label extensionwith obeticholic acid in Italian patients withprimary biliary cholangitis
P. Andreone 1, A. Floreani 2, P. Invernizzi 3,
G. Mazzella 1, J. Owens-Grillo 4,
E. Smoot Malecha 4, L. MacConell 4
1 Dipartimento di Scienze Mediche e Chirurgiche,
Universtiy of Bologna, Bologna, Italy2 Department of Surgery, Oncology and
Gastroenterology, University of Padova, Padova, Italy3 Program for Autoimmune Liver Disease,
International Center for Digestive Health,
Department of Medicine and Surgery, University of
Milan-Bicocca, Milan, Italy4 Intercept Pharmaceuticals, Inc., San Diego, CA,
United States
Introduction and aim: Obeticholic acid (OCA) is a potent and
selective farnesoid X receptor (FXR) agonist under investigation
for the treatment of primary biliary cholangitis (PBC). This anal-
ysis evaluated the long-term efficacy and safety of OCA in Italian
patients with PBC.
Material and methods: POISE was a Phase 3, 12-month,
double-blind, placebo-controlled study followed by an ongoing
open-label extension (OLE). Patients with an alkaline phosphatase
(ALP) >1.67× ULN and/or bilirubin >ULN to <2× ULN, on a stable
ursodeoxycholic acid (UDCA) dose or unable to tolerate UDCA, were
randomized to daily Placebo, OCA 5–10 mg, or OCA 10 mg.
Results: Thirty-two of 216 patients were treated at Italian
sites (Placebo, n = 11; OCA 5–10 mg, n = 11; OCA 10 mg, n = 10).
In Italian patients, both OCA groups demonstrated significant
reductions in ALP (U/L) after 12 months of double-blind treat-
ment (Placebo: 43 ± 108; OCA 5–10 mg: −114 ± 86, p < 0.01; OCA
10 mg: −132 ± 104, p < 0.01). This response was durable through
an additional 24 months of treatment during the OLE (Placebo:
−105 ± 86, p < 0.05; OCA 5–10 mg: −140 ± 78, p < 0.01; OCA 10 mg:
−122 ± 110, p < 0.05). After 12 months of double-blind treatment,
total bilirubin (�mol/L) increased in the Placebo group (2.1 ± 2.5),
but remained stable in OCA 5–10 mg and OCA 10 mg groups
(−0.6 ± 3.5, p < 0.05 and −1.1 ± 1.9, p < 0.05). The change from Base-
line in total bilirubin at month 24 of the OLE remained relatively
stable (Placebo: 1.1 ± 5.4; OCA 5-10 mg: −0.3 ± 4.5; OCA 10 mg:
0.4 ± 5.7). Five (45%) of the Placebo patients in the double-blind
phase and 8 (80%) of the Placebo patients initiating OCA in the OLE
experienced pruritus.
Conclusions: OCA given to Italian patients resulted in signifi-
cant improvements in markers of cholestasis and hepatic damage.
A durable response was evident throughout the OLE demonstrating
the safety and efficacy of long-term OCA treatment.
http://dx.doi.org/10.1016/j.dld.2017.01.044
e22 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
T-07
Impairment of coronary microvascular functionin patients with Primary Biliary Cholangitis
N. Cazzagon 1, C. Dal Lin 2, I. Franceschet 1,
L. Perini 1, G. Famoso 2, F. Tona 2, A. Floreani 1
1 Department of Surgery, Oncology and
Gastroenterology, University of Padova, Italy2 Department of Cardiac, Thoracic and Vascular
Sciences, University of Padova, Italy
Background: Primary biliary cholangitis (PBC) is characterized
by a long natural history and a low incidence of cardiovascu-
lar events despite high serum cholesterol levels. Coronary flow
reserve (CFR) is widely used to examine the integrity of coronary
microvascular circulation and it is well recognized as a predictor of
cardiovascular outcome.
Aim: To evaluate the risk of coronary microvascular dysfunction
in patients with PBC without metabolic syndrome.
Methods: 37 PBC patients (4 males and 33 females, aged 57 ± 12
years) without clinical evidence of heart disease and without
metabolic syndrome, and 37 sex- and age-matched healthy con-
trols underwent CFR by transthoracic Doppler echocardiography
(TDE). Coronary flow velocity in the left anterior descending coro-
nary artery was detected by TDE at rest and during iv. adenosine
infusion. CFR was calculated as the ratio of hyperemic diastolic
flow velocity (DFVh) to resting DFVr. Correction of DFV and CFR
for cardiac workload was also performed.
Results: The mean time between the onset of symptoms and
CFR assessment was 10 ± 5 yrs. In PBC patients CFR and corrected
CFR (cCFR) were significantly lower than in controls (3.1 ± 0.4
vs 3.7 ± 0.7, and 2.8 ± 0.7 vs 3.7 ± 0.7 respectively, p < 0.0001).
Stratifying PBC population according to a cCFR value of 2.5, 26
patients (70%) showed a cCFR >2.5 (PBC1) and 11 patients (30%)
a cCFR < 2.5 (PBC2). Corrected DFVr resulted significantly higher
in PBC2 patients, indicating the presence of a higher flow velocity
at basal condition, otherwise the other hemodynamic parameters
were significantly higher in PBC1 patients; cCFR resulted not cor-
related to any of the characteristics of liver diseases, comorbidities
(both autoimmune and cardiovascular) and Framingham risk score.
Conclusions: PBC patient had an impairment of coronary
microvascular function correlated to an increased diastolic flow
velocity at rest, suggesting a possible impairment of bioenergetics
of cardiomyocytes.
http://dx.doi.org/10.1016/j.dld.2017.01.045
T-08
CEUS LI-RADS are effective in predicting the riskhepatocellular carcinoma of liver nodules
E. Terzi, L. De Bonis, S. Leoni, F. Benevento,
A. Granito, F. Tovoli, P. Pini, L. Bolondi, F. Piscaglia
Division of Internal Medicine, Department of
Digestive Disease and Internal Medicine,
Sant’Orsola-Malpighi Hospital, University of
Bologna, Bologna, Italy
Introduction: American College of Radiology (ACR) – Liver
Imaging Reporting and Data System (LI-RADS) for CEUS is an algo-
rithm that, on the basis of CEUS patterns, categorizes patients
in different classes of risk of HCC (HepatoCellular Carcinoma),
and accounts for the characteristics differentiating HCC from CC
(CholangioCarcinoma) based on timing and intensity of contrast
changes.
Aim: Validate CEUS LI-RADS to stratify patients with different
risk of HCC focusing on LR-3 (intermediate probability for HCC),
LR-4 (high probability HCC) and LR-5 (definitely HCC) and LR-M
(probable malignancy not specific for HCC), to test the rate of HCC
in each class.
Methods: We retrospectively evaluated CEUS pattern of 146
patients with a total of 350 nodules (2005–2015) for all of whom the
diagnostic reference standard had been performed Results. A total
350 consecutive nodules were investigated. CC were 2.2%. The risk
of having HCC increases from LR-3 to LR-5. In particular, 45/75 LR-3
nodules (60%) were HCC, 90/102 (88%) LR-4 were HCC and 150/152
LR-5 (99%) were HCC (n = 149) or mixed HCC-CC (n = 1) (p < 0.001).
LR-M were 15 (4.3%) of which 6 HCC, 2 mixed HCC-CC, 7 CC.
Conclusions: CEUS LI-RADS classes are effective in predicting
the risk of HCC, with LR-5 class definitely diagnostic for HCC at
practically no risk of misdiagnosis for CC. The present algorithm
may be useful for restoring CEUS for the diagnosis of HCC and for
guiding the diagnostic approach of “atypical” nodules, all of which
remain at relatively significant risk of HCC (>50% if LR-3 or LR-4).
http://dx.doi.org/10.1016/j.dld.2017.01.046
T-09
Platelet count, spleen length and plateletcount/spleen length ratio for the diagnosis ofoesophageal varices in patients with hepaticcirrhosis. A systematic review andmeta-analysis
A. Colli 1, M. Fraquelli 2, D. Prati 3, D. Conte 2,
G. Casazza 4
1 Department of Internal Medicine, Ospedale A.
Manzoni, Lecco, Italy2 Gastroenterology and Endoscopy Unit, Fondazione
Ca’ Granda, Ospedale Maggiore Policlinico, Milano,
Italy3 Department of Transfusion Medicine and
Hematology, Ospedale A. Manzoni, Lecco, Italy4 Department of Biomedical and Clinical Sciences,
Ospedale Luigi Sacco, Università degli Studi di
Milano, Italy
Background: Current guidelines recommend endoscopy in cir-
rhotic patients at diagnosis to screen for esophageal varices (EV)
despite half patients having no identifiable EV. We aimed to
assess the diagnostic accuracy of platelet count, spleen length, and
platelet/spleen length ratio (Plt/s) as alternative non- invasive tests
for the diagnosis of EV.
Methods: We searched and included studies assessing the diag-
nostic accuracy of platelet count, spleen length, and Plt/s for the
diagnosis of EV using upper endoscopy as the reference- standard
in patients with cirrhosis. We followed the available guidelines
provided in the Cochrane Handbook for Diagnostic Test of Accu-
racy Reviews for search, data collection and analysis. No language
restrictions were applied.
Results: We included 67 studies performed in a secondary-
tertiary care-setting. Only one was at low risk of bias, as most of
them derived a posteriori the best cut-off values overestimating
accuracy.
EV of any size: indirect comparison of the three index tests,
showed that Plt/s is the most accurate. In the 17 studies with 2637
participants, using the predefined cut-off value of 909, sensitivity
was 0.93 (95% CI 0.83 to 0.97), specificity 0.84 (95% CI 0.75 to 0.91).
EV at high risk of bleeding: Plt/s was the most accurate index test
and with 909 as cut-off value (7 studies 642 participants) showed a
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42 e23
sensitivity of 0.85 (95% CI 0.72 to 0.93), and specificity of 0.66 (95%
CI 0.52 to 0.77).
Conclusions: A simple test such as cPlt/s could be used to stratify
the risk of having EV. Using 909 as cut off value, the presence of any
size EV can be excluded halving the number of useless endoscopic
procedures. However, this test is not accurate enough to replace
endoscopy for the identification of EV at high risk of bleeding that
require primary prophylaxis.
http://dx.doi.org/10.1016/j.dld.2017.01.047
T-10
Clinical presentation and outcomes ofhepatocellular carcinoma in elderly patientsreferred to a tertiary center: 5-Years experience
S. Okolicsanyi 1,2, G. Bonato 1, V. Pontecorvi 1,
A. Ciaccio 1, M. Gemma 1, M. Strazzabosco 1,2,3
1 Department of Medicine and Surgery, University of
Milano-Bicocca, Milan, Italy2 International Center for Digestive Health,
University of Milano-Bicocca, Milan, Italy3 Liver Center & Section of Digestive Diseases,
Department of Internal Medicine, Yale University
School of Medicine, New Haven, CT, USA
Background: An emerging cohort of elderly patients with
hepatocellular carcinoma (HCC) shows age-significant morbidities
without receiving optimal therapy for malignancies, mainly due to
reduced life expectancy and the current lack of strategies according
to age. This study retrospectively analyzes age-specific disparities
in patients with HCC managed in our tertiary center between 2010
and 2015 according to Barcelona Clinic Liver Cancer (BCLC) recom-
mendation and individual case discussion by a multidisciplinary
team (median f-up: 25 months).
Methods: A total of 239 consecutive patients with first diagnosis
of HCC was divided in group A below 70 years old (n = 89), group B
between 70 and 79 years (n = 100), group C above 80 years (n = 50).
Gender, etiology, Child-Pugh (CP), BCLC score and alpha fetoprotein
(AFP) level at diagnosis, type of first treatment, time to recurrence
after therapy were compared using Cochran-Mantel-Haenszel test
for ordinal variable among the 3 groups. Overall and disease specific
survival were calculated with Kaplan–Meier estimator.
Results: Patients older than 70 years were significantly more
female (34–48% in B-C vs 5.6% in A, p < 0.0001), and had more fre-
quent viral etiology (68–76% in B-C vs 59% in A, p < 0.05). Main
characteristics at diagnosis were CP score A (75%), BCLC 0/A (64%)
and AFP <20 U/L (62%), without significant difference in 3 groups.
A lower percentage of older patients received treatment (58% vs
85–83% in group A-B, p < 0.05), and this was mostly chemoem-
bolization (45%), with significant less patients undergoing surgery
(14% vs 40% in A, 34% in B, p < 0.05) and no difference in time to
recurrence, overall and disease specific survival (median 38 ± 16
months).
Conclusions: Male gender lost its predominance and viral eti-
ology was significantly increased with aging. The multidisciplinary
team approach allowed to evaluate and treat with loco-regional
therapies elderly patients, with survival outcomes not different
respect to younger patients, permitting to move the boundary of
treatment over 80 years.
http://dx.doi.org/10.1016/j.dld.2017.01.048
T-11
Ruling-in and ruling-out significant fibrosis andcirrhosis using a shear wave measurementmethod
G. Ferraioli 1, L. Maiocchi 1, R. Lissandrin 1,
C. Tinelli 2, A. De Silvestri 2, C. Filice 1
1 Infectious Diseases Department, Fondazione IRCCS
Policlinico S. Matteo, Medical School University of
Pavia, Pavia, Italy2 Clinical Epidemiology and Biometric Unit,
Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
Aims: This study aimed at prospectively assessing the cutoff
values of a point shear wave measurement (SWM) method for
ruling-in and ruling-out significant fibrosis and cirrhosis using tran-
sient elastography (TE) as the reference standard.
Materials and methods: Consecutive patients with chronic viral
hepatitis were enrolled. Liver stiffness was assessed with the SWM
method of the HI VISION Ascendus ultrasound system (Hitachi Ltd,
Japan) and with the TE method of the FibroScan®
device (Echosens,
France). For staging significant fibrosis (F ≥ 2), and cirrhosis (F = 4)
we used the TE cutoffs of 7.0 and 12.0 kiloPascal (kPa), respectively.
The diagnostic performance of the SWM method was assessed by
calculating the area under the receiver operating characteristic
(AUC) curve. To rule-in or rule-out F ≥ 2 and F = 4 the cutoffs with
specificity or sensitivity >90% were chosen.
Results: 411 individuals [218 males, 193 females; mean age,
61.2 (13.2) years] were studied. 382 (92.9%) of them were affected
by chronic hepatitis C. 179 (43.5%) individuals were in F0-F1 stage,
75 (18.2%) in F2, 41(10.0%) in F3, and 116 (28.2%) in F4.
For ruling-in F ≥ 2 the SWM cutoff was 6.95 kPa [sensitivity,
76.3% (69.7–82.0); specificity, 90.4% (84.9–94.4)] and for ruling-
out it was 5.58 kPa [sensitivity, 90.4% (85.4–94.1); specificity, 73.6%
(66.3–80.2)]. For ruling-in F = 4 the SWM cutoff was 9.15 kPa [sen-
sitivity, 83.5% (74.3–90.5); specificity, 90.1% (86.0–93.4)] and for
ruling-out it was 8.41 kPa [sensitivity, 90.1% (82.1–95.4); speci-
ficity, 82.5% (77.5–86.8)]. AUCs were 0.92 (0.89–0.94) for F ≥ 2 and
0.94 (0.91–0.96) for F = 4.
Conclusions: We propose to use a dual cutoff of SWM in order to
rule-in or rule-out significant fibrosis and cirrhosis. In the clinical
contest, this may increase the confidence in staging liver fibrosis
with non-invasive shear wave elastography technique.
http://dx.doi.org/10.1016/j.dld.2017.01.049
e24 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
T-12
Liver stiffness fibrosis thresholds of Fibroscancannot be adopted by all new elastographymachines: A comparative study
V. Salvatore 1, L. Mulazzani 1, V. Cantisani 2,
A. Colecchia 1, R. Di Donato 1, C. Felicani 3,
A. Ferrarini 1, N. Gamal 1, V. Grasso 3, G. Marasco 1,
E. Mazzotta 3, F. Ravaioli 1, G. Ruggieri 4, I. Serio 1,
J.F. Sitouok Nkamgho 1, C. Serra 3, D. Festi 1,
C. Schiavone 5, L. Bolondi 1, F. Piscaglia 1
1 Department of Medical and Surgical Sciences,
University of Bologna, Italy2 Department of Radiological Sciences, Policlinico
Umberto I, University Sapienza, Rome, Italy3 Unit of Internal Medicine and Organ Insufficiency,
S. Orsola-Malpighi Hospital, Bologna, Italy4 Division of Infectious Disease, G. d’Annunzio
University, Chieti, Italy5 Unit of Internistic Ultrasound, Dept of Medicine
and Science of Aging, G. d’Annunzio University,
Chieti, Italy
Introduction: Whether shear wave elastography techniques
provide liver stiffness results comparable to Fibroscan to an extent
that the Fibroscan thresholds can be immediately adopted has not
been tested for many of the machines recently introduced onto the
market.
Aim: The aim of the present study was to test the concordance
of the findings obtained from 7 of the most recent ultrasound elas-
tography machines having various elastography technologies with
respect to Fibroscan as a reference method.
Methods: A total of 16 hepatitis C virus (HCV)-related patients
with chronic liver disease and significant fibrosis, and having
reliable results at Transient Elastography with Fibroscan were
investigated in two intercostal spaces using 7 different elastog-
raphy machines. Both precision (an index of data dispersion) and
accuracy (an index of bias correction factors expressing different
magnitude of changes in stiffness values in comparison to the ref-
erence) were calculated for each comparison.
Results: Median stiffness values differed among the different
machines as did both precision (range 0.54–0.72) and accuracy
(range 0.28–0.87). When the average of measurements of two,
rather than the predefined intercostal space, was considered, pre-
cision significantly increased with all machines (range 0.72–0.90)
whereas accuracy improved more haphazardly and by a smaller
degree (range 0.40–0.99).
Conclusions: The present results showed the significant lack
of concordance of the majority of elastography machines with
the Fibroscan results; the moderate values of accuracy prevented
the possibility of the immediate universal adoption of Fibroscan
thresholds for defining liver fibrosis staging for all new machines.
http://dx.doi.org/10.1016/j.dld.2017.01.050
T-13
Autoimmune hepatitis in children and adults:A single centre experience
L. Perini 1, E. Nicoletto 2, E. Salami 1, P. Gaio 2,
C. Mangini 1, N. Cazzagon 1, V. Baldo 3,
M. Cananzi 2, A. Floreani 1
1 Department of Surgery, Oncology and
Gastronterology University of Padova, Padova, Italy2 Department of Pediatrics, University of Padova,
Padova, Italy3 Department of Hygiene and Public Health,
University of Padova, Italy
Autoimmune hepatitis (AIH) can be diagnosed in both children
and adults.
Aim: To compare the clinical features of AIH in a pediatric group
(GA) and in an adult population (GB).
Methods: GA included 33 patients (M:F = 12:21), mean age
8 ± 4.5 years, range 1–16; GB included 149 patients (M:F = 20:129),
mean age 45 ± 19.8 years, range 19.8–89. The mean follow-up was
57 ± 41 months in GA and 97 ± 91 months in GB. Patients were
treated with a first line therapy with prednisone ± azathioprine
and when needed with a second line therapy with mycophenolate
mofetil (MMF) + prednisone.
Results: An acute onset at presentation was recorded in 4% of
cases in GA and in 4.9% in GB, an acute liver failure onset was
recorded in 10% in GA only, an acute on chronic onset in 36% in
both groups. At onset, children showed significantly higher lev-
els of AST (1035.3 ± 1086.2 vs 534.5 ± 508.4 UI/l, p = 0.004), ALT
(1075 ± 1030 vs 675.8 ± 679.2 UI/L, p = 0.02) and lower levels of GGT
(121.6 ± 116.3 vs 181.4 ± 151.3 UI/L, p = 0.013) compared to adults.
An higher prevalence of anti-LKM positivity was observed in chil-
dren than in adults (24.5% vs 3.8%). No differences between the
two groups were observed regarding: ANA and ASMA positivity,
autoimmune comorbidities, response to the immunosuppression
after 1 year (complete response = 76.4% in GA vs 78.4% in GB, partial
response = 20.9% vs 19.6% respectively, non-responders 2.7% vs 2%
respectively). Relapse was more frequent in GB, although not sta-
tistically significant (36.2% vs 27.8%). Three patients (9%) in GA and
4(3%) in GB were treated with MMF+ prednisone. Liver transplanta-
tion was performed in 1 child and in one adult patient. Liver-related
death was observed in 1case in GA and in 5 cases in GB.
Conclusions: Children had a more severe AIH in terms of
biochemical alterations at presentation but the natural history
appeared comparable in children and adults.
http://dx.doi.org/10.1016/j.dld.2017.01.051
T-14
Effectiveness of HCV antiviral treatment inpatients with cirrhosis or advanced fibrosis andend-stage kidney disease on dialysis
F.R. Ponziani 1, M. Siciliano 1, R. Lionetti 2,
C. Pasquazzi 3, L. Gianserra 3, L. Lambiase 3,
G. D’Offizi 2, A. Gasbarrini 1, M. Pompili 1
1 Internal Medicine and Gastroenterology, Agostino
Gemelli Hospital, Rome, Italy2 Infectious and Liver diseases, IRCCS Lazzaro
Spallanzani, Rome, Italy3 Infectious Diseases, S. Andrea Hospital, Rome, Italy
Introduction: Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir
(PROD) is one of the recommended antiviral regimens for patients
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42 e25
with hepatitis C and severe renal impairment (creatinine clearance
<30 mL/min). Little is known about the safety and efficacy of PROD
in subjects with advanced fibrosis or cirrhosis undergoing dialysis.
Patients and methods: Consecutive patients with advanced
fibrosis or cirrhosis and chronic kidney disease (CKD) on dialysis
undergoing antiviral treatment were included in the study. HCV-
RNA quantification was performed at 4-week intervals; SVR was
defined as serum HCV-RNA <15 IU/mL at 4 (SVR4) or 12 (SVR12)
weeks after the end of therapy.
Results: Ten patients with CKD on dialysis (median age 55
(39–76) yrs) were treated for HCV infection (8 genotype 1b, 1
genotype 1a and 1 genotype 4d). Among them, 8 had evidence
of cirrhosis (Child – Pugh A) and 2 of advanced fibrosis (F3
Metavir) according to clinical, ultrasound or elastosonographic
parameters. Five patients were treatment experienced (PEG-
IFN ± ribavirin), and 4 had previously undergone to unsuccessful
kidney transplantation. Genotype 1b patients received PROD regi-
men without ribavirin for 12 weeks, the patient with genotype 1a
PROD + ribavirin 200 mg/d for 24 weeks, the patient with genotype
4d PRO + ribavirin 200 mg/d for 12 weeks. Grade 1 and 2 fatigue
was reported by all patients, reaching grade 3 in one of them;
grade 2 anemia was reported in the two patients receiving riba-
virin. One patient with mild ascites required an increased number
of dialysis sessions/week during therapy. Reported AEs resolved
spontaneously after the end of treatment. All patients completed
the prescribed treatment. All subjects achieved the SVR12.
Conclusions: PROD is an effective and well-tolerated HCV
antiviral regimen in patients with cirrhosis and CKD undergoing
dialysis. Strict monitoring is advisable to promptly recognize and
manage adverse events related to treatment.
http://dx.doi.org/10.1016/j.dld.2017.01.052
T-15
Validation of the Bolondi stratification forintermediate stage hepatocellular carcinoma(HCC). Clinical and therapeutical implications
A. Mega 1, M. De Giorgio 2, H. Zoller 3,
A. Finkenstedt 3, M. Felder 1, S. Fagiuoli 2,
M. Haefner 1
1 Department of Gastroenterology, Central Hospital,
Bolzano, Italy2 Department of Gastroenterology & Hepatology,
Ospedale Papa Giovanni XXIII, Bergamo, Italy3 Gastroenterologie und Hepatologie, University
Klinik fuer Innere Medizin, Innsbruck, Austria
Background: The treatment of HCC is according to the Barcelona
Clinic Liver Cancer algorithm (BCLC). HCC BCLC-B should be treated
with trans-arterial chemoembolization (TACE). Considering clinical
and tumoral aspects, many centers have adopted other treatments.
In 2012, Bolondi and colleagues, suggested a stratification of BCLC-
B patients in 4 sub-groups (B1–B4) and applying other therapeutic
strategies (transplantation, resection, radiofrequency, TACE plus
ablation, radioembolization, antitumoral therapy with Sorafenib©)
with the aim to improve overall survival (OS).
Aims: To retrospectively test whether the use of the Bolondi
stratification of BCLB patients, would have altered OS in a multi-
centric cohort of HCC patients.
Methods: The study involved 276 HCC BCLC-B patients, treated
between 2000 and 2015 in 2 large hospitals in Italy (Bolzano and
Bergamo) and in one large Austrian Hospital (Innsbruck). The OS of
patients treated according to the EASL and AASLD guidelines was
compared with the OS obtained using the Bolondi stratification.
Results: The median follow up was 6.4 yrs, with an OS of
37% at 5 yrs. Analyzing the stratification of patients in 4 sub-
groups as suggested by the Bolondi Model, there was a significative
difference in OS between B1 vs B2, B2 vs B3 and B3 vs B4
(log rank overall p < 0.001). OS analysis for type of treatment
(Bolondi model vs TACE proposed by EASL and AASLD guidelines),
was better when the Bolondi stratification was used (log rang
p < 0.001, Ranyi type test p < 0.001). In the multivariate analysis
the B1–B4 stratification is the factor which influences OS with
B2 patients performing better (p < 0.05). Patients stratified in B3
and B4 Bolondi group would have had a better outcome if treated
with liver transplantation, TACE or antitumoral therapy with
Sorafenib.
Conclusions: Our study confirms the validity of the Bolondi
stratification, which allows a more “tailored therapy” and a better
OS.
http://dx.doi.org/10.1016/j.dld.2017.01.053
T-16
Impact of direct-acting anti-HCV treatmentsbefore liver transplant on virological andclinical outcomes of HCV patients at one yearafter surgery
S. Martini 1, M. Sacco 1, S. Strona 1, A. Ottobrelli 1,
F. Tandoi 2, S. Mirabella 2, D. Cocchis 2,
M. Salizzoni 2, G.M. Saracco 1, R. Romagnoli 2
1 Gastrohepatology Unit, AOU Città della Salute e
della Scienza di Torino, University of Torino, Turin,
Italy2 Liver Transplant Center, General Surgery 2U, AOU
Città della Salute e della Scienza di Torino, University
of Torino, Turin, Italy
Introduction: In HCV-positive recipients who are viremic at
liver transplant (LT), viral recurrence is universal and biliary com-
plications occur in 25–40% of the cases. Liver stiffness (LS) ≥8.7
kilopascal (kPa) at one year after LT, was associated with all cause-
related graft loss. We evaluated the impact of pre-LT direct-acting
antivirals (DAAs) on virological and clinical outcomes at one year
after LT.
Methods: Between 07-2014 and 10-2016, 64 patients, who
received DAAs plus ribavirin before-LT, underwent LT in our Center
from brain-dead, HCV-negative donors. Sixteen patients bridged
DAAs and ribavirin from pre to post-LT to achieve/maintain HCV
RNA negativization.
Results: Median recipient age was 57 years, males 84%, BMI
26 kg/m2, 80% hepatocellular carcinoma, median MELD at LT 12
(range 6–30), genotype 1b: 44%, 3: 23%; median donor age 66 years;
median donor risk index 1.9. Five patients died within 90 days of
LT due to multi organ failure. 54/55 (98.2%) recipients reached a
sustained virological response at week 12 after LT/therapy. During
a median follow-up after LT of 377 days (range 35–839) for sur-
viving patients, we recorded: 15.6% biliary complications and 4.7%
treated acute cellular rejections. Twenty-four patients underwent
liver elastography at 1 year after LT: median LS was 6.8 kPa, with
18 (75%) patients having a LS < 8.7 kPa; 3 patients had LS > 9.5 kPa, 2
of them underwent liver biopsy, which showed mild portal inflam-
mation and focal reticular fibrosis; the third patient was cholestatic
at liver elastography.
Conclusions: DAAs pre or peri-LT achieved HCV eradication in
98% of the patients after LT; early post-LT management was sim-
plified by the absence of viremia and resulted in a low rate of acute
rejections and biliary complications. Despite a LT activity mostly
e26 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
relying on elderly donors, three-fourths of the cured patients
showed a LS corresponding to absent/mild fibrosis at 1 year after LT.
http://dx.doi.org/10.1016/j.dld.2017.01.054
T-17
Worsening of serum lipid profile after directacting antiviral treatment
S. Gitto 1, A.F.P. Cicero 2, E. Loggi 1,
M. Giovannini 2, F. Conti 1, E. Grandini 1,
V. Guarneri 1, A. Scuteri 1, G. Vitale 1, C. Cursaro 1,
C. Borghi 2, P. Andreone 1
1 Hepatology Unit, Department of Medical and
Surgical Sciences, University of Bologna and Azienda
Ospedaliero Universitaria di Bologna, Policlinico di
Sant’Orsola, Bologna, Italy2 Internal Medicine Unit, Department of Medical and
Surgical Sciences, University of Bologna and Azienda
Ospedaliero Universitaria di Bologna, Policlinico di
Sant’Orsola, Bologna, Italy
Introduction: Hepatitis C virus and host lipid metabolism show
complex interactions since lipids influence both viral replication
and lifecycle.
Aim: Our aim was to evaluate changes of glucose and lipid
metabolism in patients with chronic hepatitis C after therapy with
direct acting antivirals (DAA).
Materials and methods: All patients consecutively treated from
January to November 2015 were considered. We recorded labora-
tory and clinical data at baseline and week 24 of follow-up. Frozen
serum samples were used to assay apolipoprotein A1 (apoA1), B
(apoB) and lipoprotein (a) [Lp(a)]. Wilcoxon test was utilized to esti-
mate trends and logistic regression for predictors of lipid changes.
Results: We analyzed 100 patients, mostly cirrhotic (81%) and
with genotype 1b (59%). Ninety three patients achieved sustained
virological response (SVR) while 7 relapsed. From baseline to week
24 of follow-up, any modification of drugs, life-style and body
mass index was registered. However, insulin and Homeostasis
Model Assessment of Insulin Resistance declined (from 16.5 ± 7.3
to 11.6 ± 5.8 �IU/ml and from 3 to 2.7, p = 0.000). Non-High Density
Lipoprotein (HDL) cholesterol increased from 102 ± 29 to 116 ± 35
(p = 0.000) and Lp(a) from 5.6 ± 6.5 to 9.8 ± 11.5 mg/dl (p = 0.000).
Rise of both Low Density Lipoprotein/HDL and apoB/apoA1 ratio
was registered (from 1.79 ± 1.10 to 2.08 ± 1.05 and from 0.48 ± 0.18
to 0.53 ± 0.18 mg/dl, p = 0.000). Notably, any change in lipid profile
was recorded in patients with relapse. At univariate test for Lp(a)
increase, male gender, advanced fibrosis and ribavirin use showed
p < 0.1 but at multivariate analysis only ribavirin appeared as inde-
pendent predictor (OR 3.982, 95% CI 1.206–13.144, p = 0.023).
Conclusions: DAA led to decrease of insulin-resistance. How-
ever, relevant pro-atherogenic lipid changes were registered in
patients with SVR. Ribavirin emerged as independent predictor of
Lp(a) increase. Further studies will be necessary to evaluate cardio-
vascular balance between negative change of lipid profile and both
amelioration of glucose metabolism and viral clearance.
http://dx.doi.org/10.1016/j.dld.2017.01.055
T-18
The immunomodulatory activity of SerpinB3 anprotease-inhibitor in vivo and in vitro
A. Cappon 1, G. Villano 1, S. Quarta 1, A. Biasiolo 1,
C. Turato 1, M. Ruvoletto 1, S. Sutti 2, S. Bruzzi 2,
E. Novo 3, E. Morello 3, S. Cannito 3, E. Albano 2,
M. Parola 3, P. Pontisso 1
1 Department of Medicine, University of Padua,
Padua, Italy2 Department of Health Sciences and
Interdisciplinary Research Centre for Autoimmune
Diseases, University of East Piedmont, Novara, Italy3 Department of Clinical and Biological Sciences,
University of Turin, Turin, Italy
Introduction: NASH is associated with a higher risk of overall
mortality and HCC development. The serin protease inhibitor Ser-
pinB3 is not expressed in normal liver, but its level increases in
relation with the extent of liver damage. To date, only few data are
available on this serpin in the setting of NASH.
Aim: Aim of this study was to assess the role of SerpinB3 in a
murine model of NASH, with particular respect to inflammatory
response.
Materials and methods: Wild-type and SerpinB3 trangenic
C57BL/6 mice were fed on MCD diet for 8 weeks. At the end of the
study, mice were sacrificed and the liver was used for further anal-
ysis. Immunohistochemistry for macrophage detection was carried
out using F4/80 antibody, while inflammatory cytokines were eval-
uated on total RNA by molecular amplification techniques. Primary
mononuclear cells were isolated from healthy donors and treated
with or without SerpinB3 (200 ng/ml) for 2, 8, 24, 72 and 168 h.
Gene expression was evaluated by Q-PCR, and Real-time cell pro-
liferation was measured using the xCELLigence instrument.
Results: After 8 week of MCD diet, SerpinB3 transgenic mice
showed a significantly increased inflammatory cells infiltration in
the liver, with higher F4/80 positive cells staining, compared to wild
type mice. These findings were supported by a marked increase of
CD11b and TNF-alpha. Interestingly, the expression of IL-12, CXCL-
10 and IL-1-beta, markers associated with M1 macrophage profile,
were significantly up-regulated in the liver of treated transgenic
mice, as compared to controls. Primary monocytes treated with
SerpinB3 showed increased survival and proliferation, associated
with higher levels of TNF-alpha, IFN-alpha, IL-12 and CXCL-10.
Conclusions: These data suggest for first time that SerpinB3 may
have a direct pro-inflammatory and immunomodulatory role on
monocytes in vitro and in vivo in the contest of NASH.
http://dx.doi.org/10.1016/j.dld.2017.01.056
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42 e27
T-19
Hypoxia-inducible factor 2� drives theprogression of experimental non-alcoholic fattyliver disease by stimulating hepatocyteproduction of histidine rich glycoprotein
S. Sutti 1, E. Morello 2, S. Cannito 2, E. Novo 2,
C. Bocca 2, B. Foglia 2, S. Bruzzì 3, E. Bugianesi 1,
E. Albano 3, M. Parola 2
1 Department Medical Sciences, University of Torino,
Turin, Italy2 Department Clinical and Biological Sciences,
University of Torino, Turin, Italy3 Department Health Sciences, A. Avogadro
University, Novara, Italy
Introduction: Hypoxia and hypoxia inducible factors (HIFs) are
believed to significantly affect fibrogenic progression of chronic
liver diseases (CLD). Recently, we showed that HIF-2� expression
is up-regulated in parenchymal cells in either experimental or
human non-alcoholic fatty liver disease (NAFLD) and contributes
in sustaining liver fibrogenesis in the methionine/choline-deficient
(MCD) diet model of NAFLD.
Aims: In the present study, we provide further insides in the
mechanisms by which HIF-2� promotes the progression of exper-
imental NAFLD.
Methods: NAFLD was induced by feeding in mice with
hepatocyte-specific conditional deletion of HIF-2� (HIF-2�fl/fl/Alb-Cre mice) and control littermates with MCD and choline-
deficient l-amino acid refined (CDAA) diets. In vitro studies have
been performed using HepG2 cells overexpressing HIF-2�.
Results: In both the dietary models of NAFLD hepatocyte
deletion of HIF-2� resulted in: (i) a decrease in fatty liver
and parenchymal necrosis; (ii) amelioration in lobular inflam-
mation and in the hepatic expression of pro-inflammatory
cyto/chemokines (TNF-�, IL-12, CCL2, CXCL10); (iii) a significant
decrease in the expression of pro-fibrogenic genes (collagen 1A1,
TGF-�1, �-SMA) as well as in extracellular matrix deposition (Sir-
ius Red staining) and in the number of activated myofibroblasts.
Such an improvement in NAFLD evolution in HIF-2� deficient mice
was associated with a selective lowering of the hepatic produc-
tion of Histidine-Rich Glycoprotein (HRGP), a hepatocyte-derived
protein recently implicated in sustaining macrophage M1 activa-
tion. Accordingly, flow cytometry showed a decreased production
of IL-12 by macrophages isolated from HIF-2� fl/fl/Alb-Cre mice
receiving the MCD diet. Furthermore, in vitro experiments con-
firmed that up-regulation of HIF-2� resulted in enhanced HRGP
expression by HepG2 cells.
Conclusions: These results indicate that activation of HIF-2�in hepatocytes stimulates the progression of experimental NAFLD
through the up-regulation of HRGP production.
http://dx.doi.org/10.1016/j.dld.2017.01.057
T-20
TERT promoter and CTNNB1 gene mutationsrepresent cancer signatures specific forhepatitis B and hepatitis C relatedhepatocellular carcinoma
F. Pezzuto 1, F. Izzo 2, L. Buonaguro 1,
C. Annunziata 1, F. Tatangelo 3, G. Botti 3,
F.M. Buonaguro 1, M.L. Tornesello 1
1 Molecular Biology and Viral Oncology Unit, Istituto
Nazionale Tumori “Fondazione G Pascale” – IRCCS,
Napoli, Italy2 Hepatobiliary Surgery Unit, Istituto Nazionale
Tumori “Fondazione G Pascale” – IRCCS, Napoli, Italy3 Department of Pathology, Istituto Nazionale
Tumori “Fondazione G Pascale” – IRCCS, Napoli, Italy
Introduction and aim: Recurrent somatic mutations in the pro-
moter region of telomerase reverse transcriptase (TERT) gene and
in the exon 3 of CTNNB1 gene have been recognized as common
events in hepatocellular carcinoma (HCC) with variable frequen-
cies depending on etiology and geographical region. We analyzed
the distribution of such mutations in a cohort of hepatitis B (HBV)
and hepatitis C (HCV) related HCC patients from Southern Italy.
Materials and methods: Our cohort consisted of 122 cases of
hepatitis B (HBV) and hepatitis C (HCV) related HCCs and 7 cases of
cholangiocarcinoma and hepatocholangiocarcinoma (CC/HCC-CC).
TERT promoter and CTNNB1 gene mutations were searched in all
tumor biopsies and in autologous cirrhotic tissues.
Results: Overall, 50.4% and 26% of HCC as well as 14.3% and
none of CC/HCC-CC were mutated in TERT promoter and in CTNNB1
exon 3, respectively. TERT and CTNNB1 mutations were found more
frequently in HCV related (53.6% and 26.4%, respectively) than
HBV related (41.7% and 16.7%, respectively) HCCs and coexisted in
57.6% of CTNNB1 mutated tumors. Mutations in TERT and CTNNB1
were not associated with the functional promoter polymorphism
rs2853669. No mutations were detected in the 129 non-HCC cir-
rhotic tissues.
Conclusions: Mutations in TERT promoter and in CTNNB1 gene
represent specific cancer signatures in the pathogenesis of viral
related HCC and could be promising early biomarkers as well as
targets for tailored therapies.
http://dx.doi.org/10.1016/j.dld.2017.01.058
e28 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
T-21
Minimal increases of alpha-fetoprotein stronglypredict HCC development in caucasiancompensated HBV cirrhotics treated byentecavir or tenofovir: A 7-year longitudinalcohort study in 225 patients
A. Loglio 1, G. Grossi 1, M. Iavarone 1, M. Viganò 2,
A. Sangiovanni 1, M. Colombo 3, P. Lampertico 1
1 Division of Gastroenterology and Hepatology,
Fondazione IRCCS Cà Granda Ospedale Maggiore
Policlinico, Università degli Studi di Milano, Milan,
Italy2 Division of Hepatology, Ospedale San Giuseppe,
Università degli Studi di Milano, Milan, Italy3 Center for Translational Hepatology Research,
IRCCS Humanitas Hospital and University, Rozzano,
Italy
Background and aims: As the diagnostic accuracy of alpha-
fetoprotein (AFP) in long-term NUC treated patients with
HBV-related compensated cirrhosis remains debated, aim of the
study was to assess the sensitivity and specificity of AFP values for
HCC diagnosis.
Methods: 225 HBsAg-positive monoinfected HCC-free compen-
sated cirrhotics HCC starting ETV/TDF were consecutively enrolled
in this longitudinal cohort study (age 60 (21–81) years, AFP 2
(1–296) ng/ml, 80% males, 97% Caucasian, 88% HBeAg negative, 76%
GT D, 73% normal ALT, 65% NUC-treated). Patients were regularly
followed-up till HCC development or July 2016 with blood tests
comprehensive of AFP (≤7 ng/ml) assessed every 3-6 months and
HCC surveillance every 6 months.
Results: Overall, 5338 AFP measurements were collected during
89 (7–109) months of follow-up; 31 (13.8%) patients developed an
HCC after 48 (7–88) months (1.9% per year). Among the 212 (96%,
group A) patients who maintained persistently normal AFP levels
throughout the follow-up, 20 (9.4%) developed HCC after 48 (7–75)
months. Among the 9 (4%, group B) patients in whom AFP increased
>7 ng/ml at least at one-time point (after 53 months, range 13–82),
8 (89%) developed an HCC within 3.6 (0.3–12.3) months after AFP
increase. The only case with an AFP of to 14 ng/ml but no evidence
of HCC had lung cancer multiple hepatic metastases. Among the
remaining 4 NUC-naïve patients (group C) who maintained AFP >7
(range 18–310), HCC occurred in 3 (75%) after 48 (20–87) months.
Overall, AFP increase >7 ng/m had 71.4% sensitivity and 99.5% speci-
ficity in diagnosing HCC, with a 88.9% PPV and 90.6% NPV.
Conclusions: An AFP increase >7 ng/ml strongly predicts HCC
development in long-term NUC suppressed compensated HBV cir-
rhotic patients.
http://dx.doi.org/10.1016/j.dld.2017.01.059
T-22
MiR-122 targets SerpinB3 and is involved inSorafenib resistance in hepatocellularcarcinoma
D. Pollutri 1, F. Fornari 2, C. Turato 3, G. Villano 3,
S. Quarta 3, M. Ruvoletto 3, L. Bolondi 2,
L. Gramantieri 1, P. Pontisso 3
1 Centro di Ricerca Biomedica Applicata (CRBA),
Azienda Ospedaliero-Universitaria Policlinico S.
Orsola-Malpighi, Bologna, Italy2 Department of Medical and Surgical Sciences,
University of Bologna, Bologna, Italy3 Department of Medicine, University of Padova,
Padova, Italy
Introduction: The only first-line treatment approved for
advanced hepatocellular carcinoma (HCC) is Sorafenib. However,
many patients experience drug resistance and more effective ther-
apeutic strategies are still an unmet clinical need. In HCC MiR-122,
the most abundant liver-specific miRNA, is downregulated, while
SerpinB3 is upregulated. This serpin displays oncogenic properties,
since it increases cell death resistance, proliferation, invasion and
drug resistance.
Aims: To assess the possible relationship between miR-122 and
SerpinB3 and their influence on cell phenotype and Sorafenib resis-
tance in HCC.
Methods: HCC-derived cell lines and a di-ethyl-nitrosamine
(DEN)-induced HCC rat model were studied. QPCR and Western
blot were used to quantify miR-122, SerpinB3 and stem markers
expression. Sorafenib resistance in miR-122 transfected cells was
evaluated by cell viability and caspase-3/7 activity assays. A cohort
of 35 resected HCCs was tested to assay any correlation between
miR-122, SerpinB3 and stem cell markers expression.
Results: A bioinformatics analysis showed SerpinB3 among
miR-122 hypothetical targets. In HepG2 cells stably transfected
to over-express SerpinB3, miR-122 over-expression determined a
decrease of SerpinB3 mRNA and protein levels, whereas miR-122
inhibition caused SerpinB3 increase. Luciferase assay demonstrated
a direct interaction between miR-122 and SerpinB3 mRNA. In the
rat HCC model, high miR-122 levels were associated with nega-
tive SerpinB3 expression, while low miR-122 levels were associated
with SerpinB3 positivity. A negative correlation between miR-122
and SerpinB3 or stem cell markers was found in human HCCs. MiR-
122 over-expression determined a decrease of cell viability and an
increase of caspase activity in Sorafenib-treated HepG2 and Hep3B
cells. On the contrary, anti-miR-122 treatment caused an increase
of cell viability in Huh-7 cells following Sorafenib treatment.
Conclusions: MiR-122 targets SerpinB3 and its downregulation
associates with SerpinB3 overexpression and stem-like phenotype
in HCC. MiR-122 replacement therapy deserves attention as a pos-
sible therapeutic strategy in combination with Sorafenib for the
treatment of HCC.
http://dx.doi.org/10.1016/j.dld.2017.01.060
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42 e29
T-23
Genetic variations in PD-1 and STAT4 genes donot predict off-treatment functional cure in IFNtreated genotype D, HBeAg-negative patientswith chronic hepatitis B
E. Galmozzi, F. Facchetti, G. Grossi, A. Loglio,
P. Lampertico
A.M. and A. Migliavacca Center for Liver Disease,
Division of Gastroenterology and Hepatology,
Fondazione IRCCS Cà Granda Ospedale Maggiore
Policlinico, Università degli Studi di Milano, Milano,
Italy
Introduction and aim: Single-nucleotide polymorphisms
(SNPs) in programmed cell death-1 (PD-1) (rs10204525) and STAT4
genes (rs7574865) have been associated with hepatitis B infection.
Aim of the study was to assess if these SNPs could improve the
predictive power of other genetic signatures such as IFNL4 vari-
ants on response to interferon (IFN)-based treatment in genotype
D HBeAg-negative chronic hepatitis B (CHB) patients.
Methods: 126 HBeAg-negative CHB patients with compensated
disease that received pegylated-IFN alfa for 22 (6–48) months and
followed for 11 (1–23) years were analyzed by either TaqMan SNP
Genotyping Assays (PD-1, STAT4) and Sanger sequencing (IFNL4).
Results: The genotype distribution in the 126 patients was as
follows: GG in 106 (84%), GA in 19 (15.2%) and AA in 1 (0.8%) for
PD-1 rs10204525 (MAF 0.08); GG in 85 (68%), GT in 37 (29%) and
TT in 4 (3%) for STAT4 rs7574865 (MAF 0.18); TT/TT in 62 (49%),
TT/�G in 51 (40%), �G/�G in 13 (11%) (MAF 0.31) and CC in
107 (85%), CT in 18 (14.2%), TT in 1 (0.8%) (MAF 0.08) for IFNL4
rs368234815 and rs117648444 respectively. Twenty-eight patients
(22%) ultimately cleared HBsAg with a 15-year cumulative proba-
bility of 30%. In univariate analysis, PD-1 and STAT4 variants did
not predict the 15-year cumulative incidence of HBsAg loss (dom-
inant model, rs10204525, HR = 0.89, 95%CI = 0.31–2.6, p = 0.838;
rs7574865, HR = 1.13, 95%CI = 0.52–2.50, p = 0.745). At multivariate
analysis including also all the canonical pretreatment predictors of
response (age, gender, Cirrhosis, ALT, HBV-DNA and HBV genotype),
the only independent baseline predictors of HBsAg seroclearance
were the combined IFNL4 rs368234815 and rs117648444 geno-
types (HR = 3.95, 95%CI 1.4–11.4, p = 0.011) and the pretreatment
serum HBV-DNA levels (HR = 0.62, 95%CI 0.44–0.88, p = 0.007).
Conclusions: ThePD-1 rs10204525 and STAT4 rs7574865-
polymorphisms do not further improve the predictivity of IFNL4
variants on IFN-induced functional cure in the setting of genotype
D HBeAg-negative CHB patients.
http://dx.doi.org/10.1016/j.dld.2017.01.061
T-24
Validation of the Baveno VI criteria forscreening of esophageal varices in patients withmetabolic and alcohol related compensatedadvanced chronic liver disease
N. Mezzina 1, M. Viganò 1, T. Giulia 2, S. Labanca 1,
R. Lombardi 3, V.L. Mainardi 1, A.L. Fracanzani 3,
P. Lampertico 2, M. Rumi 1, M. Primignani 2
1 Hepatology Division, San Giuseppe Hospital,
University of Milan, Milan, Italy2 Gastroenterology and Hepatology Division,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore
Policlinico, University of Milan, Milan, Italy3 Internal Medicine, University of Milan and IRCCS
Ca’ Granda Maggiore Hospital Foundation, Milan,
Italy
Introduction: According to the Baveno VI criteria, patients with
virus-related compensated advanced chronic liver disease (cACLD)
having transient elastography (TE) values <20 kPa and platelet (PLT)
count >150.000/mmc have a very low risk of esophageal varices
(EV) needing prophylactic treatment (VNT) and can avoid screening
endoscopy.
Aims: To evaluate the Baveno VI criteria in patients with cACLD
due to alcohol-related (ALD) and non-alcoholic fatty liver disease
(NAFLD).
Materials and methods/Results: All consecutive patients with
cACLD (LS≥10 kPa or histologically proven) due to NAFLD and/or
ALD, without ascites, hepatitis C/B infection, hepatocellular carci-
noma, portal-vein thrombosis, previous gastro-intestinal bleeding
or endoscopic band ligation, non-selective beta-blockers use were
included if TE was performed within 6 months from the screening
endoscopy. Sensitivity (Sn), specificity (Sp), positive (PPV) and neg-
ative (NPV) predictive values, positive/negative likelihood ratio
[LR(+), LR(−)] were calculated. Eighty-two cases were included
(43 NAFLD, 27 ALD, 12 mixed). Nineteen (23%) had EV of which 4
(5%) had VNT. Among the 15 patients fulfilling the Baveno criteria,
none presented VNT, and one (7%) had small-sized EV, thus result-
ing in Sn = 100% and Sp = 19% in ruling-out VNT, with a PPV = 6%,
NPV = 100%, LR(+) = 1.24 and LR(−) = 0. Sn, NPV and the LR(−) were
100%, 100% and 0 in NAFLD and ALD patients, respectively, whereas
Sp was 17% and 24%. These results were still reproducible using
a less conservative threshold values for PLT (>125.000/mmc) and
TE (<30 kPa) which correctly identified 32 patients without VNT,
resulting in Sn = 100%, Sp = 41%, PPV = 8%, NPV = 100%, LR(+) = 1.7
and LR(−) = 0 with the same accuracy among sub-groups.
Conclusions: Baveno VI criteria ruling-out VNT could be safely
applied in cACLD patients due to NAFLD/ALD, thus sparing 18% of
screening endoscopy without missing VNT. In addition, the use of a
less conservative threshold of PLT and TE could increase the number
(39%) of spared endoscopy, but needs further confirmation.
http://dx.doi.org/10.1016/j.dld.2017.01.062
e30 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
T-25
Inherited prothrombotic risk factors in childrenwith extrahepatic portal veinobstruction(EHPVO). A case–control study
M. Primignani 1, I. Martinelli 2, G. Tosetti 1,
M. Cheli 3, P. Bucciarelli 2, M. Colusso 3,
D. Alberti 3,4
1 Division of Gastroenterology and Hepatology,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore
Policlinico, Milano, Italy2 A. Bianchi Bonomi Hemophilia and Thrombosis
Center, Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico, Milano, Italy3 UOC Chirurgia Pediatrica – Ospedale Papa
Giovanni XXIII, Bergamo, Italy4 UOC di Chirurgia Pediatrica – Dipartimento di
Scienze Cliniche e Sperimentali, Università di Brescia,
Italy
Background: In children, EHPVO is the commonest cause of
upper gastrointestinal bleeding. Although umbilical vein catheter-
ization or omphalitis are frequently reported causes, most
cases remain unexplained. Inherited thrombophilia has not been
extensively evaluated. We investigated thrombophilia in EHPVO
children, as compared with EHPVO in adults (without solid tumors
or cirrhosis) and in adult controls. The two groups were compared
with controls in terms of odds ratios and 95% CI.
Methods: DNA analysis for factor V Leiden (FVL) and G20210A
prothrombin gene mutation (PTG20210A) and functional/antigenic
assays for antithrombin, protein C, S were performed.
Results: 53 EHPVO children, 65 EHPVO adult and 700 controls
were studied. Thirty children (57%) had umbilical vein catheteriza-
tion. FVL and PTG20210A were found in 3 (6%) and one (2%) children
and in 2 (3%) and 14 (22%) adults, respectively: OR 2.4 (0.7–8.5) for
FVL and 0.6 (0.1–4.2) for PTG20210A in children, and 0.8 (0.1–6.4)
for FVL and 8.1 (3.8–17.5) in adults. 53% of children and 28% of
EHPVO adult had one or more deficiency of antithrombin, protein
C or S but the inheritance could be excluded in all children and in
14 of 18 adults.
Myeloproliferative disorders were excluded in children, but
caused EHPVO in 35% of adults. One risk factor for EHPVO was iden-
tified in 57% children and 40% adults. Two or more risk factors were
recognized in 15% children and 37% adults (c2 = 7.14, p = 0.028),
whereas no risk factors were identified in 28% of children and 23%
adults
Conclusions: Umbilical vein catheterization is the commonest
cause of EHPVO in children. Differently from adults, who have a high
rate of PTG20210A, inherited thrombophilia has no role in children.
The occurrence of multiple risk factors is significantly lower in chil-
dren. However, up to 30% of paediatric EHPVO occur in the absence
of any recognized risk factor.
http://dx.doi.org/10.1016/j.dld.2017.01.063
T-26
Increase in transporter MATE-1 expressioninduced by obeticholic acid correlates withhigher biliary excretion of asymmetricdimethylarginine during hepaticischemia/reperfusion injury
L.G. Di Pasqua 1, C. Berardo 1, V. Siciliano 1,
R. Viscusi 1, V. Rizzo 2, L. Adorini 3, P. Richelmi 1,
A. Ferrigno 1, M. Vairetti 1
1 Department of Internal Medicine and Therapeutics,
University of Pavia, Pavia, Italy2 Department of Molecular Medicine, IRCCS
Policlinico San Matteo, University of Pavia, Pavia,
Italy3 Intercept Pharmaceuticals, San Diego, CA, USA
Introduction and aim: We demonstrated that asymmetric
dimethylarginine (ADMA), inhibitor of nitric oxide synthases,
is excreted by bile and its clearance increases after hepatic
ischemia/reperfusion (I/R). Further biliary ADMA increase occurs
in sham and I/R groups following administration of farnesoid-X-
receptor (FXR) agonist obeticholic acid (OCA) and this increase
seems CAT-2-transporter-indipendent. In this study, we evaluated
the OCA effect on other ADMA transporters including CAT-1, OCT-1
and MATE-1 after hepatic I/R.
Methods: Male Wistar rats received orally 10 mg/kg/day of OCA
(Intercept Pharmaceuticals) or vehicle for 5 days and were sub-
jected to 60-min partial hepatic ischemia or sham-operated. After a
60-min reperfusion, serum, tissue and bile ADMA levels and hepatic
mRNA expression of CAT-1, OCT-1, MATE-1 and FXR were mea-
sured. Liver iNOS and eNOS content was evaluated.
Results: Serum ADMA levels were higher in sham rats treated
with OCA compared with vehicle. OCA administration induced
an increase in biliary ADMA levels both in sham-operated and
I/R groups, without significant changes in hepatic ADMA con-
tent. A reduction in CAT-1 expression was found in OCA-treated
sham-operated rats compared with vehicle. In I/R groups, OCA
administration did not change CAT-1 but a marked decrease in
OCT-1 was observed. An increase in MATE-1 was detected both
in sham-operated and I/R groups treated with OCA. OCA induced
an increase, although not significant, in eNOS and a significant
decrease in iNOS expression after I/R, compared with vehicle-
treated animals. A decrease in mRNA expression of FXR was found
in OCA-treated sham-operated rats compared with vehicle.
Conclusions: Since ADMA transporters such as CAT-1 and OCT-
1 were markedly downregulated and MATE-1 was upregulated in
the I/R group treated with OCA, we suggest that MATE-1 proteins,
involved in the biliary excretion of intoxicants, are also responsible
for the biliary excretion of ADMA as they provide an alternative
elimination route.
http://dx.doi.org/10.1016/j.dld.2017.01.064
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42 e31
T-27
Clinical effectiveness of enhanced surveillancein “super-high risk” cirrhotics as evaluated inthe ITA.LI.CA database
M. D’Elia 1, G. Peserico 1, F. Pelizzaro 1,
A. Meneghetti 1, A. Imondi 1, E. Giannini 2,
F. Trevisani 3, F. Farinati 1
1 Department of Surgery, Oncology and
Gastroenterology, Section of Gastroenterology,
University of Padua, Padua, Italy2 Department of Internal Medicine, Gastroenterology
Unit, University of Genoa, Genoa, Italy3 Unità di Semeiotica Medica, Dipartimento di
Scienze Mediche e Chirurgiche, Alma Mater
Studiorum, Università di Bologna, Bologna, Italy
Background: Surveillance of cirrhotics in the secondary pre-
vention of HCC is mandatory but the ideal surveillance interval is
still under discussion. The Japanese guidelines consider HCV/HBV-
related cirrhotics as “super-high risk” patients, with shorter
doubling time, and indicate an enhanced surveillance (3–4
months).
Aims of the study: Were to evaluate the impact of a three-
months enhanced surveillance (3MS) in patients with viral cirrhosis
in terms of tumor stage, survival and direct costs.
Patients and methods: The multicenter ITA.LI.CA database
(5849 HCC patients) was used. Inclusion criteria were: cirrhosis,
viral etiology and diagnosis under surveillance (3MS versus 6MS).
Overall 1576 cirrhotics met the definition of “super-high risk”: 194
underwent 3MS, 1382 6MS. The survival analysis took into account
the lead time bias (LTB) (by Schwartz’s algorithm, Cancer 1961).
Results: The 3MS did not increase the proportion of lesions diag-
nosed as “very early” (p = 0.622) or within Milan Criteria (p = 0.067).
In the 3MS patients a greater portion of HCC were multifocal
(p = 0.025), probably due to an increased likelihood of the 3MS
to diagnose more aggressive tumors. The survival of the 3MS
patients was not significantly different, also when corrected for LTB
(p = 0.987), with actually a shorter survival in the 3MS group (35
months, 95% CI 32–38, vs 42 months, 95% CI 37–43). These results
were confirmed in the multivariate analysis. Micro-economic anal-
ysis estimated an increase of 1447D in the costs for each HCC while
the cost for year of life saved was not computable.
Conclusions: In patients at “super-high risk” an enhanced 3MS
does not improve tumor stage, feasibility of curative treatments
and patients’ survival, with an increase in direct costs. It can be
concluded that “super-high risk” patients should be managed as all
the population at risk, as indicated by the European guidelines.
http://dx.doi.org/10.1016/j.dld.2017.01.065
T-28
Lobe-specific oxidative stress and matrixmetalloproteinase activation in two animalmodels of non-alcoholic fatty liver disease(NAFLD)
V. Siciliano 1, L.G. Di Pasqua 1, C. Berardo 1,
V. Rizzo 2, P. Richelmi 1, S. Perlini 1, A. Ferrigno 1,
G. Palladini 1, M. Vairetti 1
1 Department of Internal Medicine and Therapeutics,
University of Pavia, Pavia, Italy2 Department of Molecular Medicine, IRCCS
Policlinico San Matteo, University of Pavia, Pavia,
Italy
Introduction and aim: We previously demonstrated that in
models of ischemia/reperfusion and obstructive cholestasis a lobar
functional heterogeneity of the liver exists indicating that different
events occur in the different hepatic lobes (Palladini et al., 2012;
Ferrigno et al., 2014). In this study we evaluated the liver hetero-
geneity in two animal models of non-alcoholic fatty liver disease
(NAFLD).
Methods: NAFLD was induced in male Wistar rats by 4–8 week
MCD diet administration; 12-week old Obese (fa/fa) and Lean
(fa/−) male Zucker rats were also used. Serum hepatic enzymes
and TNF-alpha were quantified. Reactive oxygen species (ROS) and
malondialdehyde (MDA), index of oxidative stress, and matrix met-
alloproteinase activation (MMP-2, MMP-9) were evaluated using
liver samples from left lobe (LL), median lobe (ML) and right lobe
(RL).
Results: Liver injury in MCD and Zucker obese rats was con-
firmed by the increased hepatic enzymes release; an increase
in serum TNF-alpha occurred in MCD rats when compared with
Zucker obese rats. A lower MDA level was observed in the RL as
compared with the LL and ML in the MCD animals; the difference
was time dependent and more evident after 8 weeks. In Zucker rats,
higher MDA levels was found in LL both in Lean and Obese Zucker
rats. The same trend occurred in ROS formation both in MCD and
Zucker rats. A marked MMP-2 and MMP-9 activation occurred in
RL compared with LL and ML in MCD rats.
Conclusions: A lobar difference was detected for ROS, MDA and
MMPs activity both in MCD and Zucker rats, with higher oxida-
tive stress in the LL for all groups considered. On the contrary an
higher MMPs activation was found in RL when compared with LL
and ML. This study supports the growing evidence of a functional
heterogeneity among the liver lobes, also occurring in NAFLD rats.
http://dx.doi.org/10.1016/j.dld.2017.01.066
T-29
Vitamin D deficiency is an independent riskfactor and is predictor of infections in patientsaffected by HCV-related liver cirrhosis
A.R. Buonomo, E. Zappulo, R. Scotto, B. Pinchera,
A.E. Maraolo, F. Borrelli, G. Di Filippo, G. Borgia,
I. Gentile
Department of Clinical Medicine and Surgery,
Section of Infectious Disease, University of Naples,
Naples, Italy
Introduction: Vitamin D has other biological effects than
calcium-fosforus omeostasis. Among these effects, it plays a keyrole
in native immunity stimulation and adaptive immunity regulation.
e32 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
Material and methods: A total of 291 patients affected by HCV-
related liver cirrhosis were prospectively enrolled between 2013
and 2015 at the Infectious Disease Section of the University of
Naples “Federico II”. Cirrhosis was defined by clinically, histolog-
ically or by the means of transient elastography ≥13 kPa. Serum
vitamin D levels were dosed at enrolment. A clinical evaluation
was performed at baseline and during follow-up (three months) to
diagnose the presence of an infection.
Results: Vitamin D deficiency (VDd) (25-OH-Vitamin D
<20 ng/mL) was detected in 68.3% of patients. Overall, 102 infec-
tions were detected and urinary tract infections were the most
common one (47.1%). VDd significantly correlated with the sever-
ity of Child-Pugh classification scores (p = 0.008 Bonferroni test).
The presence of infection was significantly associated with VDd
(p < 0.001), MELD >15 (p < 0.05), hospitalization (p < 0.05), diabetes
mellitus (DM) (p < 0.05), Child-Pugh class B/C versus A (p < 0.001)
and the presence of active HCC (p < 0.001).
At multivariate analysis, VDd (p < 0.01), HCC (p < 0.05) and hos-
pitalization (p < 0.001) were independent predictors of infection at
enrolment in a model that included also Child-Pugh class B/C versus
A, MELD > 15 and DM (these three variables were not significantly
associated with infections).
In patients who did not showed signs and symptoms of an infec-
tion at enrolment (n = 226), VDd (p = 0.034), Child-Pugh class B/C
versus A (p < 0.01) and hospitalization (p < 0.001) were predictive of
a higher incidence of new infections in the following three months.
Conclusions: VDd is associated with a higher risk of infections in
patients with liver cirrhosis. Preventive strategies employing vita-
min D supplementation in this setting should be evaluated in a
randomized controlled trial. This study has been funded by “Borsa
di Studio in Epatologia 2014” provided by FIRE ONLUS.
http://dx.doi.org/10.1016/j.dld.2017.01.067
T-30
Direct acting antiviral (DAA) therapy of HCV,effects on the cryoglobulinemic vasculitis:A multi center open label study
E. Mauro 1, L. Quartuccio 2, M. Ghersetti 1,
M. Lenzi 3, S. Gitto 3, P. Andreone 3, P. Casarin 1,
S. De Vita 2, G. Pozzato 4, C. Mazzaro 5
1 Department of Internal Medicine, Pordenone
General Hospital, Pordenone, Italy2 Rheumatology Clinic, University of Udine, Udine,
Italy3 Department of Internal Medicine and Surgical
Sciences DIMEC, University of Bologna, Bologna, Italy4 Department of Clinical and Surgical Sciences,
University of Trieste, Trieste, Italy5 Clinical of Experimental Onco-Haematology Unit,
CRO Aviano National Cancer Institute IRCCS, Aviano
(PN), Italy
Background: Hepatitis C virus (HCV) is the major etiologic agent
of mixed cryoglobulinemia (MC). Prognostic effects on HCV-related
MC of (DAA) in combination with ribavirin have been shown in
some reports.
Aim: To verify efficacy and safety of interferon-free therapy in
MC.
Methods: In five Italian centers, 27 patients (14 women and 13
men, median age 69 years, range 39–74) were enrolled in 2015.
Treatment was administered according to AISF recommendations.
Results: HCV genotypes 1a were reported in 3 cases, 1b in 15
cases, genotypes 2 in 6 cases, 3 in 2 cases, 4 in 3 cases. MC was Type
II in 22 cases (81%) and Type III in 5 cases (19%). The extra-hepatic
manifestations were: purpura in 14 cases, arthralgias in 13 cases,
peripheral neuropathy in 11 cases. Metavir fibrosis score: F1 7
cases, F2 4 cases, F3 2 cases, F4 14 cases and Indolent low-grade
Non Hodgkin Lymphoma (NHL) in 3 cases. After four weeks DAA
therapy, undetectable HCV viremia was achieved in all patients
and maintained in 95% of cases after 12 or 24 week treatment.
Moreover, regression of purpura (6 cases) and reduction of cryocrit
(17 cases) were observed, but only 2 cases showed undetectable
levels of cryoglobulins at the end of treatment. The median level
of rheumatoid factor is decreased, while C4 remained low at the
Sustained Virological Response (SVR) 24. Peripheral neuropathy
improved in five cases at the end of therapy and maintained in SVR
12 and SVR 24 week. No NHL patients achieved haematological
response. Most common side effects were: fatigue, insomnia, itch
and anemia, in five cases ribavirin dose was reduced for anemia.
Conclusions: DDA plus ribavirin is safe and effective to eradi-
cate HCV, it seems to be associated with good clinical response in
vasculitis but not with response in B-NHL.
http://dx.doi.org/10.1016/j.dld.2017.01.068
T-31
Dynamic risk prediction in Primary BiliaryCholangitis using the UK-PBC cohort
M. Carbone 1,2, A. Nardi 3, H.F. Ainsworth 3,
M.A. Heneghan 3, G.M. Hirschfield 3,
D. Thorburn 3, A. Bathgate 3, M. Aldersley 3,
J.M. Neuberger 3, D.D. Stocken 3, H.J. Cordell 3,
G.J. Alexander 3, R.N. Sandford 3, D.E.J. Jones 3,
G.F. Mells 3
1 Academic Department of Medical Genetics,
University of Cambridge, Cambridge, UK2 Division of Gastroenterology, University of Milan
Bicocca, Milan, Italy3 UK-PBC Research Group, UK
Background and aims: The accurate identification of patients
with adverse long-term outcome is of key importance in primary
biliary cholangitis (PBC), particularly with the advent of novel ther-
apies. Current prognostic tools are based on Cox models that make
the assumption of proportional hazards, i.e. the hazard ratio of
each variable remains constant over time. In PBC, however, this
assumption may be unreliable for long-term prediction. Detecting
and modeling time-dependent effects may improve accuracy com-
pared with time-fixed (time-independent) models. The aim of this
study was to identify time-dependent variables in PBC that might
improve the accuracy of long-term prognostication by using data
from the UK-PBC Research Cohort.
Methods: Data on 3062 patients from the UK-PBC Research
Cohort treated with ursodeoxycholic acid (UDCA) were analyzed.
We performed Cox’s proportional hazards regression analysis of
diverse explanatory variables to derive the best-fitting Cox model.
The endpoint was a composite outcome (liver transplantation and
overall death). Where detected, non-linear effects of continuous
covariates were investigated using spline functions or fractional
polynomials. A smoothed plot of scaled Schoenfeld’s residuals pro-
vided a first crude estimate of time-varying parameters.
Results: The median follow-up was 7.4 years (interquartile
range: 4.2, 10.8). During follow-up, 306 patients (10.0%) suffered
an event: 119 patients (3.9%) underwent LT and 187 patients (6.1%)
died, of whom 97 (3.2%) of liver-related causes. The overall event-
free survival rate was 96% at 5 years, 88% at 10 years, and 74% at
15 years. The most important predictors were as follows: alkaline
phosphatase at baseline (hazard ratio [HR] = 1.12, confidence
interval [CI]: 1.08–1.16), albumin (abnormal vs normal; HR = 2.37,
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42 e33
Fig. 1.
CI: 1.73–3.24), platelets count (abnormal vs normal; HR = 2.45,
CI: 1.72–3.5), ‘delta ALP’ after twelve months of treatment with
UDCA and bilirubin (log-scale). Only for ‘delta ALP’ and bilirubin a
time dependent effect was detected and estimated together with
a confidence band (Fig. 1).
Conclusions: We identified the time-dependent effect of pre-
viously known predictive variables. Elevated bilirubin strongly
predicts adverse outcome but the risk conferred declines with time.
The risk of ‘delta ALP’ after treatment with UDCA has a slight
increase over the time. Accounting for time-dependency we can
improve the accuracy of existing prognostic models. Dynamic pre-
diction modelling represents a high-performance statistical tool to
support decision-making in patients with PBC in need of intensive
monitoring and care.
http://dx.doi.org/10.1016/j.dld.2017.01.069
T-32
Established cirrhosis at the time of diagnosispredicts adverse outcome in autoimmunehepatitis: A retrospective cohort study
A. Gerussi 1,2, N. Halliday 3, D. Roccarina 1,
F. Saffioti 1,4, P. Polly 1, M. Pinzani 1, A. Marshall 1,
D. Thorburn 1
1 UCL Institute for Liver and Digestive Health, The
Royal Free Sheila Sherlock Centre, Royal Free
Hospital, London, United Kingdom2 Department of Experimental and Clinical Medical
Sciences, Liver Unit, Clinica Medica, Udine, Italy3 Institute of Immunity and Transplantation, UCL,
London, United Kingdom4 Department of Clinical and Experimental Medicine,
Division of Clinical and Molecular Hepatology,
University of Messina, Messina, Italy
Introduction: Autoimmune hepatitis (AIH) can lead to cirrhosis,
hepatic failure and death.
Aim: To identify those clinical parameters which, when present
at diagnosis, predict liver transplant (LT) or death in AIH patients.
Materials and methods: Data from a retrospective database of
all patients with AIH, attending a tertiary liver unit since 1980, were
used. Patients who did not meet IAIHG diagnostic criteria or had
other concomitant liver diseases, acute liver failure at onset, incom-
plete data or less than 1 month follow up were excluded. Cases were
censored at the endpoint of death or LT.
Results: 137 patients were included, of which 39 had
histologically-proven cirrhosis, 16 reached the endpoint of death
or LT. Only 3 non cirrhotic patients reached the endpoint. Median
follow up since diagnosis was 62 months (IQR 121). Univariate
Cox regression analysis identified that histologically-proven cir-
rhosis (HR 12.2, p < 0.0001) correlated with adverse outcome, while
higher ALT (HR 0.012, p < 0.027) was associated with reduced risk
of adverse outcomes. Histological cirrhosis significantly increased
the risk of death or LT on multivariate Cox regression analysis (HR
14.6, p < 0.001) and was associated with reduced LT-free survival
(159 months vs 354 months respectively, p < 0.0001, log rank). On
univariate analysis, lower ALT, albumin and INR at diagnosis were
significantly associated with histological cirrhosis. Lower serum
albumin (OR 0.905, p < 0.013) and ALT (OR 0.998, p < 0.001) showed
a significant independent association with cirrhosis on binary logis-
tic regression.
Conclusions: Histological cirrhosis at diagnosis was a significant
independent predictor of all-cause death or LT. Patients with cir-
rhosis at presentation had lower ALT levels and lower albumin than
those without cirrhosis. The degree of elevation of transaminases
and hepatic synthetic dysfunction was not associated with adverse
outcomes, suggesting that presence of cirrhosis is the predominant
factor in determining patient outcomes.
http://dx.doi.org/10.1016/j.dld.2017.01.070
T-33
Cirrhosis regression does not preventhepatocellular carcinoma in patients with asustained virological response to IFN
R. D’Ambrosio 1, A. Aghemo 1, E. Degasperi 1,
A. Sangiovanni 1, M.G. Rumi 2, M. Fraquelli 3,
R. Perbellini 1, P. Bedossa 4, M. Colombo 5,
P. Lampertico 1
1 A.M. and A. Migliavacca Center for Liver Disease,
Division of Gastroenterology and Hepatology,
Fondazione IRCCS Cà Granda Ospedale Maggiore
Policlinico, Università degli Studi di Milano, Milan,
Italy2 Department of Hepatology, Ospedale San Giuseppe,
Università degli Studi di Milano, Milan, Italy3 Department of Gastroenterology and Endoscopy,
Fondazione IRCCS Cà Granda Ospedale Maggiore
Policlinico, Università degli Studi di Milano, Milan,
Italy4 Department of Pathology and INSERM U773,
Beaujon Hopital, Universitée Paris-Diderot, Clichy,
France5 Center for Translational Hepatology Research,
IRCCS Humanitas Hospital and University, Rozzano,
Italy
Introduction: Sustained virological response (SVR) to anti-
HCV treatments is associated with fibrosis re-absorption, cirrhosis
regression (CR) and reduced risk of cirrhosis-related complications.
Whether the histological changes associated with SVR have any
impact on the incidence of cirrhosis complications is still unknown.
e34 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
Aim: To prospectively assess the incidence of liver-related
events in a cohort of HCV cirrhotic SVR patients with an SVR and
post-SVR histological assessment.
Methods: We followed-up with 6-month HCC surveillance and
clinical evaluation a previously published cohort of 38 cirrhotics
with paired pre- and post-SVR liver biopsies (D’Ambrosio R, Hep-
atology 2012). At post-SVR liver biopsy (LB), 15 (39%) achieved CR
(METAVIR).
Results: After 69 (7–88) months of follow-up after LB, no
episodes of clinical decompensation or GI-bleeding were recorded
in our cohort, whilst 5 (13%) patients developed hepatocellular
carcinoma (HCC). The rates of HCC were similar in patients with
and without CR (3/21 vs. 2/15: 14% vs. 13%, p = 1.0). Histological
findings didn’t differ between patients who developed or didn’t
develop HCC. In fact, among them rates of residual cirrhosis (40%
vs. 40%, p = 1.0), collagen content [2.4 (1.7–5.9) % vs. 2.3 (0.6–15.1%),
p = 0.48] METAVIR activity (p = 0.34), residual portal inflammation
(p = 0.06) and steatosis (40% vs. 12%, p = 0.17) were similar. Sim-
ilarly, we observed no difference in immunochemistry (CK7, GS,
ASMA, CD34, CYP2E1). Clinical features and biochemical param-
eters were similar in patients with and without HCC; only gGT
remained higher in the former group [median 46 (21–57) U/l vs.
23 (14–142) U/l, p = 0.05]. The 5-year survival rates were the same,
independently on CR (96% vs. 100%, p = 1.0) or HCC development
(100% vs. 97%, p = 1.0). One CR patient died of non-liver related
complications, whilst no cases of cirrhosis-related deaths were
recorded.
Conclusions: Post-SVR histological assessment in HCV compen-
sated cirrhotics does not predict HCC risk within 5 years.
http://dx.doi.org/10.1016/j.dld.2017.01.071
T-34
Impact of von Willebrand factor andADAMTS-13 on the pro-coagulant imbalance ofpatients with cirrhosis
V. La Mura 1,2, A. Tripodi 3, N. Bitto 1, G. Tosetti 2,
V. Chantarangkul 3, L. Baronciani 3, C. Valsecchi 3,
F. Peyvandi 3, F. Salerno 1, P. Lampertico 2,
M. Colombo 2, M. Primignani 2
1 Internal Medicine-IRCCS San Donato, Department
of Biomedical Sciences for Health, University of
Milan, Milan, Italy2 Division of Gastroenterology and
Hepatology-IRCCS Ca’ Granda Maggiore Hospital
Foundation, University of Milan, Milan, Italy3 Angelo Bianchi Bonomi Hemophilia and Thrombosis
Center-IRCCS Ca’ Granda Maggiore Hospital
Foundation, Department of Clinical, Sciences and
Community Health, University of Milan, Milan, Italy
Introduction: Von Willebrand factor (VWF) is an independent
predictor of clinical outcome in cirrhosis confirming the potential
pathogenic role of hemostasis on liver damage.
Aim: The study explored: 1 – the association between VWF and
thrombomodulin-resistance (TM-R), 2 – the impact of ADAMTS-13
on VWF along with the severity of the liver disease.
Material and methods Results: Prospective collection of clin-
ical and laboratory data of 79 patients (n◦Child A/B/C = 29/35/15)
consecutively admitted for endoscopic band ligation of esophageal
varices/paracentesis. All patients were in stable hemodynamic
conditions and without clinical evidence of bacterial infection.
Examinations included VWF (antigen, VWF:Ag, and activity,
VWF:RCo) (VWF:RCo/VWF:Ag was an estimate of highly active
VWF), ADAMTS-13 activity, the main pro-(FVIII, FII) and anti-
coagulants (antithrombin, protein C). ETP-ratio (Endogenous
thrombin Potential) with/without thrombomodulin defined the
degree of TM-R and was used to explore the influence of VWF on
pro-coagulant imbalance. Liver dysfunction correlated with high
VWF:Ag, VWF:RCO and low ADAMTS-13 (p < 0.05). FVIII was the
factor with the highest degree of association with VWF:Ag and
VWF:RCO independently from MELD or Child-Pugh (multiple lin-
ear regression; p < 0.001) in accordance with the biological role
of VWF protecting FVIII from degradation. ADAMTS-13 negatively
correlated with VWF:RCO/VWF:Ag ratio, an indirect estimation of
VWF multimers. The thrombin generation curve of patients with
high VWF:Ag disclosed the lowest lag-time and time-to-peak sug-
gesting high reactivity for thrombin generation. VWF positively
correlated with the degree of TM-R independently from the sever-
ity of liver disease. Furthermore, it identified the highest proportion
of patients with TM-R over 0.78 units, the threshold of risk for
thrombosis and severe clinical outcome recently described in a ret-
rospective study of patients with cirrhosis. By contrary ADAMTS-13
was not associated with TM-R.
Conclusions: VWF/ADAMTS-13 axis is impaired along with the
severity of liver dysfunction. VWF significantly influences the pro-
coagulant imbalance detected in cirrhosis through high levels of
FVIII.
http://dx.doi.org/10.1016/j.dld.2017.01.072
T-35
DAA-based regimens in HBsAg/anti-HCVpositive patients: The need to control HBVreplication to avoid HBV reactivation
M. Macera 1, M. Stanzione 1, V. Messina 2,
G. D’Adamo 3, V. Sangiovanni 4, L. Fontanella 5,
S. De Pascalis 1, G. Stornaiuolo 1, G. Piai 6,
G.B. Gaeta 1, I. Gentile 7, N. Coppola 1
1 Public Medicine, Second University of Naples,
Naples, Italy2 AO Caserta, Caserta, Italy3 AO Nocera, Nocera, Italy4 AO Cotugno, Naples, Italy5 AO Fatebenefratelli, Naples, Italy6 Gastroenterology, AO Caserta, Italy7 Infectious diseases, Federico II University, Naples,
Italy
Background: The aim of the present study was to evalu-
ate the efficacy of Direct Antiviral Agents (DAA)-based regimen
in HBsAg/anti-HCV/HCV-RNA-positive patients (pts) with chronic
liver disease in terms of sustained virolgical response for HCV and
of reactivation of HBV infection.
Methods: We enrolled 16 HBsAg-positive pts with anti-
HCV/HCV-RNA positive-related chronic liver diseases, treated with
DAA [median age 61 years (IQR 44–65), 11 males, 10 with cir-
rhosis (Child A in 9), only 1 post-liver transplant]. Regarding the
HBV infection, only one patient was HBeAg-positive, all anti-HDV-
negative. At the time when DAA was started, 11 pts were treated
with Entecavir from 1-36 months (all HBV-DNA negative; NUC-tx
group) and 5 pts not [NUC-sparing group: HBV-DNA was negative
in 4 and positive in 1 (577 IU/ml)]. All patients were monitored for
HCV-RNA and HBV-DNA every month during the treatment and for
6 months after the stop.
Result: Of the 16 patients enrolled, 14 (87.5%) showed a HCV-
SVR and 2 a relapse. In NUC-tx group, all pts remained HBV-DA
negative. Of the 5 pts in NUC-sparing group, 2 pts remained HBV-
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42 e35
DNA negative and 3 showed a HBV reactivation (2 at first month of
DAA treatment and one at the stop of DAA). Because of NUC-rescue
Tx quickly started in all these 3, HBV-DNA became negative in 2.
Instead, in a 77-years old HBeAg negative/HBV DNA positive patient
treated with SOF + ledipasvir for a HCV-1b cirrhosis, although the
NUC-rescue therapy, HBV DNA became negative at day 90 of DAA
and a severe biochemical and clinical reactivation was observed.
Conclusion: Because of the reciprocal viral interaction between
HBV and HCV, HBV reactivation after the negativization of HCV is
possible in the pts not treated with NUC. Thus, a NUC treatment
may be hypothesized in all HBsAg positive patients before the start
of DAA.
http://dx.doi.org/10.1016/j.dld.2017.01.073
T-36
Liver microRNA hsa-miR-125a-5p may exert anoncosuppressor effect on HCC
L. Onorato 1, N. Coppola 1, G. de Stefano 2,
M. Panella 3, V. Iodice 2, C. Minichini 1, N. Mosca 3,
L. Desiato 3, N. Farella 2, M. Starace 1, G. Liorre 2,
N. Potenza 3, E. Sagnelli 1, A. Russo 3
1 Department of Mental Health and Public Medicine,
Second University of Naples, Italy2 IX Interventional Ultrasound Unit for Infectious
Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy3 Department of Environmental, Biological and
Pharmaceutical Sciences and Technologies, Second
University of Naples, Caserta, Italy
Aims: To evaluate the hsa-miR-125a-5p concentration and the
expression levels of 4 of its validated oncogenic targets in neoplastic
and in non-neoplastic liver tissue of patients with HCC.
Methods: All consecutive patients who underwent a diagnostic
liver biopsy for HCC were enrolled. For each patient, real-time PCR
was used to quantify miR-125a-5p and its targeted transcriptsin
relation to RNU6B and GAPDH, respectively, in HCC and non-HCC
liver tissue.
Results: 55 patients were included in the study; the mean age
was 70.3 ± 6.0 years and 58.1% of patients were males. The etiologic
agent was HCV in 41 patients, HBV in 10 and 4 had NASH-related cir-
rhosis (Child-Pugh class A in 89.1% of casesand classes-B/C in 10.9%).
According to the Barcelona Clinic Liver Cancer (BCLC) class, 47
(85.4%) had class A, 5 (9.1%) class B and 3 (5.5%) class C. Lower levels
of hsa-miR- 125a-5p were observed in HCC tissue than in non-HCC
liver tissues (M ± SD 4.08 ± 2.87 vs. 8.25 ± 4.53 A.U., p < 0.00001).
This difference was highly significant to statistical analysis in the
41 HCV-patients, 3.75 ± 2.8 vs. 7.97 ± 4.85 AU (p < 0.00001) and
still significant although at a lower level in the 10 HBsAg posi-
tive patients, 5.47 ± 3.13, vs. 8.94 ± 3.46AU (p = 0.036), and in the 4
patients with NASH-related cirrhosis, 4.65 ± 2.84 vs. 10.9 ± 1.16AU
(p = 0.015). When patients were stratified according to the epi-
demiological and clinical characteristics of HCC, no difference was
observed between the mean fold-regulation of the miRNA in HCC
vs. non-HCC tissue. The analysis of the expression patterns of four
validated targets showed an up-regulation of MMP11, SIRT7 and c-
Raf, with mean fold regulation values of 3, 2.1 and 1.7, respectively.
Conclusions: These data suggest an oncosuppressor effect of
microRNA hsa-miR-125a-5pon HCC; this effect could be exerted
through the regulation of its oncogenic targets MMP11, SIRT7 and
c-Raf, an observation deserving further investigation.
http://dx.doi.org/10.1016/j.dld.2017.01.074
T-37
Prognostic role of vascular endothelial growthfactor and hypoxia inducible factor in HCCpatients after conventional and DEB-mediatedchemoembolization
A. Meneghetti 1, G. Peserico 1, F. Pelizzaro 1,
C. Pozzan 1, V. Iurilli 2, R. Vezzaro 2, R. Cardin 1,
M. Piciocchi 1, D. Paccagnella 3, F. Farinati 1
1 Department of Surgery, Oncology and
Gastroenterology, Padua University, Padua, Italy2 Department of Radiology, Azienda Ospedaliera di
Padova, Padua, Italy3 Department of Gastroenterology, Ospedale
Sant’Antonio ULSS 16, Padua, Italy
Introduction/aims: Transcatheter arterial chemoembolization
(TACE) is the conventional treatment for the BCLC “intermediate”
stage HCC. TACE treatment prompts a neo-angiogenic reaction to
ischemia that probably affects its impact. Our study sought signif-
icant differences, if any, in the levels of two circulating markers of
neo-angiogenesis, Vascular Endothelial Growth Factor (VEGF) and
Hypoxia-Inducible Factor (HIF), after conventional TACE (cTACE)
and DC-Beads mediated TACE (DEB-TACE).
Methods: 170 HCC intermediate stage patients (pts) underwent
TACE (95 c-TACE, 75 DEB-TACE). VEGF and HIF (ELISA) were deter-
mined in sera/plasma, respectively, before (t0) and 4 weeks after
TACE (t1). Tumor vascularization was evaluated at t0 (angiography)
and response to treatment at t1 (CT/NMR scan, mRECIST criteria).
Results: VEGF t0 levels overall significantly correlated with
age (p = 0.031), etiology (p = 0.047), number of lesions (p = 0.001),
BCLC stage (p = 0.008) and progressive disease after treatment
(p = 0.0001). VEGF was significantly higher in non-naïve pts with
previous TACE (p = 0.017). HIF t0 levels significantly correlated
with previous TACE (p = 0.041) and response (p = 0.044). In C-TACE
pts VEGF significantly increased from t0 to t1 (overall p = 0.0001,
C-TACE 0.008, DEB-TACE 0.001), especially in pts with partial
response (p = 0.001) or stable/progressive disease (p = 0.007). HIF
levels significantly decreased from t0 to t1 (p = 0.029) overall and
in partial response-pts. VEGF and HIF at t0 were positively corre-
lated (p = 0.017). VEGF t0 levels, tumor size and Child-Pugh score
emerged as independent predictors of survival, with no significant
results regarding HIF. DEB-TACE and C-TACE groups didn’t differ
in terms of mRECIST response rate, side effects and survival (22
months for C-TACE C.I. 18–26 and 28 for DEB-TACE C.I. 21–35,
p = 0.665; overall 24 months C.I. 20–28).
Conclusions: VEGF was confirmed as an independent predic-
tor of survival and of response to TACE. HIF levels dropped after
treatment and did not correlate with pts’ prognosis. DEB-TACE and
C-TACE have similar effectiveness, side effects and impact on sur-
vival.
http://dx.doi.org/10.1016/j.dld.2017.01.075
e36 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
T-38
Absolute quantification of intrahepatic HBVcovalently-closed-circular DNA by dropletdigital PCR
G.P. Caviglia 1, M.L. Abate 1, A. Olivero 1, C. Rosso 1,
A. Ciancio 1, E. Bugianesi 1, G.M. Saracco 2,
A. Smedile 1
1 Department of Medical Sciences, University of
Turin, Turin, Italy2 Department of Oncology, University of Turin, Turin,
Italy
Introduction: Novel antiviral strategies for chronic hepati-
tis B virus (HBV) treatment are under development in order to
achieve not only viral suppression but covalently-closed-circular
DNA (cccDNA) elimination. Therefore, a sensitive quantification of
intrahepatic cccDNA is becoming crucial.
Aim: To develop a new assay for cccDNA absolute quantification
using droplet digital PCR (ddPCR) technology.
Materials and methods: Plasmid AM-12 containing whole HBV
genome and DNA extracts from HBsAg-positive and -negative
liver specimens were used for assay characterization. Intrahep-
atic total DNA was isolated by phenol/chloroform method. DNA
concentration and quality were assessed by NanoDrop ND1000
(NanoDrop Technologies). For cccDNA quantification, plasmid-
safe ATP-dependent DNase (Epicentre) was added to digest linear
single- and double-strand DNA. Digested samples were further
purified by phenol/chloroform. Specific primers and FAM-labeled
probe flanking HBV DNA gap region were used for cccDNA quan-
tification. Intrahepatic cccDNA values were normalized for cellular
DNA content using RPP30 probe assay (BioRad) and reported as
cccDNA copies/cell.
Results: A 10-fold dilution of AM12 plasmid was used to test
linearity (105–100 copies/ddPCR reaction, R2 = 0.9998, p < 0.0001)
and concordance correlation coefficient between expected and
observed values (rc = 0.9953, 95%CI 0.9927–0.9970). Reproducibil-
ity was assessed by intra- and inter-run tests using 2 different
cccDNA-positive DNA extracts. Average coefficient of variation
(CV) was 8.29% and 7.92% for intra- and inter-run test, respec-
tively. To test cccDNA recovery, quantification of cccDNA was
performed on digested and undigested paired samples; average
cccDNA copies/ddPCR reaction were 153 ± 23 vs. 434 ± 36, respec-
tively (recovery = 35%; p < 0.0001). Probit analysis was performed to
determine lower limit of quantification (LLoQ) and detection (LLoD)
using 10 replicates of a serially diluted cccDNA-positive sample.
LLoQ was 1.1 × 10−4 copies/cell equal to 2.4 copies/ddPCR reaction
whereas LLoD was 3.4 × 10−5 copies/cell equal to 0.8 copies/ddPCR
reaction.
Conclusions: Our ddPCR-based cccDNA quantitation system is
sensitive and could be suitable for monitoring patients with chronic
HBV infection during antiviral treatment.
http://dx.doi.org/10.1016/j.dld.2017.01.076
T-39
Hepatocellular carcinoma and metabolic riskfactors in a main reference center in Italy
R. Ibrahim Kamal Jouness, C. Rosso, M. Marietti,
G.P. Caviglia, A. Nascè, D. Campion,
A. Cantamessa, P. Carucci, E. Bugianesi
Division of Gastroenterology and Hepatology,
Department of Medical Sciences, University of
Torino, Turin, Italy
Background and aims: Hepatocellular carcinoma (HCC) is
increasingly reported to be related with metabolic risk factors, par-
ticularly in patients with nonalcoholic fatty liver disease (NAFLD)
and Chronic Hepatitis C (CHC).
Methods: Following the introduction of a centralized specialist
team to manage patients with HCC, we characterized the demo-
graphics of patients referred to the GI Division at the University
Hospital of Torino and sought the relationship between the severity
of HCC and their metabolic comorbidities.
Results: In total 1039 patients with HCC were consecutively
referred since 2011. The large majority were HCV (n = 640, 61.6%),
followed by HBV (n = 126, 12.1%), NAFLD (n = 86, 8.3%) and alco-
hol (n = 157, 15.1%). Across the 5-years period (2011–2016), there
was a trend in increase of HCV- and NAFLD-HCC, while alcohol-
HCC decreased and HBV-HCC was stable. In the same time lag, the
age of patients with HCV-HCC progressively decreased (p < 0.001),
while it was unchanged in the other etiologies. Diabetes mellitus
(DM) was diagnosed in 30% of the whole HCC cohort (23% in HCV-,
28.3% in HBV-, 51% in NAFLD- and 47% in alcohol-HCC). Barcelona
Clinic Liver Cancer (BCLC) stage was inversely related with BMI
(OR 0.64, 95% CI 0.42–0.98; p = 0.0384) in the whole cohort and
in the NAFLD-HCC cohort it was directly related to the presence
of DM (OR 11.3, 95% CI 2.1–62.1; p = 0.0052). However, the asso-
ciation between DM and BCLC score was not maintained when
the analysis was restricted to Child-Pugh A. Diabetic patients were
less likely to be treated by surgery (OLT or liver resection) in the
whole HCC cohort. Accordingly, DM was associated with multiple
loco-regional treatments (p = 0.041).
Conclusions: DM is associated with HCC severity according to
BCLC score in the NAFLD-HCC cohort and it is also associated with
multiple loco-regional therapy and less likelihood of surgical treat-
ment in the whole HCC cohort.
http://dx.doi.org/10.1016/j.dld.2017.01.077
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42 e37
T-40
Entecavir monotherapy improves renalfunction in patients developing renal sideeffects during long-term tenofovir treatmentwithout compromising virological response: Amulticenter real-life study in 103 patients
M. Viganò 1, G. Grossi 2, A. Loglio 2,
M. Cappelletti 1, S. Zaltron 3, F. Castelli 3,
P. Andreone 4, V. Messina 5, R. Ganga 6,
N. Coppola 7, A. Marrone 8, M. Russello 9,
A. Marzano 10, G. Taliani 11, M. Fasano 12,
S. Fagiuoli 13, E. Villa 14, F. Bronte 15,
T. Santantonio 16, G. Brancaccio 17, F. Facchetti 2,
P. Lampertico 2
1 UO Epatologia, Ospedale San Giuseppe, Università
degli Studi di Milano, Milan, Italy2 Divisione di Gastroenterologia ed Epatologia,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore
Policlinico, Università degli Studi di Milano, Milan,
Italy3 Clinica Malattie infettive e tropicali, Spedali Civili
Brescia, Università degli Studi di Brescia, Brescia,
Italy4 Dipartimento di Scienze Mediche e Chirurgiche,
Università di Bologna, Bologna, Italy5 UOC Malattie Infettive, AO S. Anna e S. Sebastiano,
Caserta, Italy6 SC Medicina Interna, Ospedale S. Michele AO
Brotzu, Cagliari, Italy7 Malattie Infettive, Seconda Università di Napoli,
Dipartimento Salute Mentale e Medicina Preventiva,
Naples, Italy8 Dipartimento di Scienze Mediche, Chirurgiche,
Neurologiche, Metaboliche e dell’Invecchiamento,
Seconda Università di Napoli, Naples, Italy9 UOS Epatologia e Malattie gastroenteriche
dell’A.R.N.A.S. Garibaldi-Nesima, Catania, Italy10 UO Gastroenterologia Universitaria, Ospedale San
Giovanni Battista, Città della Salute e della Scienza di
Torino, Turin, Italy11 Unità di Malattie Infettive e tropicali,
Dipartimento di Medicina Clinica, Università La
Sapienza, Roma, Italy12 Malattie Infettive Ospedale Triggiano, Triggiano,
Italy13 Dipartimento di Gastroenterologia, Epatologia e
Trapianto di fegato, Ospedale Papa Giovanni XXIII,
Bergamo, Italy14 Divisione di Gastroenterologia, AOU Policlinico di
Modena, Università di Modena e Reggio Emilia,
Modena, Italy15 Unità di Gastroenterologia ed epatologia, DiBiMIS,
Università di Palermo, Palermo, Italy16 Dipartimento di Medicina Clinica e Sperimentale,
Università degli Studi di Foggia, Italy17 Cattedra di Malattie Infettive, Seconda Università
di Napoli, Naples, Italy
Introduction: Tenofovir disoproxil fumarate (TDF) is a recom-
mended first-line therapy for chronic hepatitis B (CHB) patients.
However, reduced estimated glomerular filtration rate (eGFR),
hypophosphatemia and Fanconi syndrome have been reported in
some TDF-treated patients. We assessed whether entecavir (ETV)
may be a safe and effective rescue strategy for such patients.
Methods: Serum creatinine, eGFR, serum P, fraction of P re-
absorption (TmPO4/GFR), ALT and HBV DNA were collected every
4 months.
Results: 103 CHB patients (mean age 63 years, 49% cirrhosis, 26%
NUCs-naïve, 41% diabetes and/or arterial hypertension, 98% unde-
tectable HBV DNA) consecutively switched from TDF to ETV due
to renal toxicity were included in this multicenter study. At base-
line (TDF stop and ETV start), patients have been treated with TDF
(41% on reduced doses) for a median time of 35 (3–112) months;
63% had eGFR <60 mL/min, 60% P <2.3 mg/dL and 43% TmPO4/GFR
<0.60 mmol/L, 2 patients had TDF-induced Fanconi syndrome. Dur-
ing 27 months (range: 4–93) of ETV treatment (dosed according
to previous LMV-R and eGFR) all renal parameters improved sig-
nificantly: serum creatinine from 1.26 to 1.11 mg/dL (p < 0.0001),
eGFR from 54 to 65 mL/min (p = 0.003), P from 2.2 to 2.6 mg/dL
(p < 0.0001), TmPO4/GFR from 0.47 to 0.62 mmol/L (p < 0.0001).
Kidney glomerular and tubular dysfunction improved in 46% and
73% of patients, respectively. Renal function fully recovered in
two patients with TDF-induced Fanconi syndrome after 16 and 24
months of ETV therapy. Four out of 48 (8%) LMV-R patients had viro-
logical failure due to ETV-R (4–48 months of treatment, HBV DNA:
112–244 IU/mL, no ALT increase). Early TDF rescue was effective in
all of these patients.
Conclusions: A TDF to ETV switch improves glomerular and
tubular function in most patients developing kidney dysfunction
while on long-term TDF treatment. However, renal function fully
recovered in 38% of the patients, only.
http://dx.doi.org/10.1016/j.dld.2017.01.078
T-41
Copper levels contribute together with the myconcogene to liver transformation
C. Porcu 1, L. Antonucci 2, B. Barbaro 1,
C. Balsano 1,2
1 Institute of Molecular Biology and Pathology
(IBPM)-CNR, Rome, Italy2 Laboratory of Molecular Virology and Oncology,
Francesco Balsano Foundation, Rome, Italy
Introduction: Hepatocellular carcinoma (HCC) represents the
third most frequent cause of cancer death. Biometals metabolism
results significantly altered in tumors: in particular, high serum and
tissue levels of copper were found in HCC patients.
Aim: The purpose of this study was to evaluate the role of cop-
per in liver tumorigenesis, exploiting the action of a known copper
chelator, the ammonium tetrathiomolybdate (TM), alongside to the
assessment of the effect of Omomyc, a dominant negative that it
inhibits the transcriptional activity of myc.
Materials and methods: Human hepatic HepaRG cells were
treated with different concentrations (20, 35 and 50 �M) of CuSO4,
while hepatoma HepG2 and HuH7.5 cells were treated with 50
and 100 �M of TM. These cell lines were also engineered to
express Omomyc under the control of a doxicycline inducible pro-
moter. We evaluated the intracellular copper content by atomic
absorption, cell viability by MTS assay, gene expression by RT-
PCR, protein levels by western blot, the binding of myc on
Ctr1 promoter by ChIP. Cell cycle and death were analyzed by
FACs.
Results: HepaRG treated with CuSO4 showed an increase
of S and G2/M phases, associated with an elevated expres-
sion of pcna, cyclins D, E and B and any increase of cell death.
Accordingly, we highlighted a significant copper up-regulation of
myc. Copper increased the binding of myc on Ctr1 promoter, the
e38 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
main transporter of copper in hepatocytes. Accordingly, HepG2 and
HuH7.5 treated with TM displayed a strong down-regulation of myc
and the activation of Omomyc, determined a significant reduction
of the intracellular copper content and a reduced expression of Ctr1.
Conclusions: Our data indicate that it exists a positive feedback
between myc and copper intake in liver cells. Thus, the high levels
of copper in liver parenchyma could contribute to the onset of a
favorable conditions for cell transformation.
http://dx.doi.org/10.1016/j.dld.2017.01.079
T-42
Screening of oesophagogastric varices invirus-related compensated advanced chronicliver disease: Beyond the Baveno VI criteria
G. Tosetti 1, V. La Mura 2, A. Aghemo 1,
P. Lampertico 1, R. D’Ambrosio 1, M. Viganò 3,
G. Grossi 1, M. Fraquelli 1, M. Colombo 1,
M. Primignani 1
1 Division of Gastroenterology and Hepatology,
University of Milan and IRCCS Ca’ Granda Maggiore
Hospital Foundation, Milan, Italy2 Internal Medicine, Biomedical Science for Health,
IRCCS Policlinico San Donato, University of Milan,
Italy3 Division of Hepatology, Ospedale San Giuseppe,
Università di Milano, Milan, Italy
Background: According to Baveno VI consensus, patients with
virus-related compensated advanced chronic liver disease (cACLD),
liver stiffness <20 kPa and platelet count >150,000/mm3 can safely
avoid endoscopy because of a negligible risk of varices requiring
prophylaxis. Such threshold values have been retrospectively val-
idated in several series and allow sparing screening endoscopy in
10 to 32% of patients. However, the accuracy of less conservative
threshold values for TE and platelet count has not been addressed
yet.
Aim: To assess the accuracy of less conservative threshold val-
ues for TE (<25 kPa; <30 kPa) and platelet count (>125,000/mm3;
>100,000/mm3) in a cohort of HBV and HCV untreated cACLD
patients.
Methods: Virus-related cACLD patients undergoing endoscopic
screening for varices were evaluated. Exclusion criteria were:
TE unavailable/unsuccessful, current hepatocellular carcinoma or
other neoplasm, portal vein thrombosis, previous liver decompen-
sation, known OV, splenectomy, interferon exposure within one
year.
Results: 165 of 318 patients fulfilled inclusion criteria. Fourty-
three (26%) had varices; of these, 14 (8%), all identified by the
Baveno VI criteria, had varices requiring prophylaxis. Less con-
servative criteria for TE (<25 kPa or <30 kPa) and platelet count
(>125,000/mm3) maintained the highest accuracy (100% sensitiv-
ity and 100% negative predictive value) and would have spared
endoscopy in 44% and 49% of patients, respectively (p < 0.001 vs
Baveno VI criteria, McNemar test). Further lowering platelet count
threshold to 100,000/mm3 would result in additional saving of
endoscopies (up to 56% or 64% for <25 kPa or <30 kPa TE value),
but 7% or 15% patients with varices requiring prophylaxis would
have been missed, respectively.
Conclusions: Whereas Baveno VI criteria are valid and repro-
ducible in untreated viral-related cACLD to rule out varices
requiring prophylaxis, but allow sparing no more than 30% endo-
scopies, l less conservative threshold values for TE (up to <30 kPa)
and platelet count (up to >125,000/mm3) could further spare up
to 49% endoscopies without losing accuracy.
http://dx.doi.org/10.1016/j.dld.2017.01.080
T-43
Clinical outcomes with long-term sorafenibtreatment: A multicenter, real-life study
R. Sacco 1, S. Parodi 1, T. Zolfino 2, C. Saitta 3,
L. Marzi 4, N. Simonetti 1, S. Attardo 5, M. Rossa 5,
G. Bresci 1, G. Cabibbo 5
1 U.O. Gastroenterologia e Malattie Ricambio-AOUP,
Pisa, Italy2 S.C. Gastroenterologia, AO Brotzu, Cagliari, Italy3 Divisione di Epatologia Clinica e Molecolare,
Dipartimento di Medicina Interna-Università di
Messina, Messina, Italy4 U.O. Gastroenterologia, AOU di Modena-Policlinico,
Modena, Italy5 Sezione di Gastroenterologia, Di.Bi.M.I.S.,
Universita’ di Palermo, Palermo, Italy
Background and aim: The efficacy of sorafenib in patients
with advanced HCC has been shown in multiple clinical trials and
‘field-practice’ experiences. However, only scant information is
available on the characteristics and clinical outcomes of patients
who maintain sorafenib therapy over a long term. In this multi-
center, field-practice study, we evaluated outcomes and safety of
sorafenib in HCC in a cohort of patients receiving long-term treat-
ment.
Patients and methods: HCC patients were retrospectively iden-
tified from 5 Italian referral centers. Enrolled subjects had received
sorafenib treatment for ≥12 months.
Results: 53 patients were enrolled. Mean age at HCC diagnosis
was 65 ± 12 years. Most patients were males (88.7%), had por-
tal vein hypertension (67.9%) and esophageal varices (66%). Prior
locoregional treatments were administered to 69.8% of patients,
with TACE being the most frequent. Child-Pugh (CP) A class was
the most represented (94.3%), followed by CP B (9.4%). Twenty-five
patients (47.2%) had BCLC-C disease and 25 BCLC-B. 86% of patients
had alpha fetoprotein (AFP) level ≤400 ng/l. The most common
underlying etiology was hepatitis infections from C virus (54.7%)
and B virus (20.8%), followed by alcohol use (18.9%). 21/53 (39.6%)
patients had cirrhosis.
Median duration of treatment was 22.3 (12.3–93.6) months,
and the mean daily dose of sorafenib was 537 ± 167 mg. Seven
complete responses (13.2%) were reported; 84.9% of patients expe-
rienced stable disease, with a median response duration of 16
(range, 4–72) months. Median OS was 28.1 (13.1–93.4) months.
AEs were reported in 84.9% of cases, with diarrhea (53.3%), asthe-
nia/fatigue (42.2%) and hand-foot syndrome (35.6%) being the most
frequent AEs.
Conclusions: This multicentre, ‘field-practice’ study highlights
that sorafenib treatment could result in long-term control of HCC
without any major safety issue. In particular, BCLC-B patients seem
to have a prolonged treatment duration.
http://dx.doi.org/10.1016/j.dld.2017.01.081
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42 e39
T-44
DAAs treatment in HCV recurrence after livertransplantation: Clinical usefulness ofnon-invasive methods
F. Ravaioli, M.R. Tamè, G. Marasco, L. Vizioli,
M.C. Morelli, A.D. Pinna, F. Conti, P. Andreone,
A. Colecchia, D. Festi, Research Center for the
Study of Hepatitis (CRS)
Department Medical and Surgical Sciences,
University of Bologna, Bologna, Italy
Introduction: Hepatitis C virus (HCV) recurrence after liver
transplantation (LT) is highly associated with graft severe fibrosis
within 5 years. New direct-acting antiviral agents (DAA) achieve
sustained virological response (SVR) in almost 90% of patients and
it is associated with a significant improvement in clinical outcomes.
Liver (LSM) and spleen (SSM) stiffness measurement by transient
elastography (TE) [Fibroscan] are used to identify liver fibrosis also
in liver transplant recipients. Fibrosis-4 Score (FIB-4) and Aspar-
tate aminotransferase-platelet ratio index (APRI index) are further
non-invasive biomarkers validated for fibrosis evaluation.
Aims: To evaluate changes of LSM, SSM, FIB-4 and APRI Index
at the end of DAAs treatment (EOT) and at 24 weeks of follow-up
(FU24) in patients with HCV recurrence after LT and with advanced
fibrosis stage.
Materials and methods/Results: We enrolled 45 patients (73%
male, median age 63, median of 75 months from LT to DAA; 67% F4,
C-P A in 91%, 96% of the patients achieved SVR24) with HCV recur-
rence after LT, who received DAA treatments. LSM, SSM, FIB-4 and
APRI fibrosis scores and biochemical tests were performed before
DAAs treatment (BL), at EOT and FU24 after. In SVR patients, non-
invasive tests for liver fibrosis assessment significantly changed
(p-value < 0.0001).
(Median; kPa) BL EOT FU24 p-Value
LSM 14.2* 10.4◦ 8.9# <0.0001
LSM Delta% EOT-BL −24% (−9% to 31%)
LSM Delta%FU24-BL −41% (−25% to 53%)
SSM 45* 42.1◦ 35.8# <0.0001
APRI 1.13* 0.47◦ 0.43 <0.0001
FIB4 3.83* 2.68◦ 2.33 <0.0001
* p < 0.05 BL vs EOT.◦
p < 0.05 EOT vs FU24.# p < 0.05 BL vs FU24.
Conclusions: LSM, SSM reduced in SVR HCV patients with
advanced fibrosis after LT not only at EOT but also at FU24, while
serum fibrosis biomarkers only change after EOT, thus suggesting
that TE more accurately detects the long term positive effect of DAA
treatment.
http://dx.doi.org/10.1016/j.dld.2017.01.082
T-45
Liver stiffness and serum fibrosis biomarkervariations after DAAs treatment: Predictive rolein HCC development in cirrhotic patients
F. Ravaioli 1,∗, G. Mazzella 1, P. Andreone 1,
F. Conti 1, S. Brillanti 1, F. Buonfiglioli 1, I. Serio 1,
G. Verucchi 1, M.L. Bacchi Reggiani 2, G. Marasco 1,
A. Colecchia 1, D. Festi 1, Research Center for the
Study of Hepatitis (CRS)
1 Department of Medical and Surgical Sciences,
University of Bologna, Bologna, Italy2 Department of Experimental, Diagnostic and
Specialty Medicine, University of Bologna, Bologna,
Italy
Introduction: Direct acting antivirals (DAAs) are an effective
treatment in HCV patients since SVR is achieved in more than 90%
of the patients after 12–24 months. However, HepatoCellular Car-
cinoma (HCC) development risk does not seem to reduce in SVR
patients after DAA-treatments. Recently, it has been suggested that
liver stiffness measurement (LSM) by Fibroscan [Echosens®
] can
predict the HCC risk in liver cirrhosis patients.
Aims: Evaluate the role of LSM and clinical parameters as pre-
dictors of HCC development in patients treated with DAAs.
Materials and methods/Results: In 110 HCV-related cirrhotic
patients (F4 >12.5 kPa) before (BL) and at the end of treatment
(EOT) with DAAs, TE and laboratory tests were performed. AST
to platelet ratio test (APRI) and Fibrosis-4 score (FIB4) were also
assessed. Patients were followed- up for one years after EOT. LSM
variation was expressed as percentage (%). Uni and multivariate
logistic regression analysis was used to identify prognostic factors
for HCC development after DAA. LSM, APRI Test and FIB4 score
significantly (p < 0.001) reduced from BL to EOT. The median
percentage variation between EOT and BL (DELTA% EOT-BL) was
−24.4% (IQR −40% to 14%). Factors associated with increased HCC
development after DAAs treatment (p-value < 0.05) at univari-
ate analysis were MELD, Child-Pugh, Oesophageal varices, HCC
history, LSM EOT, LSM EOT (cut-off = 13.6 kPa) (OR = 3.906;
95% CI = 1.02–14.89), LSM DELTA%EOT-BL (OR = 12.577;
95% CI = 1.56–88.97), LSM DELTA%EOT-BL (cut-off = −24.4%)
(OR = 15.721; 95% CI = 1.69–36.76), APRI EOT (OR = 6.701; 95%
CI = 1.94–23.20), FIB4 BL and EOT.
At multivariate model only Child-Pugh Score (OR = 5.3214;
95% CI = 1.943–14.571) and DELTA%EOT-BL (OR = 24.828; 95%
CI = 2.12–291.63) were independent predictors of HCC develop-
ment (p < 0.05).
Conclusions: Our preliminary result indicates that in cirrhotic
HCV-related patients treated with DAA a reduction of less than
24.4% DELTA% (EOT-BL) LSM, together with Child-Pugh Score can
predict HCC development. Further studies are needed on a larger
population to confirm our data.
http://dx.doi.org/10.1016/j.dld.2017.01.083
e40 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
T-46
An elevated degree of genetic variabilitycharacterizes Hepatitis Delta Antigen (HDAg)and correlates with high levels of serumHDV-RNA: Implication for disease progressionand design of new pharmacological targets
L. Colagrossi 1, R. Salpini 1, R. Scutari 1, A. Battisti 1,
L. Piermatteo 1, A. Bertoli 1, C. Minichini 2,
P. Trimoulet 3, H. Fleury 3, E. Nebuloso 4,
M. De Cristofaro 4, G. Cappiello 4, A. Spanò 4,
V. Malagnino 5, T. Mari 6, A. Barlattani 6,
N. Iapadre 7, M. Lichtner 8, C.M. Mastroianni 8,
I. Lenci 9, C. Pasquazzi 10, G.M. De Sanctis 11,
A. Galeota Lanza 12, M. Stanzione 13,
G. Stornaiuolo 13, M. Marignani 10, L. Sarmati 5,
M. Andreoni 5, M. Angelico 9, C.F. Perno 1,
N. Coppola 2, V. Svicher 1
1 Department of Experimental Medicine and Surgery,
Tor Vergata University, Rome, Italy2 Department of Mental Health and Public Medicine,
Section of Infectious Diseases, Second University of
Naples, Naples, Italy3 Laboratoire de Virologie, Hôpital Pellegrin tripode,
Bordeaux, France4 Sandro Pertini Hospital, Rome, Italy5 Infectious Diseases Unit, Tor Vergata University
Hospital, Rome, Italy6 Nuovo Regina Margherita Hospital, Rome, Italy7 San Salvatore Hospital, L’Aquila, Italy8 Department of Public Health and Infectious
Diseases, Sapienza University, Rome, Italy9 Hepatology Unit, Tor Vergata University Hospital,
Rome, Italy10 Department of Gastroenterology, S. Andrea
Hospital, Rome, Italy11 Umberto I Hospital, Rome, Italy12 Gastroenterology Unit, AO Cardarelli, Naples, Italy13 Viral Unit, Second University of Naples, Naples,
Italy
Introduction: HDV-antigen (HDAg) interacts with HBV surface
protein (HBsAg). No information is available on the extent of genetic
variability in HDAg and its impact on virological parameters.
Methods: Among 78 patients (pts) with chronic HBV + HDV
infection, HDAg gen-1 sequences are obtained for 47 pts and HBsAg
gen-D sequences for 31 pts.
Shannon Entropy (SE) is used to measure the extent of amino
acid variability at each HDAg- and HBsAg-position in overall pop-
ulation and by stratifying patients according to serum HDV-RNA:
18 pts with HDV-RNA < 5logIU/ml defined as low-viremic and 29
with HDV-RNA > 5logIU/ml defined as highly-viremic. Positions
with SE = 0 are defined conserved.
Results: A lower % of conserved residues is observed in HDAg
than HBsAg (49.5% vs 69.2%, P < 0.001). In particular, HDAg-domains
with a lower % of conserved positions are multimerization-domain
(MD, aa: 31–52) and RNA-binding domains (RDBs, aa: 2–27;
97–107; 136–146), followed by nuclear-localization signal (NLS, aa:
68–88) and viral-assembly signal (VAS, aa: 195–214) (% conserved
residues: 27.3%, 31.3%, 52.4% and 70%, respectively).
Stratifying pts according to HDV-RNA, a higher degree of genetic
variability is observed in highly-viremic than in low-viremic pts
(%conserved residues: 55.6% vs 65.9%, P = 0.037). In addition, HDAg-
mutations S6R, A22S and L90S significantly occur more frequently
in highly-viremic than in low-viremic pts (S6R: 24.1%[7/29] vs
0%[0/18], P = 0.034; A22S: 72.4%[21/29] vs 33.3%[6/18], P = 0.015;
L90S: 31%[9/29] vs 0%[0/18], P = 0.008). In particular, median (IQR)
serum HDV-RNA in presence of ≥1 of these mutations is 5.7
(5.1–6.3) vs 4.4 (3.8–5.6) in their absence (P = 0.003). S6R and A22S
reside in RDB-I, while L90S is close to NLS (domains crucial for HDV
life-cycle), suggesting that these mutations can confer a replicative
advantage to HDV.
Conclusions: An extensive genetic variability in HDAg corre-
lates with elevated serum HDV-RNA, suggesting a still ongoing
evolutionary HDV adaptation to human host. This genetic vari-
ability should be taken into account for the design of novel
pharmacological targets.
http://dx.doi.org/10.1016/j.dld.2017.01.084
T-47
Spleen stiffness measurement: A usefulprognostic tool in HCV patients treated withDAAs regimens
F. Ravaioli 1, G. Marasco 1, M.L. Bacchi Reggiani 2,
G. Mazzella 1, F. Buonfiglioli 1, A. Porro 1,
S. Brillanti 1, A. Colecchia 1, D. Festi 1, Research
Center for the Study of Hepatitis (CRS)
1 Department of Medical and Surgical Sciences,
University of Bologna, Bologna, Italy2 Department of Experimental, Diagnostic and
Specialty Medicine, University of Bologna, Bologna,
Italy
Introduction: The new Hepatitis C Virus (HCV) treatment
with direct-acting antivirals (DAA) reaches a sustained virologic
response (SVR) in more than 90% of the patients and an improve-
ments of liver stiffness (LSM) by transient elastography (TE)
[Fibroscan] has been reported. Recently, it has been shown that
portal hypertension, evaluated with hepatic venous pressure gra-
dient, ameliorates after DAA treatment. Spleen (SSM) stiffness
measurement by TE can be used for non-invasive assessment and
monitoring of portal hypertension (PH) in CHC patients; however,
to date no evidence on the role of SSM by TE in CHC patients treated
with DAA is available.
Aims: Evaluate the role of SSM and LSM in HCV patients treated
with DAA.
Materials and methods/Results: 100 HCV patients (73% male,
median age 63, 93% CP-A, 93%, 95% SVR24) with advanced liver
fibrosis who received DAA treatments were prospectively evalu-
ated. SSM, LSM together with biochemical tests were performed
before (BL), at the End of Therapy (EOT) and 24 wk (FU24) after DAA.
In 10 SSM was not technically feasible. Table shows the results: SSM
and LSM were significantly reduced at EOT and FU24 (p < 0.0001);
however, SSM significantly decreased in F4, but not in F3 patients.
BL EOT FU24 p-Value
SSMAll (n = 90) 49.6 44 35.6 <0.0001
F3 (n = 15) 27.4 28.9 27 n.s
F4 (n = 75) 63.8 48.8 39 <0.0001
LSMAll (n = 100) 15.1 11.4 10.1 <0.0001
F3 (n = 25) 10.4 8.7 6.1 <0.0001
F4 (n = 75) 17.3 13.5 12 <0.0001
Conclusions: SSM and LSM by TE decreased in all patients
at EOT and FU24 after DAA, suggesting a possible treatment’s
effect on inflammation and fibrosis and consequently on PH. The
changes in SSM may be mainly due to a portal pressure reduction,
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42 e41
being present only in F4 patients. SSM and LSM represent a useful
prognostic tools in patients treated with DAA.
http://dx.doi.org/10.1016/j.dld.2017.01.085
T-48
The role of Spleen Stiffness measurement aspredictor of HCC recurrence after curativeresection in cirrhotic patients
G. Marasco 1,∗, A. Colecchia 1, A. Colli 2,
G. Casazza 3, F. Ravaioli 1, A. Cucchetti 1,
M. Cescon 1, A.D. Pinna 1, D. Festi 1
1 Department of Medical and Surgical Sciences,
University of Bologna, Bologna, Italy2 Department of Internal Medicine, Manzoni Hospital
Lecco, Lecco, Italy3 Department of Clinical and Biochemical Sciences,
University of Milan, Milano, Italy
Introduction: Hepatocellular carcinoma (HCC) is a frequent
complication in patients with chronic liver diseases and one of
the most common malignancies worldwide. Liver resection is the
gold standard treatment option for patients with solitary tumors;
however, tumor recurrence complicates 70% of cases of hepatic
resection at 5 years. Recently it has been demonstrated that the
degree of portal hypertension (PH) measured by HVPG is directly
correlated with the risk of developing HCC. We recently docu-
mented that spleen (SSM) and liver (LSM) stiffness measurement
are accurate non-invasive markers of portal hypertension in cirrho-
sis.
Aims: The aim of our study was to identify the role of SSM and
LSM as predictors of HCC recurrence after curative resection.
Materials and methods/Results: 157 patients with HCC who
underwent curative resection between 2008 and 2014 were
prospectively enrolled to assess early (<12 months) and late (>24
months) recurrence. The results of LSM and SSM assessed with
TE (Fibroscan®
, Echosens) together with clinical and histological
data were collected before surgery and their association with early
or late recurrence was assessed by uni and multivariate logistic
regression analysis. Forty-nine (49) patients with early and 22 with
late HCC recurrence were identified during follow-up period. At
univariate analysis, early recurrences were associated with eti-
ology, number of nodules, HCC diameter and grading, infiltrated
resection margins and satellitosis. Multivariate analysis showed
that only viral (HCV, HBV) etiology, tumor diameter and margin
infiltration were independently associated with early recurrence
with an area under the curve (AUC) of 0.73. At univariate analysis
late recurrence was associated only with SSM (p = 0.0027) with an
AUC of 0.70.
Conclusions: Early HCC recurrence is associated with HCC clin-
ical and pathological features; late recurrence was best predicted
by the assessment of SSM, thus suggesting a role of portal hyper-
tension in the development of HCC late recurrence.
http://dx.doi.org/10.1016/j.dld.2017.01.086
T-49
Impact of adrenal dysfunction on psoas musclethickness assessed by computed tomography inpatients with liver cirrhosis
G. Privitera, L. Spadaro, D. Russo, S. Marchisello,
F. Purrello
Department of Clinical and Experimental Medicine,
University of Catania, Catania, Italy
Background and aims: Sarcopenia and adrenal insufficiency
(AI) are common features of cirrhosis and contribute to mortality.
Nausea and weight loss represent common symptoms of AI and
may participate to muscle waste. The aim of our study was to eval-
uate the role of AI on psoas muscle thickness assessed by CT in a
cohort of cirrhotics.
Methods: 74 cirrhotic patients were examined. Laboratory
parameters of malnutrition (albumin, pre-albumin, transferrin and
lymphocytes) were assessed. Axial (APMT) and Transversal psoas-
muscle-thickness (TPMT) were measured on CT at the level of the
umbilicus. Psoas-muscle-thickness was normalized to stature by
division by height (APMT/h and TPMT/h). Adrenal function was
assessed using the Standard-Dose-short-synacthen test. A peak
cortisol > 18 �g/dl was defined normal.
Results: AI was present in 23 patients. The severity of cirrho-
sis graded by Child-Pugh and MELD was increased in AI compared
to normal adrenal function (NAF) patients (p = 0.001). AI patients
exhibited lower values of pre-albumin (6 ± 3 vs 10 ± 8; p = 0.03)
and transferrin (150 ± 84 vs 220 ± 76; p = 0.003) compared to NAF
subjects. A significant reduction of TPMT values was observed in
female compared to male (23.5 ± 6 vs 31 ± 8; p = 0.002). Cirrhotics
with AI showed increased levels of both APMT (44 ± 6 vs 20 ± 5;
p = 0.02) and TPMT (32 ± 8 vs 27 ± 7; p = 0.03) compared to NAF. A
significant correlation was found between TPMT/h and peak cor-
tisol values (r = 0.38; p = 0.01). When we stratified our population
using TPMT/h < 16.8 mm/h, the number of NAF patients was signif-
icantly increased compared to AI (p = 0.01). Finally, after stratifying
our our population according to ascites presence, we observed a
significant reduction of APMT in ascites (37 ± 5 vs 43 ± 7; p = 0.02).
Conclusion: Our data suggest that adrenal dysfunction does
not contribute to sarcopenia in cirrhotic patients. Cortisol is an
important catabolic hormone, and its deficiency seems to play a
protective role on muscle waste in cirrhotic patients.
http://dx.doi.org/10.1016/j.dld.2017.01.087
e42 Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
T-50
Validation of a simple scoring system to predictsorafenib effectiveness in patients withhepatocellular carcinoma
R. Tortora 1, A. Casadei Gardini 2, G. Cordone 1,
G. Marisi 3, F.G. Foschi 4, M. Scartozzi 5,
R. Granata 1, L. Faloppi 5, S. Cascinu 6,
N. Silvestris 7, O. Brunetti 7, V.O. Palmieri 8,
G. Ercoloani 9, G.G. Di Costanzo 1
1 Transplantation-Liver Unit, Cardarelli Hospital,
Naples, Italy2 Medical Oncology, Istituto Scientifico Romagnolo
per lo Studio e Cura dei Tumori, Meldola, Italy3 Biosciences Laboratory, Istituto Scientifico
Romagnolo per lo Studio e Cura dei Tumori, Meldola,
Italy4 Internal Medicine, Faenza Hospital, Faenza, Italy5 Medical Oncology, University Hospital Cagliari,
Cagliari, Italy6 Hematology and Oncology, University of Modena
and Reggio Emilia, Modena, Italy7 Medical Oncology, Cancer Institute “Giovanni Paolo
II”, Bari, Italy8 Biomedical Sciences and Human Oncology,
University of Bari, Bari, Italy9 Surgical Oncology, General Hospital
Morgagni-Pierantoni, Forlì, Italy
Background and aims: Sorafenib is the recommended treat-
ment in patients with advanced stage hepatocellular carcinoma
(HCC). Previously, we constructed a simple scoring system based
on the occurrence of main sorafenib off-target effects (OTE); that
was able to predict patient’s outcomes after four weeks of ther-
apy. The aim of the present study is to validate this score in an
independent, real-life cohort.
Methods: Clinical records of 275 outpatients treated with
sorafenib in 8 Italian centers from September 2008 to September
2015 were retrospectively analysed. Skin toxicity, diarrhoea and
arterial hypertension, occurring within the first month of therapy,
were the OTEs considered to calculate the score. At each OTE was
assigned 1 point if present; with the score ranging between 0 and 3.
Results: Median overall survival (OS) was 10.8 months; median
time-to-progression (TTP) was 5.1 months. A progressive increase
in median OS and TTP was observed from patients with score 0
to patients with score 3 (p = 0.000). The survival probability at 6,
12, and 24 months was 55.1%, 24.5%, and 7.9% in patients with
score 0; 62.8%, 40.4%, and 19.6% in patients with score 1; 85.6%,
59.0%, and 22.8% in patients with score 2; 100%, 80.9%, and 46.2% in
patients with score 3, respectively. Disease control rate in patients
with score 0, 1, 2, 3 was 34.3%, 51.6%, 80.9%, and 96.3%, respectively
(p = 0.000). Complete or partial response was absent in patients
with score 0, but it occurred in 12.1%, 23.5% and in 44.4% of patients
with score 1, 2 and 3 respectively (p = 0.000). Multivariate analysis
showed that only performance status and the simple score were
independently associated with OS.
Conclusions: We validated a scoring system useful to predict
outcomes in sorafenib treated patients with HCC. This score is sim-
ple to calculate and for its characteristics is an ideal tool to be
implemented in daily clinical practice.
http://dx.doi.org/10.1016/j.dld.2017.01.088
Digestive and Liver Disease 49S (2017) e43–e70
Contents lists available at ScienceDirect
Digestive and Liver Disease
journa l homepage: www.e lsev ier .com/ locate /d ld
Abstracts of the 50th A.I.S.F. – Italian Association for the Study of the
Liver – Annual Meeting 2017 Rome, February 23rd–24th, 2017:
Selected Posters Friday
F-01
Advanced BCLC hepatocellular carcinomaincludes a very heterogeneous patientpopulation treatable with different therapiesand with different prognosis
F. Garuti 1, E.G. Giannini 2, L. Bucci 1, M. Valente 1,
B. Lenzi 1, F. Trevisani 1, on behalf of Italian Liver
Cancer (ITA.LI.CA) group
1 Department of Medical and Surgical Sciences,
Semeiotica Medica, Bologna, Italy2 Department of Internal Medicine, University of
Genova, Genova, Italy
Introduction: The Barcelona Clinic Liver Cancer advanced stage
(BCLC-C) of hepatocellular carcinoma (HCC) includes heteroge-
neous patients. Sorafenib is the recommended treatment.
Aim: To investigate: overall survival (OS) of BCLC-C stage
patients, subclassified by Performance Status (PS) and tumoral fea-
tures; treatment distribution; results of Sorafenib therapy.
Materials and methods: Retrospective analysis of 837 consec-
utive patients diagnosed with advanced HCC from 2008 to 2014.
Patients were divided as follows: 386 with stand-alone PS1, i.e.
without other BCLC-C characteristics (PS1); 147 with stand-alone
PS2 (PS2); 224 with macrovascular invasion (MVI), regardless of
PS; 51 with extra-hepatic spread (EHS), regardless of PS; 29 with
both MVI + EHS, regardless of PS.
Results: Patients with MVI, EHS and MVI + EHS presented with
larger, more frequently with multifocal/infiltrating/massive HCC
and higher alpha-fetoprotein levels compared to PS1 and PS2 sub-
jects. Median OS was 38.6 months in PS1 patients, 22.3 months in
PS2, 11.2 months in EHS, 8.2 months in MVI, and 3.1 in MVI + EHS
(p < 0.001). OS was longer in patients with peripheral than in those
with central MVI (11.2 vs. 7.1 months; p = 0.005). In PS1 patients
prevailed loco-regional therapies (39.6%) and in PS2 the best sup-
portive care (BSC; 42.2%). Sorafenib and BSC were the main utilized
treatments in patients with MVI, EHS and MVI + EHS. Sorafenib
achieved different OS according to the type of MVI (peripheral: 14.2
months, central: 8.2 months), EHS (11.1 months), or MVI + EHS (4.1
months). Sorafenib was significantly superior to BSC in MVI and EHS
groups but not in MVI + EHS patients. Child-Pugh class, ascites, MVI,
EHS, AFP and treatment were independent predictors of mortality.
Conclusions: (1) PS1 alone is not a sufficient criterion to allo-
cate HCC patients to the advanced BCLC stage; (2) BCLC-C patients
should be sub-classified according to PS and tumoral features; (3)
Sorafenib confirms its superiority to BSC in patients with MVI and
EHS.
http://dx.doi.org/10.1016/j.dld.2017.01.089
F-02
A genic and epigenetic combination therapy forliver cancer
L. Rinaldi 1, G. Franci 2, V. Folliero 2, L. Palomba 2,
R. Isticato 3, C. Zannella 2, R. di Francia 4,
I. De Sio 5, G. Morelli 6, S.Lastoria 7, L. Altucci 8,
C. Pedone 6, A. Ascione 9, L.E. Adinolfi 1,
M. Galdiero 2
1 Department of Medical, Surgical, Neurological,
Metabolic and Geriatric Science, Università della
Campania Luigi Vanvitelli, Naples, Italy2 Department of Experimental Medicine, Università
della Campania Luigi Vanvitelli, Naples, Italy3 Department of Biology Federico II University,
Naples, Italy4 Department of Hematology, Foundation C. Pascale,
Naples, Italy5 Department of Clinical and Experimental Internal
Medicine, Università della Campania Luigi Vanvitelli,
Italy6 Department of Pharmacology, Federico II
University, Naples, Italy7 Department of Diagnostic, Foundation C. Pascale,
Naples, Italy8 Department of Biochemistry, Biophysics and
Pathology, Università della Campania Luigi
Vanvitelli, Naples, Italy9 Department of Internal Medicine, Buon Consiglio
Fatebenefratelli, Naples, Italy
Introduction and aim: Genetic and epigenetic mechanisms are
the baseline of cancer initiation, progression and prognosis. Liver
cancer can be the result of viral infections, metabolic disorder,
1590-8658/
e44 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
genetic variation/mutation and epigenetic deregulation. Among
those phenomena evidence of oncosuppressor gene silencing like
p53 and TRAIL represent the major class of liver cancer patients.
Aim of the project is the re-activation of silenced apoptotic path-
way in liver cancer models, plasmidic gene delivery and epigenetic
treatment.
Material and methods: HepG2 ATCC were selected for all
the experiments. Lipofectamine 2000 (Invitrogen) was used for
pEGFP-TRAIL and pEGFP-p53 (Addgene plasmids) and the respec-
tive control were selected and propagated in LB broth in order to
obtain the necessary amount. Plasmid were purified with Invitro-
gen PureLink (Thermo) kit. GFP (Green Fluorescent Protein) was
acquired via FACS excalibur DB analysis. MS.275 (HDACi class I)
was acquired from selleckchem.
Results: Cell cycle analysis was achieved on HepG2 cells
transfected with TRAIL-GFP and pEGFP-p53 recombinant protein.
Results were analysed with Cell-Quest and ModIFit software. Data
shown the re-expression of selected recombinant proteins in over
than 30% cells post 24 h from transfection. The transfected cells
were treated post 24 h with MS-275 for other 8 h and the cells were
collected. The total protein extract was analysed by Western blot
and the apoptosis pathways were evaluated via caspase activation
proteins. In details we detect the relative bands for caspase 8 and
caspase 9 full lengths and activated form in transfected cells and
post MS-275 treatment.
Conclusion: Results showed the possibility to restore the
expression of pro-apoptotic gene TRAIL and p53 in a liver cancer
model HepG2. Moreover, the treatment with epigenetic modula-
tors MS-275 enhanced the pro-apoptotic effect mediated by the
re-expression of those silenced genes.
http://dx.doi.org/10.1016/j.dld.2017.01.090
F-03
Risk factors of early emergent hospitalreadmission and 6-month mortality in patientswith cirrhosis after a recovery from bacterial orfungal infection
F. Morando, S. Piano, S. Rosi, M. Stanco, C. Pilutti,
E. Vettore, A. Romano, S. Fasolato, M. Tonon,
A. Brocca, A. Sticca, P. Angeli
Department of Medicine, University of Padova,
Padova, Italy
Introduction and aims: In patients with cirrhosis, infections
represent a frequent trigger for complications, increasing fre-
quency of hospitalizations and mortality rate. The study aims to
identify predictors of early readmissions (30-days) and to iden-
tify predictors of midterm mortality (6-months) in patients with
liver cirrhosis discharged after a hospitalization for bacterial and/or
fungal infection.
Materials and methods: All patients with cirrhosis discharged
from the University Hospital of Padova after an admission for a
bacterial and/or fungal infection from January 2010 and July 2016,
were included in the study and followed up for at least 6-months.
Results: 199 patients with liver cirrhosis were included in the
study. C-reactive protein (CRP) was found to be the only indepen-
dent predictor of early readmission due to an infection (OR = 1.76;
p = 0.004). Considering early readmissions as a whole, the CRP
value at discharge was found to be an independent predictor of
readmission (OR = 1.91; p = 0.022), as well as the diagnosis of acute-
on-chronic liver failure (ACLF) during the hospital stay (OR = 2.48;
p = 0.008) and the hospitalization in the last 30 days previous to the
admission/inclusion in the study (OR = 1.50; p = 0.042).
Moving to the second part of analysis, age (HR = 1.05;
p = 0.001), diabetes mellitus (HR = 2.14; p = 0.010), refractory
ascites (HR = 2.21; p = 0.008), MELD score at discharge (HR = 1.11;
p < 0.001), diagnosis of sepsis (HR = 2.40; p = 0.019) and CRP values
at discharge (HR = 1.73; p = 0.002) were found to be independent
predictors of 6-months mortality.
Conclusions: CRP showed to be an independent predictor of
early hospital readmission and of 6-months mortality in patients
with cirrhosis after a hospitalization for bacterial and/or fungal
infection. We identified a cut-off value of CRP, 10 mg/L, able to
stratify patients at low or high risk of readmission and mortality.
CRP values could be used, both in the stewardship of antibiotic
treatment and to identify fragile patients that deserve a strict
surveillance program.
http://dx.doi.org/10.1016/j.dld.2017.01.091
F-04
Effectiveness of percutaneous ethanol injectionin relation to hepatocellular carcinoma size: Asingle centre experience
G.G. Di Costanzo, R. Granata,
M. Sanduzzi-Zamparelli, L. Falco, G. Cordone,
R. Tortora
Department of Transplantation – Liver Unit,
Cardarelli Hospital, Naples, Italy
Background and aims: Percutaneous ethanol injection (PEI) for
hepatocellular carcinoma (HCC) has been progressively replaced by
thermal ablation due to its predictable ablation volume and better
efficacy in nodules >20 mm. Nonetheless, PEI remains still used in
selected patients with very small or high-risk located nodules, and
data on its efficacy in relation to nodule volume are scanty. Aim
of this study was to evaluate PEI response rate in nodules with
different size.
Methods: Clinical records of 291 naïve HCC patients treated
with PEI between 1991 and 2010 at our Unit were retrospectively
analysed. Tumor response and recurrence were evaluated at CT or
MRI after four weeks, and then every six months from the proce-
dure according to mRECIST-criteria. Main outcome was complete
tumor-response (CTR), secondary outcomes were HCC recurrence
and time to progression (TTP).
Results: Median follow-up was 20 months (range: 2–189). All
patients had cirrhosis; 59.1% were Child-A; 30.2% Child-B and 10.6%
Child-C. The overall CTR rate was 58.7% (171/291), 81.3% (61/75)
in patients with lesions sized 10–20 mm (Group 1); 59% (52/88)
in patients with lesions of 21–30 mm (Group 2); 60% (36/60) for
lesions 31–40 mm (Group 3), and 29.5% (20/68) for lesions >40 mm
(Group 4). Fourty-two/171 CTR patients had more than one lesions:
11 patients in Group 1, 18 in Group 2; 8 in Group 3 and 5 in Group
4. Fifty-nine/120 of non-CRT patients had more than one lesion.
The overall and local recurrence rate was 46% (28/61) and 36% for
Group 1, 52% (27/52) and 15% for Group 2, 50% (18/36) and 28% for
Group 3, and 60% (12/20) and 30% for Group 4, respectively. Median
TTP was 21 months in Group 1; 11 months in Group 2, 12 months
for Group 3 and 9 months for Group 4. Median overall-survival 28
months (range: 2–189).
Conclusion: PEI efficacy is mainly influenced by the size of the
nodule. Although the introduction of thermal ablative treatments,
in selected cases PEI may be still employed even in nodules >20 mm.
http://dx.doi.org/10.1016/j.dld.2017.01.092
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e45
F-05
In HBeAg-negative chronic HBV infection,HBsAg levels profoundly differ amongHBV-genotypes and can be affected by theextent of HBsAg variability: Can quantitativeHBsAg truly reflect intra-hepatic HBV reservoir?
R. Salpini 1, A. Battisti 1, O. Anastasiou 2, U. Gill 3,
L. Colagrossi 1, A. Bertoli 1, L. Fabeni 4, V. Fini 1,
L. Piermatteo 1, A. Iuvara 5, V. Malagnino 6,
C. Cerva 6, M. Lichtner 7, C. Mastroianni 7,
G. De Sanctis 8, M. Paoloni 9, M. Marignani 10,
C. Pasquazzi 10, N. Iapadre 11, T. Mari 12,
G. Parruti 13, I. Vecchiet 14, L. Sarmati 6,
M. Andreoni 6, M. Angelico 15, S. Grelli 1,5,
P. Kennedy 3, J. Verheyen 2, C.-F. Perno 1,
V. Svicher 1
1 Department of Experimental Medicine and Surgery,
Tor Vergata University, Rome, Italy2 Institute of Virology, University-Hospital,
University Duisburg-Essen, Essen, Germany3 Hepatology, Centre for Immunobiology, Blizard
Institute, Barts and The London School of Medicine &
Dentistry, QMUL, London, UK4 Antiretroviral Drug Monitoring Laboratory,
National Institute for Infectious Diseases, L.
Spallanzani, IRCCS, Rome, Italy5 Microbiology and Virology Unit, Tor Vergata
University Hospital, Rome, Italy6 Infectious Diseases Unit, Tor Vergata University
Hospital, Rome, Italy7 Department of Public Health and Infectious
Disease, “Sapienza” University, Rome, Italy8 “Umberto I” University Hospital, Rome, Italy9 Infectious Disease Unit, “S.S. Filippo e Nicola”
Hospital, Avezzano, Italy10 Department of Gastroenterology, “S.Andrea
Hospital”, Rome, Italy11 “San Salvatore Hospital”, L’Aquila, Italy12 “Nuovo Regina Margherita” Hospital, Rome, Italy13 Infectious Disease Unit, Pescara General Hospital,
Pescara, Italy14 Clinic of Infectious Diseases, Department of
Medicine and Science of Aging, University “G.
d’Annunzio” Chieti-Pescara, Chieti, Italy15 Hepatology Unit, Tor Vergata University Hospital,
Rome, Italy
Introduction: HBsAg-levels are proposed as marker of intra-
hepatic HBV-reservoir. A recent in-vitro study showed variation in
HBsAg-production in different HBV-genotypes. Limited informa-
tion is available on HBsAg-levels in patients infected with different
HBV-genotypes in HBeAg-negative chronic HBV-infection.
Methods: This study includes 301 consecutive-patients with
HBeAg-negative chronic HBV-infection, drug-naïve, and monitored
for >1 year: 126 inactive-carriers with persistent serum HBV-
DNA <2000 IU/ml and normal transaminases (group-A), and 175
with persistent serum HBV-DNA >2000 IU/ml (group-B). Degree of
HBsAg-variability is measured by mean genetic-distance.
Results: Median (IQR) HBV-DNA is 2.8 (2.3–2.9) and 4.1
(3.7–5.2) IU/ml, while median (IQR) ALT is 28 (21–38) and 34
(25–55) U/L in group-A and -B, respectively. HBV-genotypes are:
D = 72.2%, A = 15.9%, E = 11.9% in group-A, and D = 78.3%, A = 14.3%,
E = 7.4% in group-B.
In group-A, median (IQR) HBsAg is significantly lower in
genotype-D than in genotype-A and -E (730 [204–2932] vs. 5741
[3526–14,290] and 10,288 [7172–13,408] IU/ml, P < 0.001). Simi-
lar results are observed in group-B (3436 [1466–8126] vs. 7992
[5069–21,221] and 10,825 [6544–18,216] IU/ml, P < 0.01). More-
over, in group-A, HBsAg-levels <1000 IU/ml (proposed to define
genotype-D patients as inactive-carriers) are observed in 57.1% of
genotype-D, 15.0% of genotype-A and 0% of genotype-E (P < 0.001).
In group-A, the degree of HBsAg C-terminus genetic-variability
(aa: 170–226, known to modulate HBsAg-secretion) is higher
in genotype-D and progressively declines in genotype-A and -
E (0.033 + 0.023 for D, 0.029 + 0.015 for A, 0.026 + 0.012 for E).
By stratifying group-A according to HBsAg-levels in genotype-D,
the degree of HBsAg C-terminus genetic-variability is significantly
higher in patients with HBsAg < 1000 IU/ml than in patients with
HBsAg > 1000 IU/ml (0.041 + 0.024 vs. 0.022 + 0.017, P < 0.001).
Conclusions: HBsAg-levels in HBV genotype-D are significantly
lower than in genotype-A and -E in different phases of HBeAg-
negative chronic HBV-infection including inactive-carrier status. In
genotype-D infected patients, higher genetic-variability in HBsAg
C-terminus correlates with lower HBsAg-levels (presumably by
impairing proper HBsAg-secretion). In this setting, HBsAg-levels
cannot be a direct measure of intrahepatic cccDNA reservoir,
supporting HBV-genotyping to better characterize patients with
HBeAg-negative chronic HBV-infection.
http://dx.doi.org/10.1016/j.dld.2017.01.093
F-06
Hepatocellular carcinoma recurrence rate inHCV infected patients treated with directantiviral agents. A single center experience
R. Granata, G.G. Di Costanzo,
M. Sanduzzi Zamparelli, M. Guarino, G. Cordone,
G. D’Adamo, R. Tortora
Department of Transplantation – Liver Unit,
Cardarelli Hospital, Naples, Italy
Background and aims: In the last few years many HCV patients
with previous diagnosis of hepatocellular carcinoma (HCC) have
been treated with direct antiviral agents (DAAs) for HCV infection.
However there are conflicting data on HCC-recurrence rate after
DAAs therapy. Aim of this study was to prospectively evaluate the
rate of HCC recurrence following sustained virological response
(SVR) by DAAs.
Methods: From April 2015 to September 2016 we consecutively
enrolled HCV-infected patients previously treated for HCC at our
Unit. All patients had a free-disease survival from HCC of at least
6 months before starting DAAs. The efficacy of HCC therapy was
evaluated according to mRecist criteria at CT or MRI, within 30 days
from the start of therapy. All patients underwent DAAs therapy,
selected on an individual basis according to the recommendation
issued by the AISF.
Results: A total of 71 patients were enrolled. Among them, 42
patients had available data on SVR status and were considered for
the analysis. M/F ratio was 21/15. Median age of the patients was
73 years (range: 52–85). Median follow-up was 12 months after the
beginning of treatment (range: 6–18). Genotype distribution was as
follows: 36 patients infected with genotype 1 (85.7%), 5 with geno-
type 2 and 1 patients with genotype 3. SVR was achieved in 38/42
patients (90.5%). HCC recurrence was observed in 11/38 patients
with SVR (28.9%). Median time for recurrence was 9 months from
the start of therapy with a range of 1–13 months. Two patients
showed recurrence during therapy. Among the patients who did
e46 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
not achieve SVR, 1/4 showed HCC recurrence after 10 months from
end of treatment.
Conclusions: Treatment with DAAs are highly effective even in
patients with advanced liver disease. Nonetheless, in patients with
previous history of HCC, the eradication of HCV did not reduce the
risk of short and medium term recurrence.
http://dx.doi.org/10.1016/j.dld.2017.01.094
F-07
Effects of treatment with Maraviroc a CCR5inhibitor on a human hepatic stellate cell line
N. Coppola 1, A. Perna 2, A. Lucariello 2,
S. Martini 1, M. Macera 1, M.A. Carleo 3,
G. Guerra 4, V. Esposito 5, A. De Luca 2
1 Department of Mental Health and Preventive
Medicine, Section of Infectious Diseases, Second
University of Naples, Italy2 Department of Mental Health and Preventive
Medicine, Section of Human Anatomy, Second
University of Naples, Italy3 Department of Infectious Disease and Infectious
Emergencies, Immunodepression and Systemic
Infections Unit, P.O. Cotugno – A.O. Ospedali dei
Colli, Naples, Italy4 Department of Medicine and Health Sciences,
University of Molise, Campobasso, Italy5 Department of Infectious Disease and Infectious
Emergencies, General Infectious Diseases Unit, P.O.
Cotugno – A.O. Ospedali dei Colli, Naples, Italy
Aims: We evaluated the effects of the treatment with the CCR5
inhibitor Maraviroc on LX-2, a human hepatic stellate cell line
(HSC), derived from normal human stellate cells spontaneously
immortalized.
Methods: LX-2 viability was determined using MTT [3-
(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]; the
cells, pretreated with Maraviroc and TGF-�1, have been studied by
Western blot assay to evaluate the expression of cyclin D1, p21, p53,
collagen type I, a-SMA, TGF-b1. The expression of MMP-2, MMP9,
TIMP-1 and TIMP-2 were evaluated by RT-PCRs in correlation to
GADPH expression to standardize differences in the quantity of
cDNA used in the PCR reaction.
Results: Treatment with Maraviroc resulted in a block in S phase
of LX-2 cells with increased expression levels of cyclin D1 and p21
while the expression of p53 was reduced. Treatment with Maravi-
roc was also able to block the accumulation of fibrillar collagens
and extracellular matrix proteins (ECM), as demonstrated by the
decrease of specific markers as Collagen type I, �-SMA and TGF-�1.
In addition we observed a down regulation of both metalloproteins
(MMP-2, MMP-9), used for the degradation of the extracellular
matrix and their inhibitors (TIMP-1, TIMP-2).
Conclusions: The identification of a compound that may mod-
ulate the dynamic of liver fibrosis could be crucial in all chronic
liver diseases. Maraviroc could play an important role because, in
addition to its own anti-HIV activity, it could reduce the release of
pro-inflammatory citokynes implicated in liver fibrogenesis, mak-
ing this drug particularly recommended for antiretroviral regimens
chosen to treat HIV/HCV coinfected patients.
http://dx.doi.org/10.1016/j.dld.2017.01.095
F-08
Child-Pugh score predicts ribavirinoverexposure in cirrhotic patients treated withdirect-acting antiviral agents
V. Guardigni, L. Badia, M. Rinaldi, S. Ianniruberto,
P. Viale, G. Verucchi
Department of Medical and Surgical Sciences,
Research Centre for the Study of Hepatitis, University
of Bologna, Bologna, Italy
New direct-acting antivirals (DAAs) regimens have led to high
rate of HCV eradication even in individuals with cirrhosis. Use of
ribavirin (RBV) in the era of DAAs is still recommended for difficult-
to-treat patients. Role of RBV therapeutic drug monitoring (TDM) in
the age of 2nd generation DAAs has not been elucidated yet and data
on RBV TDM among patients with advanced cirrhosis treated with
RBV and DAAs are lacking. Aim of our retrospective study was to
determine whether RBV levels differ according to cirrhosis stage in
a cohort of subjects with advanced liver disease treated with inter-
feron (IFN)-free DAA-regimens and RBV. We included patients with
HCV and cirrhosis, Child-Pugh (CP) A or B, GFR ≥ 60 ml/min, who
started DAAs and RBV (weight-based dosage) between October
2014 and February 2016 at Outpatient Clinic of Infectious Dis-
eases at University Hospital of Bologna. RBV concentrations were
assessed by high-performance Liquid Chromatography in plasma
collected before next dose of drug (Ctrough). We focused our analysis
on the first 8 weeks. We studied 68 patients: 54 with compen-
sated and 14 with decompensated liver disease (CP score <7 and
≥7, respectively). As shown in Fig. 1, patients with decompen-
sated cirrhosis had significantly higher RBV levels at 1, 2, 4 and
8 weeks, with all p < 0.025. RBV levels were positively correlated
with loss of Hb at week 4 and 8 (with r > +0.27 and p < 0.04). In
71.4% of Child Pugh B patients (vs. 50% in CP A), a reduction of RBV
dosage was necessary during the treatment. At multivariate analy-
sis (adjusted for confounders), only per kg RBV dosage and CP score
remained significantly associated (95%CI 35.6, 286, p = 0.013; 95%CI
35, 348, p = 0.017, respectively) to RBV levels in the first 8 weeks.
Liver failure might affect RBV clearance leading to an overexpo-
sure and increased related toxicities in decompensated cirrhosis.
Our findings underscore the importance of RBV TDM and early dose
adjustments in these patients and suggest that an initial lower dose,
rather than weight-based, of RBV might be preferred in those with
advanced liver disease (CP ≥ 7) treated with new DAAs.
Fig. 1.
http://dx.doi.org/10.1016/j.dld.2017.01.096
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e47
F-09
Serum markers for early diagnosis of HCC inHCV cirrhotic patients with SVR to DAAtreatment
A. Sangiovanni 1, R. D’Ambrosio 1, G. Lunghi 2,
M. Bruccoleri 1, E. Alimenti 1, M. Borghi 1,
R. Perbellini 1, A. Aghemo 1, M. Iavarone 1,
M. Colombo 3, P. Lampertico 1
1 Gastroenterology and Hepatology Unit, Fondazione
IRCCS Ca’ Granda Ospedale Maggiore Policlinico,
University of Milan, Milan, Italy2 Virology Unit, Fondazione IRCCS Ca’ Granda
Ospedale Maggiore Policlinico, University of Milan,
Milan, Italy3 Center for Translational Research Humanitas,
IRCCS Hospital and University, Rozzano, Italy
Introduction: Serum markers for the diagnosis of HCC were
withdrawn from Western Scientific Societies recommendation
because of scanty performance, however there is no data on sensi-
tivity and specificity of tumor markers in HCV patients with SVR to
DAA treatment.
Aim of this study is to define the changes of serum values of AFP,
PIVKA, SCCA-IgM after DAA treatment and to define their diagnostic
performance for the diagnosis of HCC in HCV cirrhotic patients with
SVR.
Material and methods: we enrolled 22 HCC patients and 66
sex and aged matched cirrhotic patients with no history of HCC,
all of them with SVR12 after DAA treatment. AFP (Fujrebio), PIVKA
(Fujrebio), and SCCA IgM Xeptagen) were tested at HCC diagnosis in
HCC patients and at starting DAA and of SVR 12 in cirrhotic patients.
Results: After DAA treatment AFP median value significantly
falls from 16 to 7 ng/ml (p < 0.0001), while PIVKA and SCCA-
IgM remained unchanged (36 vs. 38 mAU/ml, p = 0.96 and 127
vs. 122 U/ml, p = 0.06, respectively). AFP was significantly lower
in cirrhotic patients on SVR12 than in HCC patients (7 vs.
12 ng/ml, p < 0.05), while PIVKA and SCCA-IgM were similar (38 vs.
49 mAU/ml, p 0.61 and 122 and 133 U/ml, respectively). Consider-
ing a cut-off value of 20 ng/ml for AFP, 80 mAU/ml for PIVKA and
156 U/ml for SCCA-IgM, sensitivity of AFP, PIVKA and SCCA-IgM
after DAA treatment were 37%, 41%, 45%, respectively, specificity
98%, 86%, 56%, respectively, PPV 0.86, 0.5 and 0.4, NPV 0.80, 0.81
and 0.69, diagnostic accuracy 81%, 68%, 52%, respectively.
Conclusions: AFP, but not PIVKA and SCCA-IgM value signifi-
cantly decreases after DAA treatment. Sensitivity of AFP >20 ng/ml
for HCC diagnosis in cirrhotic patients was nearly absolute after
DAA treatment.
http://dx.doi.org/10.1016/j.dld.2017.01.097
F-10
Eradication of HCV in patients awaiting livertransplantation does not increase drop-out dueto HCC progression
S. Shalaby 1, A. Zanetto 1, A. Vitale 2, A. Ferrarese 1,
I. Bortoluzzi 1, M. Gambato 1, M. Senzolo 1,
G. Germani 1, C. Mescoli 3, A. Romano 4,
E. Gringeri 2, G. Zanus 2, P. Angeli 4, U. Cillo 2,
P. Burra 1, F.P. Russo 1
1 Multivisceral Transplant Unit, Department of
Surgery, Oncology and Gastroenterology, Padua
University Hospital, Padua, Italy2 Hepatobiliary Surgery and Liver Transplantation
Unit, Department of Surgery, Oncology and
Gastroenterology, Padua University Hospital, Padua,
Italy3 Surgical Pathology & Cytopathology Unit,
Department of Medicine, Padua University Hospital,
Padua, Italy4 Unit of Internal Medicine and Hepatology,
Department of Medicine, Padua University Hospital,
Padua, Italy
Introduction: The loss of intrahepatic immune surveillance, due
to viral eradication with Direct Antiviral Agents (DAAs), may be
associated with increased recurrence of HCC in HCV patients who
previously achieved complete response. Data on the impact that
this may have in terms of drop-out in HCV-HCC patients awaiting
liver transplantation (LT), are lacking.
Materials and methods: All HCV-HCC patients listed for LT
between 01/2015–05/2016, and successfully treated with DAAs
achieving SVR, were retrospectively evaluated (cases). For each
patient clinical, serological, virological data and HCC characteris-
tics were taken into account. A group of untreated patients listed
for HCV-related cirrhosis and HCC, with similar HCC-characteristics
were also enrolled (controls).
Results: Forty-nine patients were enrolled (23 cases/26 con-
trols); HCC characteristics at time of LT-listing were comparable
between the 2 groups: median HCC nodules number was 2 (range
0–4) in cases group vs. 2 (range 0–6) in controls (p = NS); median
nodules total diameter was 22 mm (range 0–65) in cases group vs.
22 mm (range 0–53) in controls (p = NS). Median follow-up was 7
months (range 4–19) in cases group vs. 5 months (range 3–19) in
controls group, during which 2/23 (8.7%) and 1/26 (3.8%) drop-out
events due to HCC-progression between cases and controls were
respectively registered (p = NS). Comparing radiologic images at
the beginning and end of FU, no significant differences in terms
of radiologic-progression were highlighted (p = NS).
8/23 (35%) patients treated with DAAs and 13/26 (50%) controls
underwent LT, and histopathological analysis of HCC performed on
explanted liver showed no differences in terms of median num-
ber of HCC nodules [5 (range 1–14) vs. 3 (range 0–14), p = NS] and
median maximum diameter [26 mm (range 10–65 mm) vs. 28 mm
(range 0–80 mm), p = NS], tumor differentiation [G3-HCC% 13% vs.
15%, p = NS] or microvascular invasion [cases% 38% vs. 23%, p = NS].
During post-LT FU 1/8 DAAs treated patient (11%) and 1/12 control
(8.3%) experienced HCC-recurrence (p = NS).
Conclusions: Viral eradication does not seem to be associated
with increased risk of drop-out due to neoplastic disease-
progression in HCV-HCC patients awaiting LT. Therefore, DAAs
treatment can be safely offered to this patient population.
http://dx.doi.org/10.1016/j.dld.2017.01.098
e48 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
F-11
FAK depletion/inhibition reduces theexpression of liver cancer stem cells markers
I. Romito 1, D. Gnani 1, S. Artuso 2, C. De Stefanis 1,
N. Panera 1, A. Crudele 1, C. Balsano 3,
E. Carcarino 4, V. Nobili 5, R. Rota 4, C. Leonetti 2,
A. Alisi 1
1 Liver Research Unit, Bambino Gesù Children’s
Hospital, IRCCS, Rome, Italy2 Experimental Preclinical Laboratory, Regina Elena
National Institute, Rome, Italy3 Institute of Molecular Biology and Pathology,
National Research Council, Rome, Italy4 Department of Oncohematology, Bambino Gesù
Children’s Hospital, IRCCS, Rome, Italy5 Hepato-Metabolic Disease Unit, Bambino Gesù
Children’s Hospital, IRCCS, Rome, Italy
Introduction: Hepatocarcinoma (HCC) is one of the most com-
mon human cancers. New insights into HCC pathogenesis have
demonstrated that there are two theories concerning the mecha-
nism of hepacarcinogenesis: (i) a stochastic model, which includes
all genetic and epigenetic changes transforming mature hepato-
cytes in tumour cells; and (ii) a hierarchical model, which is based
on cancer stem cell (CSCs) hypothesis. We recently found that the
knockdown of focal adhesion kinase (FAK), may reduce in vitro and
in vivo HCC growth.
Aim: In this study, we pointed to investigate how FAK deple-
tion/inhibition may reduce HCC growth and if these mechanisms
may involve CSCs.
Materials and methods: FAK depletion was performed by trans-
duction with shRNA lentiviral particles in HCC cells. While FAK
inhibition was obtained by a chemical drug (FAKi). PTK2 plasmid
was used to over-express FAK. Cell cycle and apoptosis were inves-
tigated by cytofluorimetry. mRNA and protein expression were
evaluated by Real-time PCR and western blotting.
Results: We found that FAK depletion/inhibition was able to
reduce in vitro HCC by inducing cell cycle arrest into G2/M, and
consequent apoptosis. The main role of FAK on these effects was
confirmed by the rescue of protein expression after transfection of
the PTK2 plasmid, which is able to revert G2/M phase arrest and
apoptosis in FAK-depleted HCC cells. Furthermore, we found that
FAK-mediated apoptosis may occur in p53 wild type HCC cells or in
a p53-mutant HCC cells, and in both cases p21 was up-regulated.
Finally, these events occur in parallel with alteration of genes
related to CSC features, such as Nanog, Oct-4 and Gankyrin that
were significantly down-regulated by FAK depletion/inhibition.
Conclusions: In summary, our results suggest that FAK deple-
tion/inhibition by pharmacological approaches might reduce
tumour mass and local tumor progression by altering the home-
ostasis of both HCC cells and liver CSCs.
http://dx.doi.org/10.1016/j.dld.2017.01.099
F-12
In HCV infected patients with cirrhosisSquamous Cell Carcinoma Antigen (SCCA)-IgMlevels may contribute to identify the individualrisk of HCC development after antiviral therapy
G. Ricco 1, D. Cavallone 1, P. Pontisso 2,
G. Fassina 3, A. Gallotta 3, P. Colombatto 1,
F. Oliveri 1, V. Romagnoli 1, B. Coco 1, A. Salvati 1,
F. Bonino 4, M.R. Brunetto 1,5
1 Hepatology Unit and Laboratory of Molecular
Genetics and Pathology of Hepatitis Viruses,
Reference Center of the Tuscany Region for Chronic
Liver Disease and Cancer, University Hospital of Pisa,
Pisa, Italy2 Department of Medicine, University of Padua,
Padua, Italy3 Xeptagen S.p.A., VEGA Science Park, Marghera,
Venice, Italy4 UPMC Institute for Health, Chianciano Terme,
Siena, Italy5 Department of Clinical and Experimental Medicine,
University of Pisa, Pisa, Italy
Introduction: In HCV-infected patients with cirrhosis the risk of
hepatocellular carcinoma (HCC) persists even after Direct-Acting-
Antivirals-(DAAs)-induced HCV clearance. Therefore, biomarkers
of the residual HCC risk are still an unmet need. Serum levels
of squamous-cell-carcinoma antigen-immunoglobulin-M (SCCA-
IgM) were associated with higher risk of HCC development.
Aim: To retrospectively evaluate the kinetics of SCCA-IgM dur-
ing DAAs in HCV-infected patients with cirrhosis with and without
subsequent HCC development.
Methods: Among 572 HCV pts with cirrhosis DAAs-treated
according to Italian Drug Agency (AIFA) from February 2015 to
August 2016 at the Hepatology-Unit of Pisa University-Hospital we
enrolled all 20 HCC cases (de novo/recurrence), 24 pts previously
treated for HCC and 41 without HCC. SCCA-IgM serum-levels were
measured at therapy-start (BL), after 12 and 24 weeks by ELISA
(Hepa-IC, Xeptagen S.p.A., Venice, Italy). All pts completed DAAs
treatment, 2 experienced a relapse.
Results: Overall, 9 (10.6%) and 11 (13.0%) patients were diag-
nosed with recurrent or newly-developed HCC, after a median of
24.9 (4.7–65.7) weeks from the end-of-therapy. The remaining 24
(28.2%) and 41 (48.2%) patients, with and without history of HCC,
remained HCC-free during a comparable follow-up.
Fig. 1.
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e49
Median SCCA-IgM values were not significantly different
between the four groups at baseline, week-12 and 24 (p = 0.300,
p = 0.448 and p = 0.378, respectively) after therapy-start. On-
therapy median SCCA-IgM-levels decreased similarly in all groups.
None of the patients with BL-SCCA-IgM values <100 AU/mL (8/85,
9.1%) developed HCC. A Receiver-Operating-Characteristics-(ROC)
analysis showed that the diagnostic performances of SCCA-IgM
levels in discriminating pts with or without HCC development,
improved significantly in pts with lower HCV-RNA (Fig. 1) reaching
the highest diagnostic accuracy (100% Sensitivity/Specificity) for a
viremia below 500,000 UI/mL.
Conclusions: SCCA-IgM serum levels alone or in combination
with BL HCV-RNA could contribute to better define the individual
risk of HCC development in the first 18 months after DAAs-
treatment in HCV-infected patients with cirrhosis. Our findings
prompt further investigation in larger cohorts.
http://dx.doi.org/10.1016/j.dld.2017.01.100
F-13
Validation of Liver Imaging Reporting and DataSystem (LI-RADS) Version 2014
A. Pecorelli 1, R. Nani 1, F. Sala 1, D. Pinelli 2,
M. De Giorgio 2, G. Magini 2, M. Colledan 2,
S. Fagiuoli 2, S. Sironi 1
1 Department of Radiology, Università degli studi
Milano-Bicocca, ASST Papa Giovanni XIII, Bergamo,
Italy2 ASST Papa Giovanni XXIII, Bergamo, Italy
Introduction: Liver Imaging Reporting and Data System (LI-
RADS) attempts to standardize the interpretation of liver lesions
detected at computed tomography (CT) and magnetic resonance
(MR) in cirrhotic patients on surveillance for hepatocellular carci-
noma (HCC), stratifying them on the probability of HCC (categories
LR3, LR4 and LR5 as intermediate probability, probably and defi-
nitely HCC, respectively).
Aim: This study aims to assess the diagnostic accuracy of LI-
RADS categories.
Materials and methods: We retrospectively reviewed CT and
MR images of 47 patients consecutively submitted to liver resection
or transplantation for HCC from January 2015 to June 2016. Liver
lesions were classified according to LI-RADS (LR3 = 21, LR4 = 26,
LR5 = 27). Sixteen lesions belonged to categories LRT that refers
to HCC treated with loco-regional approaches. Reference standard
was histological sample. Diagnostic accuracy was assessed with
receiver operating curve analysis and defined by area under the
curve and 95% confidence interval. Continuous values are expressed
as mean and standard deviation, categorical variables as number
and percentage.
Results: CT or MRI were performed 1.7 ± 1.2 months before sur-
gical procedure.
Ninety liver lesions (diameter 22.8 ± 19.2 mm) were detected at
imaging: 66 were histologically proven HCC and 24 were negative.
HCC was confirmed in: 11/21 (52.4) lesions classified as LR3,
21/26 (80.8) classified as LR4 and 26/27 (96.3) classified as LR5.
HCC was also confirmed in 8/16 (50.0) LRT lesions, despite no signs
of recurrence at imaging.
After removing LRT observations the overall diagnostic accu-
racy of each LI-RADS category was: LR3 = 0.274 (0.121–0.426),
LR4 = 0.525 (0.366–0.684), LR5 = 0.693 (0.564–0.822).
Sensibility, specificity, positive predictive value (PPV) and
negative predictive value (NPV) progressively increased across
categories: LR3 (17.2%, 37.5%, 52.4%, 11.3%), LR4 (36.2%, 68.7%,
80.8%, 22.9%), LR5 (44.8%, 93.7%, 96.3%, 31.9%).
Conclusions: In cirrhotic patients a liver lesion categorized as
LR5 can be confidently diagnosed as HCC. However, the low sen-
sibility implies that a relevant number of neoplastic nodules are
eventually missed. Moreover, a high proportion of HCC are still
detected among LR3 categories.
These findings highlight the need of further refinements of
imaging features emerging from LI-RADS.
http://dx.doi.org/10.1016/j.dld.2017.01.101
F-14
Multiclass HCV resistance to interferon-freedirect acting antivirals regimens in real lifefailures advocates for tailored second-linetherapies
V.C. Di Maio 1, V. Cento 1, I. Lenci 2, M. Aragri 1,
S. Barbaliscia 1, S. Francioso 2, S. Paolucci 3,
M. Melis 4, G. Verucchi 5, C. Masetti 2,
N. Coppola 6, C.F. Magni 7, V. Micheli 8,
T. Pollicino 9, T. Ruggiero 10, S. Landonio 7,
A. Mancon 8, M. Starace 6, F. De Leonardis 2,
F. Santopaolo 2, A. Bertoli 1, F.P. Antonucci 1,
C. D’Ambrosio 11, V. Calvaruso 12, M.C. Sorbo 1,
F. Morisco 13, C. Pasquazzi 14, I. Maida 4,
A. Picciotto 15, A. Di Biagio 16, B. Bruzzone 17,
L. Sticchi 17, V. Ghisetti 10, R. Cozzolongo 18,
D. Romagnoli 19, V. Boccaccio 20, A. Grieco 21,
J. Vecchiet 22, G. D’Ettorre 23, M. Merli 24,
G.B. Gaeta 6, A. Ciancio 25, L. Marinaro 10,
E. Polilli 26, P. Cacciatore 26, P. Andreone 27,
G. Barbarini 28, R. Gulminetti 29, S. Novati 29,
V. Pace Palitti 30, P. Tarquini 31, M. Puoti 32,
V. Sangiovanni 33, G. De Stefano 33, A. Giorgini 34,
M. Paoloni 35, N. Caporaso 13, S. Babudieri 4,
G. Gubertini 7, S. Bruno 20, M. Andreoni 36,
A. Pellicelli 11, G. Parruti 26, G. Raimondo 9,
F. Baldanti 3, G. Rizzardini 7, A. Craxì 12,
M. Angelico 2, C.F. Perno 1,
F. Ceccherini-Silberstein 1, on behalf of HCV
Virology Italian Resistance Network Group
(Vironet C)
1 Department of Experimental Medicine and Surgery,
University of Rome Tor Vergata, Rome, Italy2 Hepatology Unit, University Hospital of Rome Tor
Vergata, Rome, Italy3 Virologia Molecolare, Fondazione IRCCS Policlinico
San Matteo, Pavia, Italy4 Infectious Diseases Unit, University of Sassari,
Sassari, Italy5 Policlinico S. Orsola-Malpighi, Bologna, Italy6 Infectious Diseases and Viral Hepatitis Unit, Second
University of Naples, Naples, Italy7 Division of Infectious Disease, ASST Fatebenefratelli
Sacco, Milan, Italy8 Clinical Microbiology, Virology and Bioemergencies,
ASST Fatebenefratelli Sacco, Milan, Italy9 Department of Internal Medicine, University
Hospital of Messina, Messina, Italy10 Unit of Infectious Diseases, Laboratory of
Microbiology and Virology, “Amedeo di Savoia”
Hospital, Turin, Italy
e50 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
11 Hepatology Unit, San Camillo Forlanini Hospital,
Rome, Italy12 Gastroenterology, “P. Giaccone” University
Hospital, Palermo, Italy13 Department of Clinical Medicine and Surgery,
University “Federico II” of Naples, Naples, Italy14 Infectious Diseases, Sant’Andrea Hospital – “La
Sapienza” University, Rome, Italy15 Division of Hepatology, IRCCS San Martino, IST
Genova, Genoa, Italy16 Infectious Disease, IRCCS AOU San Martino – IST,
Genova, Italy17 Hygiene Unit, IRCCS AOU San Martino-IST, Genoa,
Italy18 Department of Gastroenterology, Scientific
Institute for Digestive Disease “Saverio de Bellis”
Hospital, Castellana Grotte, Bari, Italy19 Department of Biomedical, Metabolic and Neural
Sciences, University of Modena and Reggio Emilia,
Modena, Italy20 Internal Medicine, Humanitas University,
Rozzano, Milan, Italy21 Liver Transplant Unit, Catholic University of Rome,
Rome, Italy22 Infectious Disease Clinic, Hospital of Chieti, Chieti,
Italy23 Department of Public Health and Infectious
Diseases, “La Sapienza” University of Rome, Rome,
Italy24 Gastroenterology, “La Sapienza” University of
Rome, Rome, Italy25 Unit of Gastroenterology, University of Turin,
Department of Medical Sciences, Città della Salute e
della Scienza di Torino Molinette Hospital, Turin,
Italy26 Infectious Disease Unit, Pescara General Hospital,
Pescara, Italy27 Department of Medical and Surgical Sciences,
University of Bologna, Bologna, Italy28 Division of Infectious and Tropical Diseases,
Fondazione IRCCS Policlinico San Matteo, Pavia, Italy29 Institute of Infectious Diseases, University of
Pavia, Pavia, Italy30 Hepatology Unit, Pescara General Hospital,
Pescara, Italy31 Infectious Disease, Hospital “G. Mazzini”, Teramo,
Italy32 Department of Infectious Diseases, Hospital
Niguarda Ca’ Granda, Milan, Italy33 Hospital Cotugno, Naples, Italy34 General Medicin Unit, SST Santi Paolo e Carlo,
Milan, Italy35 Infectious Disease Unit, Avezzano General
Hospital, Avezzano, Italy36 Infectious Diseases, University Hospital of Rome
Tor Vergata, Rome, Italy
Background: This study aims to characterize resistance-
associated-substitutions (RAS) in a large cohort of HCV patients
who failed an Interferon-free Direct-Acting-Antivirals (DAA)
containing-regimen.
Methods: Among 325 patients failing a DAA Interferon-free-
regimen, 261 (GT1a-1b-2c-3a/h-4a/d/n/r = 57-91-12-64-37; 79.4%
cirrhotic; 70.6% treatment-experienced, 16 with DAA), with avail-
able Sanger-sequencing test at failure were analyzed.
Results: The majority of patients experienced a relapse
(84.5%) and 59.0% failed a recommended-regimen according
to 2015 guidelines: simeprevir + sofosbuvir ± ribavirin (N = 58),
daclatasvir/ledipasvir + sofosbuvir ± ribavirin (N = 23/39), 3D/2D
(paritaprevir/ombitasvir ± dasabuvir) ± ribavirin (N = 23), sofosbu-
vir + ribavirin (GT2, N = 11). Interestingly, 4.2% of failures had
a misclassified genotype. Overall, 59.0% of patients showed
at least one RAS related to the DAA-failure; RASs prevalence
was higher in breakthrough/non responders than in relapsers
(92.3% vs. 50.9%, p < 0.001) and in patients with unfavorable
IL28 CT/TT vs. patients with IL28 CC (57.7% vs. 12.5%, p = 0.024).
RASs prevalence varied according to the DAA-class used (92.4%
NS5A-RASs [N = 105], 72.3% NS3-RASs [N = 101], 34.5% dasabuvir-
RASs [N = 29]), 20.6% sofosbuvir-RASs [N = 218]) and according
to HCV-GT. In NS5A-failing patients, Y93H was the most fre-
quent NS5A-RAS (61.9%), though with different prevalence among
genotypes (15.4% GT1a; 90.0% GT1b; 82.6% GT3a; 40.0% GT4).
Furthermore, 40.0% of patients presented ≥2 NS5A-RASs, with
complex patterns more frequently in GT1b failures (67.5%, e.g.
Y93H + L31M/I).
Failures to sofosbuvir-regimens showed frequent presence of
L159F ± C316N (14.7%), particularly in GT1b (37.3%), followed by
S282T in 3.6%. Notably, 42.9% of patients treated with ≥2 DAA
classes showed multiclass-resistance. Overall, 6.1% of patients
showed RASs in all 3 targets and 13.0% of patients showed also
extra-target-RASs, probably due to natural resistance. Finally, 11
patients, all cirrhotic, experienced at least 2 subsequent virologic-
failures to interferon-free DAA-regimens.
Conclusions: In this real life setting, RASs prevalence at failure
was remarkably high in all genes tested (with a partial exception
for NS5B). This multiclass-resistance advocates for HCV resistance-
testing at failure in all 3 genes for the best second-line therapeutic
tailoring.
http://dx.doi.org/10.1016/j.dld.2017.01.102
F-15
Liver stiffness and portal hypertension predictfailure to DAA treatment in a real-life cohort ofHCV-infected patients treated withrecommended regimens
C. Masetti, F. De Leonardis, P. Rossi, A. Bosa,
D. Di Paolo, M. Milana, F. Santopaolo, A. Pecchioli,
S. Di Nardi, S. Francioso, I. Lenci, L. Baiocchi,
A. Brega, T. Marianelli, F. Antenucci, M. Angelico
Liver and Transplant Unit, Policlinico Tor Vergata,
Rome, Italy
Interferon-free regimens have dramatically improved HCV
treatment. Unfortunately, a few patients fail to reach a sustained
virological response even with direct-acting antiviral agents (DAA).
Little is known about risk factors associated with treatment failure.
Among 369 HCV-infected patients who started an optimal
(according to 2016 EASL guidelines) DAA treatment, we included
253 with at least a 12-week follow up after treatment completion.
The cohort included mainly males (n = 154, 60.8%), with cirrhosis
(n = 168, 66.4%), of whom 25.6% (47/183) showed clinically signif-
icant portal hypertension, as evidenced by presence of esophageal
varices. Most patients (n = 152, 60.1%) were infected with geno-
type 1, 51 (20.1%) with genotype 2, 30 (11.8%) and 20 (8%) with
genotype 3 and 4, respectively. Patients underwent treatment with
sofosbuvir (n = 50, 20.1%), sofosbuvir/simeprevir (n = 34, 13.3%),
sofosbuvir/daclatasvir (n = 26, 10.3%), sofosbuvir/ledipasvir (n = 80,
31.5%), ombitasvir/paritaprevir/ritonavir with (n = 56, 22.1%) or
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e51
without (n = 7, 2.7%) dasabuvir. Data were processed by intention-
to-treat (ITT) with univariate and multivariate analyses.
The population included 229 patients who achieved SVR-12
(90.5%) and 24 (9.5%) who failed for any reason: virological relapse
(n = 9), death (n = 10) or drop-out (n = 5). At univariate analysis, cir-
rhosis (p = 0.005), presence of medium/large esophageal varices
(p = 0.0001), a higher liver stiffness (p = 0.00007), previous HCC
(p = 0.002), diabetes (p = 0.006), viral genotype 2 (p = 0.02), low
platelet count (p = 0.02), low total cholesterol level (p = 0.001), INR
prolongation (p = 0.02) and a higher MELD score (p = 0.000001)
were all significantly associated with treatment failure. Failure
was unrelated to HCV viral load (p = 0.16) and treatment sched-
ule (p = 0.25). At stepwise multivariable logistic regression, only
liver stiffness and the presence of medium or large esophageal
varices were associated with treatment failure (p = 0.02, p = 0.02 and
p = 0.01 respectively), with an area under ROC curve of 0.93.
In a real-life setting, around 10% of HCV-infected patients fails
after DAA treatment. Failure is strongly associated with high liver
stiffness and clinically significant portal hypertension.
http://dx.doi.org/10.1016/j.dld.2017.01.103
F-16
Laparoscopic ablation for HCC: proposal of a6-months mortality score for patient selectionbased on more than 1000 procedures
A. Bertacco 1, A. Marchini 1, A. Vitale 1, C. Ungaro 1,
F. D’Amico 1, E. Gringeri 1, D. Neri 1, D. Bassi 1,
G. Zanus 1, R. Carandina 2, C. Aliberti 2, U. Cillo 1
1 Department of Surgery, Oncology and
Gastroenterology, Hepatobiliary Surgery and Liver
Transplantation, Padua University, Padua, Italy2 Oncology Radiodiagnostics, Oncology Institute of
Veneto, Institute for the Research and Treatment of
Cancer (IRCCS), Padua University, Padua, Italy
Background: Trans-arterial-chemoembolization is the only
therapeutic option for patients unsuitable for liver resection or
percutaneous ablation according to international guidelines. The
aim of our study was to evaluate safety and efficacy of video-
laparoscopic (VLS) ablation as a therapeutic option for these HCC
patients and to define an early mortality predictor score to help
clinicians in patient selection.
Methods: We collected patients with HCC who were unsuitable
for liver resection and/or percutaneous ablation and who under-
went VLS ablation (microwave, or radiofrequency) in the period
2004–2015. Early mortality (6-months) was the primary endpoint;
perioperative morbidity and long term survival were secondary
endpoints.
Results: 1091 procedures in 903 patients (median age, 64 years)
were performed following a liberal selection policy (child B-C
35%; BCLC B-C-D 38%). We had not perioperative mortality but
6-months mortality was 10.5%. The overall morbidity was 33.6%
with a median length of hospital stay of 2 days. Independent pre-
dictors of 6-months mortality resulted both variables related to
liver function (Child Pugh, Portal Hypertension, ascites, sodium,
performance status) and to tumor aggressiveness (Milan criteria,
alpha-fetoprotein). A simple user-friendly score based on these 7
variables (score from 0 to 7) performed as an accurate predictor
of 6-months mortality (area under ROC curve = 0.78). A cut-off of 4
proved to be a good tool for patient selection (6 months mortality
<10%) and for identifying patients with optimal long-term survival
(median survival 53 vs. 14 months, p < .0001)
Conclusions: VLS ablation seems to be a safe and effective
treatment in patients who are ineligible for liver resection and/or
percutaneous ablation. We proposed a simple score to help clini-
cians in selecting patients for this procedure to obtain a curative
long term survival profile.
http://dx.doi.org/10.1016/j.dld.2017.01.104
F-17
Treatment with direct-acting antiviral agents isassociated with improvement of renal functionin a cohort of HCV-infected patients withchronic kidney disease
C. Masetti, F. De Leonardis, P. Rossi, A. Bosa,
D. Di Paolo, M. Milana, F. Santopaolo, A. Pecchioli,
S. Di Nardi, S. Francioso, I. Lenci, L. Baiocchi,
A. Brega, F. Antenucci, T. Marianelli, M. Angelico
Liver and Transplant Unit, Policlinico Tor Vergata,
Rome, Italy
HCV is recognized as an independent risk factor for chronic kid-
ney injury. DAAs use has been approved in HCV-infected patients
with renal impairment, but little is known about their effect on
renal function.
Study includes 42 HCV-infected patients with eGFR (MDRD-4)
levels below 60 ml/min (38 in stage III, 2 in stage IV and 2 in stage
V according to KDIGO guidelines) treated with DAAs. Population
includes mainly males (24, 57.1%) cirrhotics (32, 76.2%). Twelve
(28.5%) patients had clinical portal hypertension, 10 (23.8%) had
diabetes and 11 (26.1%) had detectable cryoglobulines. Genotype
1 infection was present in 27 (64.3%), genotype 2 and 3 in 13
(31%) and 2 (4.7%) patients respectively. Thirty-six patients (85.7%)
received a sofosbuvir-containing regimen (in 18 as monother-
apy and in 18 in combination), while the other 6 patients had
ombitasvir/paritaprevir/ritonavir plus dasabuvir.
Paired T-test analysis was used to detect any modification in
eGFR and creatinine levels at baseline and at the end-of-treatment
(EOT).
HCV RNA was undetectable at EOT in all patients. No adverse
events were observed. The majority (74.3%) of patients showed
improvement of both creatinine and eGFR. Mean creatinine level
decreased from 1.4 ± 1.3 mg/dl at baseline to 1.31 ± 1.1 mg/dl at
EOT (p = 0.017) with an increase in eGFR from 50.1 ± 10.7 to
57.1 ± 16.4 ml/min (p = 0.0002). This improvement was significant
even including only cirrhotic patients with an increase in eGFR
from 52.1 ± 7.2 to 60.2 ± 14.9 ml/min (p = 0.00088). Seven patients
(16.6%) experienced a worsening in renal function with a decrease
in eGFR from 51.1 to 45.2 ml/min. All patients had CKD stage III, 5
were cirrhotic (1 in CPT-B) and 6 had sof-based regimens.
DAAs treatment in a HCV-infected population with impaired
renal function is associated with improved eGFR and creatinine.
Treatment is safe also in patients receiving sof-based regimens,
though a slight decrease in eGFR is observed in some.
http://dx.doi.org/10.1016/j.dld.2017.01.105
e52 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
F-18
Natural HCV resistance is common in Italy anddifferently associated to genotypes
M.C. Sorbo 1, V. Cento 1, A. Bertoli 1, I. Lenci 2,
E. Polilli 3, C. Masetti 2, L. Gianserra 4, E. Teti 5,
E. Biliotti 6, C.F. Magni 26, M. Aragri 1, V. Micheli 7,
M. Melis 8, L.A. Nicolini 11, S. Marenco 10,
V. Calvaruso 12, S. Paolucci 13, F. Baldanti 13,
F. Morisco 14, M. Siciliano 15, V. Pace Palitti 16,
P. Andreone 17, B. Bruzzone 18, N. Coppola 19,
T. Ruggiero 27, M. Lichtner 20, B. Menzaghi 21,
D. Romagnoli 22, N. Iapadre 23, V.C. Di Maio 1,
F. De Leonardis 2, M. Milana 2, P. Cacciatore 3,
A. Pieri 3, L. Sarmati 5, S. Landonio 26,
A. Gasbarrini 15, M. Puoti 24, A. Craxì 12, V. Vullo 25,
A. Pellicelli 9, S. Babudieri 8, G. Rizzardini 26,
G. Taliani 6, M. Andreoni 5, C. Pasquazzi 4,
G. Parruti 3, M. Angelico 2, C.F. Perno 1,
F. Ceccherini-Silberstein 1
1 Experimental Medicine and Surgery, University of
Rome “Tor Vergata”, Rome, Italy2 Hepatology Unit, University Hospital of Rome “Tor
Vergata”, Rome, Italy3 Infectious Diseases Unit, Pescara General Hospital,
Pescara, Italy4 Infectious Diseases Unit, Sant’Andrea Hospital –
“Sapienza” University, Rome, Italy5 Infectious Diseases Unit, University Hospital of
Rome “Tor Vergata”, Rome, Italy6 Tropical Diseases, Umberto I Hospital – “Sapienza”
University, Rome, Italy7 Clinical Microbiology, Virology and Bioemergencies,
ASST Fatebenefratelli Sacco, Milan, Italy8 Clinical and Experimental Medicine, University of
Sassari, Sassari, Italy9 Hepatology Unit, San Camillo Forlanini Hospital,
Rome, Italy10 Division of Hepatology, IRCCSAOU San
Martino-IST, Genoa, Italy11 Infectious Diseases Unit, IRCCSAOU San
Martino-IST, Genoa, Italy12 Gastroenterology,“P.Giaccone” University
Hospital, Palermo, Italy13 Molecular Virology, Fondazione IRCCS Policlinico
San Matteo, Pavia, Italy14 Gastroenterology, “Federico II” University, Naples,
Italy15 Gastroenterology, Catholic University of Rome,
Rome, Italy16 Hepatology Unit, Pescara General Hospital,
Pescara, Italy17 Medicine and Surgery, University of Bologna,
Bologna, Italy18 Hygiene Unit, IRCCSAOU San Martino-IST, Genoa,
Italy19 Infectious Diseases Unit, Second University of
Naples, Naples, Italy20 Infectious Diseases Unit, “Sapienza” University,
Latina, Italy21 Infectious Diseases Unit, Ospedale di circolo di
Busto Arsizio, Varese, Italy22 Department of Biomedical, Metabolic and Neural
Sciences, NOCSAE Baggiovara, Baggiovara, Italy
23 Infectious Diseases Unit, S. Salvatore Hospital,
L’Aquila, Italy24 Hospital Niguarda Ca’ Granda, Milan, Italy25 Infectious Diseases Unit, Umberto I Hospital –
“Sapienza” University, Rome, Italy26 1st Division of Infectious Diseases, ASST
Fatebenefratelli Sacco, Milan, Italy27 Unit of Infectious Diseases, Laboratory of
Microbiology and Virology, “Amedeo di Savoia”
Hospital, Turin, Italy
Introduction: Natural resistance associated substitutions
(RASs) are highly variable prevalent across different HCV genotypes
(GTs) and countries. We investigated natural RASs frequency, and
NS5A-RASs impact on treatment efficacy, in a large Italian real-life
database including the 4 main HCV-GTs.
Methods: RASs in NS3/NS5A/NS5B (N = 1032/833/496) were
analysed in 1193 HCV-infected DAA-naïve patients (pts; 68%
treatment-experienced; 55% cirrhotic; 5% HIV co-infected). Sanger-
sequencing was performed by home-made protocols on 714 GT1a,
989 GT1b, 135 GT2c, 333 GT3a, 190 GT4a/d samples. RASs with
fold-change >100 were defined as major.
Results: Overall, 415/1193 (35%) pts showed natural RASs, inde-
pendently by cirrhosis, with important GT/subtypes differences.
GT1a/1b/4a frequently showed NS3-RASs (52-20-36%, respec-
tively), with major-RAS 80K (17%) in GT1a and 168A/E/T/V in
GT2c/4d (3–4%). Also in NS5A, GT1a/1b/4a showed the high-
est RASs prevalence (10-31-38%, respectively), higher in IFN/RBV
experienced-patients (35%) vs. IFN-naive (22%, p = 0.02) only in
GT1b. Major NS5A-RASs were detected in 10% GT1a (28V-30H/R-
31M-93C/H), 9% GT1b (30R-93H), 5% GT2c (31M-93H), 4% GT3a
(93H) and 2% GT4d (30S). In NS5B, the 159F and 316N sofosbu-
vir putative-RASs were exclusively detected in GT1b (13% and 19%)
often associated (phy-correlation = 0.67, p < 0.001). Among 372 pts
with NS3/NS5A/NS5B resistance-test, 10% showed multiple RASs,
mainly NS3 + NS5A RASs (mainly in GT1-4); 2 GT1b pts showed
RASs on 3 drug-targets.
Lastly, natural RASs impact was evaluated in 138 pts treated
with NS5A-inhibitors. 4/26 non-cirrhotic pts with minor-baseline
NS5A-RASs (GT1b: 30Q, 31M, 58S, 92T) reached a sustained viral
response (SVR). 4/112 cirrhotic pts, showed major-baseline NS5A-
RASs: 2 pts (GT1b: 93H; GT4d: 30S) treated with not-recommended
regimens, experienced virologic failure; 2 (GT1b: 93H; GT1a: 30R)
received a recommended-regimen with RBV, reached SVR.
Conclusions: Natural RASs are common across all HCV-GTs in
Italy. Up to 10% of pts show multi-class RASs, though only the major
mutations seem clinical relevant. Therefore, qualitative identifica-
tion of only major-RASs is required to properly guide DAA-based
therapy.
http://dx.doi.org/10.1016/j.dld.2017.01.106
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e53
F-19
HCV resistance test guided retreatments afterprotease inhibitors failures can induce maximalefficacy rate in real-life
V. Cento 1, S. Barbaliscia 1, I. Lenci 2, T. Ruggiero 3,
C. Masetti 2, C.F. Magni 4, V. Micheli 5,
S. Paolucci 6, Y. Troshina 7, E. Biliotti 8, M. Milana 2,
M. Melis 9, E. Teti 10, L. Lambiase 11,
B. Menzaghi 12, L.A. Nicolini 13, S. Marenco 14,
V.C. Di Maio 1, M. Aragri 1, A. Pecchioli 2,
A. Bertoli 1, F.P. Antonucci 1, L. Sarmati 10,
C. Sarrecchia 10, M. Macera 15, N. Coppola 15,
E. Danieli 16, D. Romagnoli 17, A. Pellicelli 18,
S. Bonora 3, S. Babudieri 9, A. Di Biagio 13,
A. Picciotto 14, S. Novati 6, M. Siciliano 19,
V. Messina 20, E. Claar 21, F. Baldanti 6,
C. Pasquazzi 11, A. Ciancio 7, M. Puoti 16,
V. Ghisetti 3, M. Andreoni 10, G. Taliani 8,
G. Rizzardini 4, M. Angelico 2, C.F. Perno 1,
F. Ceccherini-Silberstein 1
1 Department of Experimental Medicine and Surgery,
University of Rome Tor Vergata, Rome, Italy2 Hepatology Unit, University Hospital of Rome Tor
Vergata, Rome, Italy3 Infectious Diseases, “Amedeo di Savoia” Hospital,
Turin, Italy4 1st Division of Infectious Diseases, ASST
Fatebenefratelli Sacco, Milan Italy5 Clinical Microbiology, Virology and Bioemergencies,
ASST Fatebenefratelli Sacco, Milan Italy6 Molecular Virology, Policlinic Foundation San
Matteo, Pavia, Italy7 Gastroenterology, Department of Medical Sciences,
City of Health and Science of Turin, University of
Turin, Turin, Italy8 Tropical Diseases, Umberto I Hospital – “Sapienza”
University, Rome, Italy9 Infectious Diseases Unit, Department of Clinical and
Experimental Medicine, University of Sassari, Italy10 Infectious Diseases, University Hospital of Rome
Tor Vergata, Rome, Italy11 Infectious Diseases, Sant’Andrea Hospital –
“Sapienza” University, Rome, Italy12 Infectious Diseases, Ospedale di Circolo di Busto
Arsizio, ASST Valleolona, Varese, Italy13 Infectious Diseases, Department of Health Sciences
(DISSAL), University of Genoa-AOU IRCCS San
Martino-IST, Genova, Italy14 Division of Hepatology, University of Genoa-AOU
IRCCS San Martino-IST, Genova, Italy15 Infectious Diseases, Department of Mental and
Physical Health and Preventive Medicine, Second
University of Naples, Naples, Italy16 Infectious Diseases, Hospital Niguarda Ca’ Granda,
Milan, Italy17 Department of Biomedical, Metabolic and Neural
Sciences, NOCSAE Baggiovara, Modena, Italy18 Gastroenterology, San Camillo Hospital, Rome,
Italy19 Gastroenterology, “Cattolica” University of Rome,
Rome, Italy20 Infectious Diseases Unit, AO Caserta, Italy
21 Hepatology, Ospedale Evangelico Villa Betania,
Naples, Italy
Background and aims: We analyzed the efficacy of retreatment
after protease inhibitors (PI) plus pegylated-interferon (pegIFN)
and ribavirin (RBV)-failure with various IFN-free regimens, and the
role of genotypic-resistance-testing (GRT) in real-life settings.
Methods: This is a multi-center observational real-
life study including 121 patients retreated after PI
(telaprevir–boceprevir–simeprevir) plus pegIFN and RBV fail-
ure. Sustained-virological-response (SVR) was evaluated at week
12 of follow-up. GRT was performed by Sanger-based home-made
protocols.
Results: In this setting, 121 patients (cirrhotic = 86.8%) were
retreated after PI-failure following 3 different strategies: (A)
with “GRT-guided” regimens (N = 18); (B) with “AASLD/EASL rec-
ommended, not GRT-guided” regimens (N = 72); (C) with “Not
recommended, not GRT-guided” regimens (N = 31). Overall SVR
rate was 91%, with differences according to strategy choice: all 18
patients treated with “GRT-guided” regimens reached SVR (100%),
despite heterogeneity in treatment-duration, PI-inclusion and RBV
use; 68/72 patients (94.4%) receiving a second-line regimen accord-
ing to guidelines achieved SVR; SVR was strongly reduced (77.4%)
among the 31 patients who received a “not recommended, not
GRT-guided regimen” (p-trend < 0.01).
Overall, 37/121 patients were retreated with a PI (simeprevir,
paritaprevir) and 33/37 (89.2%) achieved SVR. The 4 failing GT-1a
cirrhotic patients (all in option C) used a simeprevir-containing
regimen; 3/4 showed historical R155K NS3-RAS. All 7 patients
treated with a paritaprevir-containing plus RBV regimen reached
SVR, regardless treatment-duration and performance of a baseline-
GRT.
Conclusion: Retreatment after first-generation PI-failure can
induce a maximal SVR rate if guided by GRT in real-life, greater than
SOF + NS5A inhibitors plus RBV for 12/24 weeks, as recommended
by guidelines. PIs can be fruitfully reconsidered if appropriately
chosen after a punctual GRT-based RASs evaluation.
Keywords: HCV-resistance; NS5A-inhibitors; Protease-
inhibitors; HCV-failure
http://dx.doi.org/10.1016/j.dld.2017.01.107
e54 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
F-20
Impact of Acute-on-Chronic Liver Failure (ACLF)on response to treatment with terlipressin andalbumin in patients with type 1 hepatorenalsyndrome
S. Piano 1, H. Schmidt 2, X. Ariza 3, A. Amoros 4,
A. Romano 1, E. Solà 3, A. Gerbes 5, M. Bernardi 6,
C. Alessandria 7, J. Trebicka 8, T. Gustot 9,
F. Nevens 10, V. Arroyo 4, P. Gines 3, P. Angeli 1
1 Unit of Internal Medicine and Hepatology,
University of Padova, Padua, Italy2 Klinik für Transplantationsmedizin,
Universitätsklinikum Münster, Germany3 Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD,
Barcelona, Spain4 EF-CLIF and EASL-CLIF Consortium, Barcelona,
Spain5 Department of Medicine II, University Hospital
LMU Munich, Liver Center Munich, Munich, Germany6 Department of Medical and Surgical Sciences,
University of Bologna, Bologna, Italy7 Division of Gastroenterology and Hepatology, San
Giovanni Battista Hospital, Turin, Italy8 Department of Internal Medicine I, University of
Bonn, Bonn, Germany9 Erasme Hospital, Université Libre de Bruxelles,
Brussels, Belgium10 University Hospital Gasthuisberg, KU Leuven,
Leuven, Belgium
Introduction and aims: Type 1 hepatorenal syndrome (HRS)
is the most life threatening type of renal failure in cirrhosis. Ter-
lipressin and albumin is effective in treating HRS. According to
the EASL-CLIF consortium definition, patients with type-1 HRS
meet ACLF criteria, however, the impact of ACLF grade on the
response to treatment has never been assessed. The aims of our
study were: (a) to evaluate predictors of response to treatment with
terlipressin and albumin in patients with type-1 HRS(reduction
in serum creatinine[sCr] < 1.5 mg/dl); (b) to evaluate predictors of
90-day mortality.
Methods: In this multicenter European study patients with
type-1 HRS treated with terlipressin and albumin were included.
Demographic, clinical and laboratory data were collected before
the initiation of treatment. Patients were followed up until death,
liver transplantation or 90 days.
Results: 298 patients were included. Patients were treated for
a median of 8 days and response was found in 53% of them.
Responders were more likely to have a precipitating event of
HRS (76 vs. 65%; p = 0.037), had lower bilirubin (3.3 vs. 4.8 mg/dl;
p = 0.003), lower INR (1.6 vs. 1.8; p = 0.004) and lower sCr (2.7
vs. 3.2 mg/dl; p < 0.001) than non-responders. Response rate had
a stepwise decrease moving from grade-1 to grade-3 ACLF (60,
48 and 29% for grade 1, grade 2 and grade 3, respectively;
p < 0.001). In multivariate analysis the presence of precipitating
events (OR = 2.08; p = 0.008), baseline sCr (OR = 0.21; p = 0.001) and
ACLF grade (OR = 0.62; p = 0.005) were found to be independent pre-
dictors of response to treatment. During the 90-day follow-up 40%
of patients died. Responders to treatment had a lower transplant-
free mortality rate than non responders (33 vs. 68%; p < 0.001). In
multivariate analysis, age (HR = 1.05; p < 0.001), white blood cell
count (HR = 1.03; p = 0.015), ACLF grade (HR = 2.09; p < 0.001) and
response to treatment (HR = 0.42; p < 0.001) were found to be inde-
pendent predictors of 90-day mortality.
Conclusions: ACLF grade is a main determinant of response to
terlipressin and albumin in patients with type-1 HRS. ACLF grade
affects survival independently from the response to treatment. New
therapeutic strategies should be developed for patients with type-1
HRS and extrarenal organ failures.
http://dx.doi.org/10.1016/j.dld.2017.01.108
F-21
Low viremic HBeAg negative HBsAg carriers:Clinical outcome and non invasive diagnosticaccuracy for chronic hepatitis B or inactiveinfection by combinations of HBV markers
F. Oliveri 1, L. Surace 1, D. Cavallone 1,
P. Colombatto 1, G. Ricco 1, N. Salvati 2, B. Coco 1,
V. Romagnoli 1, R. Gattai 1, A. Salvati 1,
F. Moriconi 1, Q. Yuan 3, F. Bonino 4,
M.R. Brunetto 1,5
1 Hepatology Unit and Laboratory of Molecular
Genetics and Pathology of Hepatitis Viruses,
Reference Centre of the Tuscany Region for Chronic
Liver Disease and Cancer, University Hospital of Pisa,
Pisa, Italy2 Department of Economics and Management,
University of Pisa, Pisa, Italy3 National Institute of Diagnostics and Vaccine
Development in Infectious Diseases, School of Public
Health and School of Life Science, Xiamen University,
Xiamen, China4 University of Pittsburgh Medical Center Institute
for Health, Chianciano Terme, Italy5 Adjunct Professor of Internal Medicine, University
of Pisa, Pisa, Italy
Background and aims: HBeAg negative chronic HBV infection
is associated with a wide spectrum of clinical conditions ranging
from inactive infection (IC) to chronic hepatitis B (CHB), that some-
time mimics IC. A higher diagnostic accuracy in diagnosing the
different phases of HBeAg negative infection would improve the
management of this subset of HBsAg carriers.
Patients and methods: We performed a long-term prospec-
tive single center cohort study in 153 carriers with baseline serum
HBV-DNA ≤20,000 IU/mL and normal transaminases. HBV-DNA,
HBsAg, HBV “core-related” antigen (HBcrAg) and total-anti-HBc
were quantified at baseline (bl) and yearly (HBV-DNA and HBsAg).
Results: After 1-year 3-monthly monitoring, 87 (56.9%) sub-
jects were classified as Inactive-Carriers (IC, ≤2000-IU/mL), 46
(36%) as Low-Viremic-Active-Carriers (LV-AC, ≤20,000-IU/mL) and
20 (13.1%) as chronic-hepatitis-B patients (CHB, >20,000-IU/mL).
IC and LV-AC were followed-up for additional 57.2 (8.5–158.3)
months. CHB was independently associated with higher base-
line HBV-DNA (P = 0.030), total-anti-HBc (P < 0.001) and ALT
(P = 0.001). HBV-reactivation did not occurred in any carrier with bl-
HBsAg ≤ 1000-IU/HBV-DNA ≤ 2000-IU/mL (NPV-100%). Thereafter
none IC reactivated, 19 (21.8%) cleared HBsAg [independently asso-
ciated with older-age (P = 0.004), lower bl-HBsAg (P < 0.001), higher
HBsAg yearly-decline (P < 0.001)]. One LV-AC (2.2%) developed
CHB, 25 (54.3%) remained stable and 20 (43.5%) became IC [inde-
pendently associated with lower bl-HBsAg (P = 0.008)]. The best
single-point CHB diagnostic-accuracy was 84.2% by total-anti-HBc
(98.2%-NPV). The HBV-DNA/total-anti-HBc/HBcrAg combination
identified IC with 89.5% diagnostic-accuracy, 93% sensitivity, 84.8%
specificity (Table 1).
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e55
Table 1Diagnostic performance in identification of carriers with inactive infection.
Single markers Combining 2 markers Combining 3 markers Combining 4
markers
HBV-DNA
≤2000 IU/mL
HBsAg
≤1000 IU/mL
HBcrAg
≤3 Log
Anti-HBc
≤16,937 IU/mL
HBV-DNA
≤2000 IU/mL
and HBsAg
≤1000 IU/mL
HBV-DNA
≤2000 IU/mL
and HBcrAg ≤3
Log
HBV-DNA
≤2000 IU/mL
and Anti-HBc
≤16,937 IU/mL
HBV-DNA
≤2000 IU/mL
and HBsAg
≤1000 IU/mL
and HBcrAg ≤3
Log
HBV-DNA
≤2000 IU/mL
and HBsAg
≤1000 IU/mL
and Anti-HBc
≤16,937 IU/mL
HBV-DNA
≤2000 IU/mL
and HBcrAg ≤3
Log
and Anti-HBc
≤16,937 IU/mL
HBV-DNA
≤2000 IU/mL
and HBsAg
≤1000 IU/mL
and HBcrAg ≤3
Log and Anti-HBc
≤16,937 IU/mL
Sensitivity 100.0% 69.0% 96.5% 95.3% 69.0% 96.5% 95.4% 66.3% 67.8% 93.0% 65.1%
Specificity 60.6% 60.6% 22.7% 54.5% 83.3% 74.2% 74.2% 84.8% 89.4% 84.8% 90.9%
PPV 77.0% 69.8% 61.9% 73.2% 84.5% 83.0% 83.0% 85.1% 89.4% 88.9% 90.3%
NPV 100.0% 59.7% 83.3% 90.0% 67.1% 94.2% 92.5% 65.9% 67.8% 90.3% 66.7%
DA 83.0% 65.4% 64.5% 77.6% 75.2% 86.8% 86.3% 74.3% 77.1% 89.5% 76.3%
Conclusions: HBeAg-negative carriers with viremia persistently
≤20,000 IU/mL show a benign clinical outcome with transition to
IC in almost half of LV-AC and to Occult-HBV-Infection in 20% of
IC within 5 years; however 13.1% of individuals with low viremia
at presentation are CHB patients: 1-year HBV-DNA monitoring
resulted the most accurate diagnostic approach. The single point
HBV-DNA/HBsAg measurement can halve the carriers requiring
12 month monitoring. The best IC diagnostic-accuracy combining
HBV-DNA/total-anti-HBc/HBcrAg needs to be confirmed in further
studies.
http://dx.doi.org/10.1016/j.dld.2017.01.109
F-22
Thromboelastographic evaluation ofhemostatic balance in cirrhotic patients withinfection
E. Nadal 1, P. Simioni 2, L. Spiezia 2, P. Angeli 3,
S. Fasolato 3, A. Zanetto 1, A. Ferrarese 1,
S. Shalaby 1, G. Germani 1, F.P. Russo 1, P. Burra 1,
M. Senzolo 1
1 Multivisceral Transplant Unit, Department of
Surgery, Oncology and Gastroenterology, University
of Padua, Padua, Italy2 Thrombotic and Hemorrhagic Diseases Unit,
Department of Medicine, University of Padua, Padua,
Italy3 Internal Medicine and Hepatology, Department of
Medicine (DIMED), University of Padua, Padua, Italy
Introduction: Bacterial infection is a complication in decom-
pensated cirrhosis representing a precipitating factor for “Acute on
Chronic Liver Failure” and its effect on the hemostatic balance is
poorly understood.
Aim: To assess hemostatic balance during infection.
Materials and methods: 39 cirrhotic patients were analyzed
prospectively, including 23 infected and 16 noninfected patients.
For comparison 23 infected without cirrhosis were included. Each
patient was assessed using haemocoagulative thrombelastome-
try ROTEM test. In addition, 10 cirrhotic patients were studied
before and after the infection passed using impedance aggregom-
etry (Multiplate®
).
Results: When compared cirrhotics, patients with infection
reported a more hypocoagulable state and hyperfibrinolysis than
those without (CT EXTEM media ± SD: 78 ± 33 s vs. 57 ± 27,
p = 0.002; ML EXTEM media ± SD: 2.26 ± 1.6% vs. 1.00 ± 0.2%,
p = 0.031). These coagulation abnormalities were maintained also
when compared with patients without cirrhosis. Our findings
suggested a reduction of the intrinsic and extrinsic pathway
(AUC INTEM and EXTEM media ± SD: 6890 ± 1215 vs. 4460 ± 1474,
p = 0.0001 and 6854 ± 1232 vs. 4050 ± 1439, p = 0.0001 respec-
tively) as well as of fibrinogen levels (AUC in FIBTEM media ± DS:
3521 ± 1656 vs. 1257 ± 1053, p = 0.0001). After resolution of infec-
tion, recovery of coagulation changes depended on the rebalance
of secondary heamostasis (before and after infection MCF INTEM
media ± SD: 48 ± 9.7 mm vs. 50.50 ± 14 mm, p = 0.001. MCF EXTEM
media ± SD: 45.9 ± 13 mm vs. 49 ± 13.5 mm, p = 0.026. ML INTEM
media ± SD: 4.78 ± 2.9% vs. 2.44 ± 1.5%, p = 0.012) together with
platelet reactivity (ADP media ± SD: 32 ± 21 vs. 35 ± 21, p = 0.029;
TRAP media ± SD: 53 ± 43 vs. 72 ± 37, p = 0.125; COL media ± SD:
29 ± 24 vs. 36 ± 21, p = 0.001).
Conclusions: In cirrhotic patients, infection is associated with
a hypocoagulable and hyperfibronolytic state which could be
improved after resolution of infection. Furthermore independent
factors such as platelet aggregation could contribute to the clot
strength.
http://dx.doi.org/10.1016/j.dld.2017.01.110
F-23
Ultrasound-guided Percutaneous IrreversibleElectroporation (IRE) of HepatocellularCarcinoma (HCC) not suitable for surgery orthermal ablation: Initial report on safety andefficacy from a western center
A. Giorgio 1, P. Gatti 1, C. Coppola 1, A. Calvanese 1,
F. Amendola 1, B. Santoro 1, M.G. Merola 1,
F. Merola 1, P. Matteucci 2, V. Giorgio 3
1 Tortorella Clinical Institute, Interventional
Ultrasound Unit, Salerno, Italy2 Radiation Oncology Department, Campus
Biomedico University of Rome, Rome, Italy3 Internal Medicine and Gastroenterology Area,
Fondazione Policlinico Universitario A. Gemelli,
Catholic University of Rome, Rome, Italy
Introduction and aim: IRE is a new non-thermal ablation
technique for ablation of liver tumors that uses electrical pulses
inducing necrosis of tumoral cells without damage of vascular or
biliary structures. We report our western experience on the first
seven patients treated with IRE.
Materials and methods: Seven patients (5 males; age range
49–67 ys, mean 56 y) with HCC not suitable for surgery or ther-
mal ablation consecutively seen in our Institution were included.
Diagnosis of HCC was based on histological diagnosis in all patients.
Only one patient had liver cirrhosis. HCC diameter ranged from 2 to
6 cm (mean 2.6 cm). All nodules were located at liver hylum and in
all cases dilatation of biliary tree was present. Only one patient had
a non-metallical biliary stent. The only controindication for IRE was
the presence of a cardiac disease. The follow-up ranged from 6 to
e56 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
24 months (mean 13 months). IRE was performed percutaneously
under ultrasound guidance using Nanoknife®
system and insertion
of 2 needles (19G) at a distance of 2 mm. Efficacy of procedure was
evaluated with CEUS and enhanced CT one month after IRE.
Results: On imaging, complete necrosis was achieved in all
patients. Only in one patient 2 sessions of IRE were needed to obtain
complete necrosis. Six patients are still alive, while one patient died
6 months after IRE for stroke. No deaths occurred after procedure.
Only one patient presented with a small, symptomless hematoma
found on US seven days after IRE.
No other complications (either major or minor) occurred: in
particular no injury to biliary tree was observed.
Conclusions: IRe of HCC not suitable for resection or ablation
seems safe and effective in treatment of HCC closed to vascular
and/or biliary structures. A larger number of cases will confirm such
promising tool.
http://dx.doi.org/10.1016/j.dld.2017.01.111
F-24
Transjugular intrahepatic portosystemic shuntis a safe and effective approach in cirrhoticpatients with splanchnic vein thrombosis
A. Airoldi 1, S. De Nicola 1, G. Perricone 1,
M. Vangeli 1, R. Viganò 1, R. Vercelli 2,
C. Migliorisi 2, M. Solcia 2, F. Barbosa 2, F. Musca 3,
A. De Gasperi 4, L.S. Belli 1, A.G. Rampoldi 2
1 Epatologia e Gastroenterologia, ASST Grande
Ospedale Metropolitano Niguarda, Milan, Italy2 Radiologia Interventistica, ASST Grande Ospedale
Metropolitano Niguarda, Milan, Italy3 Cardiologia 4, ASST Grande Ospedale
Metropolitano Niguarda, Milan, Italy4 Anestesia e Rianimazione 2, ASST Grande Ospedale
Metropolitano Niguarda, Milan, Italy
Introduction: TIPS is a well-known treatment strategy in por-
tal hypertension complications but its role, applicability and safety
in cirrhotic patients with splanchnic vein thrombosis are not com-
pletely established.
Aim: To compare clinical outcomes between patients with or
without splanchnic thrombosis at the time of TIPS placement.
Methods and results: From February 2014 to July 2016, 50
consecutive patients (40 males) underwent TIPS placement at
Niguarda Hospital and were analyzed for various clinical outcomes
including mortality, early complications (≤72 h) and success rate.
Median follow up was 16 months (4–32). Forty-seven patients
(94%)were cirrhotics (Child Pugh score A24%, B68% and C8%).
Median age was 56 years (range 29–78), the main etiologies of
liver disease were alcohol (15 cases, 30%) and viral disease (18
cases, 36%). Indication for TIPS placement was refractory ascites
in 19 patients (38%), variceal bleeding in 10 (20%) and splanchnic
thrombosis in 18 (36%). Splanchnic thrombosis had been com-
plicated by ascites in 6 patients (33%) and by digestive bleeding
in 10 (20%); only 2 patients (11%) had a single vessel involved
(portal vein), 11 (61%) had thrombosis of 2 vessels and 5 (28%) of
3 vessels (portal, mesenteric and splenic trunk). Overall the death
rate after the first 6 weeks from TIPS placement was 6%. Patients
with and without splanchnic thrombosis at baseline (18 vs. 29)
did not behave differently in terms of sepsis (33% vs. 24%, p = 0.52),
bleeding related complications (11% vs. 3%, p = 0.54), days of hos-
pitalization (13 vs. 16 days, p = 0.5), need for TIPS revision (11% vs.
17%, p = 1) and occurrence of hepatic encephalopathy (50% vs. 27%,
p = 0.21). All patients with thrombosis received anticoagulation
therapy, thirteen patients with thrombosis (72%) had a complete
or partial recanalization within 3 months from intervention.
Conclusions: TIPS is a realistic therapeutic option for patients
with splanchnic thrombosis as it is associated with a favorable clin-
ical outcome and the risk profile is in line with that observed for
other indications.
http://dx.doi.org/10.1016/j.dld.2017.01.112
F-25
Decreased alpha-fetoprotein levels in HCVcirrhotic patients after direct-acting antiviralagents therapy. Does this indicate a reducedrisk of hepatocellular carcinoma?
F. De Leonardis, C. Masetti, P. Rossi, D. Di Paolo,
A. Bosa, M. Milana, F. Santopaolo, S. Cucchiarelli,
A. Pecchioli, S. Francioso, I. Lenci, A. Brega,
T. Marianelli, F. Antenucci, S. Di Nardi, L. Baiocchi,
M. Angelico
Liver and Transplant Unit, Policlinico Tor Vergata,
Rome, Italy
The risk of hepatocellular carcinoma (HCC) in HCV+ cirrhotic
patients attaining sustained virological response (SVR) is debated.
Although alpha-fetoprotein (AFP) has a limited usefulness in HCC
surveillance due to poor sensitivity, recent data showed that high
levels predict HCC development in patients achieving SVR after
peginterferon/ribavirin therapy. We thus investigated serum AFP
changes in a cohort of cirrhotics treated with direct-acting antiviral
agents (DAAs).
The study comprised 143 consecutive HCV cirrhotics (76M/67F;
mean age 64.4 ± 11.2) receiving an optimal DAA treatment
(2016 EASL guidelines), including 7 (5.4%) in Child-Pugh B/C
stage and 10 (7.0%) with previous HCC. Genotype-1 infection
was present in 88 (61.5%). DAAs schedules included: sofosbuvir
(n = 28, 19.6%), sofosbuvir/simeprevir (n = 24, 16.8%), sofosbu-
vir/daclatasvir (n = 13, 9.0%), sofosbuvir/ledipasvir (n = 48, 33.6%)
and ombitasvir/paritaprevir/ritonavir ± dasabuvir (n = 30, 21.0%).
AFP values were assayed at baseline and after treatment. Predic-
tors of >50% AFP reduction (AFP-Response) were investigated by
univariate and multivariate analyses.
SVR-12 was achieved in 137 patients (95.8%). Mean
AFP decreased significantly (p < 0.000001) from baseline
(15.9 ± 23.8 ng/ml) to the end of follow-up (4.9 ± 3.7 ng/ml).
While a decrease of AFP was observed in the vast majority,
40.5% patients showed AFP-Response. Patients with AFP <6 ng/ml
increased from 39.2% to 73.1% (p = 0.0001). During the follow-up, 2
patients developed HCC (2/2 without AFP-Response). At univariate
analysis, no previous HCC, DAAs schedule, elevated ALT and high
AFP at baseline appeared significant predictors of AFP-Response.
MELD and SVR had no significant impact on AFP-Response. At
multivariable logistic regression (n = 116), AFP-Response was
associated with high baseline AFP levels (p = 0.0009) and sofos-
buvir/simeprevir therapy (p = 0.02), with an area under the ROC
curve of 0.89.
In HCV cirrhotic patients, DAA therapy significantly reduces AFP
levels, particularly in those with high baseline values. Whether this
favorable AFP trend underscores a diminished residual risk of HCC
in the long-term requires more extended studies.
http://dx.doi.org/10.1016/j.dld.2017.01.113
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e57
F-26
Bacterial infection is an uncommon occurrencein cirrhotic patients undergoing endoscopicvariceal ligation
S. Maimone 1, G. Caccamo 1, R. Filomia 1,2,3,
S. Sabatini 2, M.S. Franzè 2, C. Saitta 1, K. Sitajolo 2,
M.A. Aragona 2, F. Saffioti 3, C. Pitrone 2,
I. Cacciola 1, G. Squadrito 1,2,3,4, G. Raimondo 1,2,3
1 Division of Clinical and Molecular Hepatology,
University Hospital of Messina, Messina, Italy2 Department of Internal Medicine, University
Hospital of Messina, Messina, Italy3 Department of Clinical and Experimental Medicine,
University Hospital of Messina, Messina, Italy4 Department of Human Pathology of the Adult and
Evolutive Age, University Hospital of Messina,
Messina, Italy
Introduction and aim: Patients with cirrhosis are at high risk
of developing bacterial infections (BIs), in particular in occasion of
invasive procedures. Aim of this prospective study was to investi-
gate the incidence of BIs in cirrhotic patients undergoing elective
endoscopic variceal ligation (EVL).
Patients and methods: We enrolled 60 cirrhotic patients (51
males; mean age 66.2 ± 11.07 years) consecutively hospitalized
from March 2015 to June 2016, for a total of 112 EVL proce-
dures. EVL was performed by multiple-band ligator, applying 3–7
bands at each session until variceal eradication. Full blood cells
count, C-Reactive Protein (c-RP), Procalcitonine (PCT) and blood
cultures (aerobic and anaerobic mediums) were performed before
EVL and within 24 h after the procedure and were then compared
by Wilcoxon test.
Results: Twenty (33.3%) had virus-related, 12 (20%) alcoholic
and 28 (46.7%) metabolic/cryptogenic liver disease. Child-Pugh
class A/B/C distribution was 29/26/5, respectively; mean MELD
score was 10.6 ± 3. Fifteen patients (25%) had hepatocellular car-
cinoma. Blood cultures were negative in all samples before EVL,
whereas 3/112 (2.67%) cultures tested positive after procedures.
The bacteria isolated were Staphylococcus epidermidis and Strep-
tococcus mitis in 2 and 1 cases, respectively. Of note, none of
these three patients showed any evidence of clinically relevant
infection or change of c-RP, PCT and WBC values suggesting
that the positivity of cultures was expression of a transient bac-
teremia. There was no statistically significant difference before and
after endoscopic procedures in median white blood cells (WBC)
[4200 (1600–14,500) cells/mmc vs. 4550 (1700–14,000) cells/mmc;
p = 0.4]; PCR [0.4 (0.1–8.7) mg/dL vs. 0.47 (0.1–9.8) mg/dL, p = 0.2];
PCT [0.06 (0.03–2.09) ng/mL vs. 0.1 (0.01–2.56) ng/mL, p = 0.6].
Conclusions: EVL is not a risk factor for BIs in patients with
cirrhosis.
http://dx.doi.org/10.1016/j.dld.2017.01.114
F-27
Frailty index is a strong predictor of in-hospitaloutcomes and mortality after discharge incirrhotic patients
G. Caccamo 1, G. Basile 2, S. Maimone 1,
D. Vadalà 1, T. Crea 1, M.S. Franzè 1, A. Sitibondo 1,
R. Filomia 1, C. Saitta 1, I. Cacciola 1,
G. Squadrito 1,3, G. Raimondo 1,4
1 Division of Clinical and Molecular Hepatology,
University Hospital of Messina, Messina, Italy2 Unit of Geriatrics, Department of Clinical and
Experimental Medicine, University Hospital of
Messina, Messina, Italy3 Department of Human Pathology of the Adult and
Evolutive Age, University Hospital of Messina,
Messina, Italy4 Department of Clinical and Experimental Medicine,
University Hospital of Messina, Messina, Italy
Background: Frailty is a multiply determined vulnerability state
causing a higher risk of adverse outcomes including death.
Aim: To evaluate the impact of the frailty measured by Rock-
wood frailty index (FI) on in-hospital outcomes and mortality after
discharge in a cohort of hospitalized cirrhotic patients.
Methods: We applied the FI to 101 cirrhotic patients (72% male;
65.6 years ± 12.2 SD) consecutively hospitalized from January to
May 2015. Using medical, nursing and laboratory records we esti-
mated FI taking into account 45 potential combinable deficits. The
ratio between the number of deficits presented by each patient and
the 45 considered deficits corresponds to FI: a value >0.25 identifies
a frail patient.
Results: Cirrhosis was cryptogenic in 40% of cases; viral in 39%,
alcoholic in 21%. CPT class distribution was 51A/30B/20C, median
MELD score was 11.0 (6.0–29.0). Thirty-five/101 (34.6%) and 29/101
(28.7%) patients were frail at admission (FI-a) and discharge (FI-d),
respectively. No difference was found in FIa between CPT-B and C
[16/30 (53.3%) vs. 15/20 (75%), p = 0.1]. Frail patients had a longer
in-hospital stay (17 ± 14.8 vs. 10.8 ± 14.3 days; p = 0.04); a higher
probability of re-hospitalisation within 3 months [23/35 (65.7%)
vs. 40/66 (60.6%), p = 0.005]; a higher in-hospital mortality [5/35
(14.3%) vs. 2/66 (3%), p = 0.03]; a higher mortality either at 3 months
[14/29 (48.3%) vs. 8/72 (11.1%), p < .001], 6 months [18/29 (62.1%)
vs. 10/72 (13.8%), p < .001], and 12 months [18/29 (62.1%) vs. 16/72
(22.2%), p < .001]. Patients with a FI-d > 0.25 had a risk of mortality
higher than that predicted by CPT and MELD.
Mortality risk
3 months 6 months 12 months
HR 95% CI p HR 95% CI p HR 95% CI p
FI-d > 0.25
30.8 6.1–155.9 <0.0001 39.0 9.9–156.2 <0.0001 27.9 7.3–106.3 <0.0001
CPT 1.6 1.3–1.9 <0.0001 1.5 1.3–1.8 <0.0001 1.4 1.2–1.6 <0.0001
MELD 1.16 1. 1–1.2 <0.0001 1.15 1.1–1.2 <0.0001 1.11 1.05–1.17 <0.0001
Conclusion: FI strongly predicts in-hospital outcomes and mor-
tality after discharge in hospitalized cirrhotic patients.
http://dx.doi.org/10.1016/j.dld.2017.01.115
e58 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
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Efficacy of early empiric antibiotic treatmentand its impact on short-term mortality incirrhotic patients with subsequentidentification of the infecting bacteria
G. Caccamo 1, M.S. Franzè 2, R. Filomia 1,
P. Mondello 3, I.A. Paolucci 3, K. Sitajolo 2,
M.A. Aragona 2, T. Lembo 2, C. Saitta 1, I. Cacciola 1,
G. Squadrito 1,2,3,4, G. Raimondo 1,2,3,4,5,
S. Maimone 1
1 Division of Clinical and Molecular Hepatology,
University Hospital of Messina, Messina, Italy2 Department of Internal Medicine, University
Hospital of Messina, Messina, Italy3 Department of Infectious Disease, University
Hospital of Messina, Messina, Italy4 Department of Human Pathology of the Adult and
Evolutive Age, University Hospital of Messina,
Messina, Italy5 Department of Clinical and Experimental Medicine,
University Hospital of Messina, Messina, Italy
Introduction: Empiric antibiotic treatment (EAT) is mandatory
in cirrhotic patients with bacterial infections (BIs).
Aim: To analyze antibiotic sensitivity of bacteria isolates from
microbiological culture and to assess the efficacy of EAT in terms of
clinical outcomes and short-term mortality in patients with micro-
biological cultures proven bacterial infections.
Patients and methods: We retrospectively evaluated 157
BIs in 146 cirrhotics [55.5% male; age 65.8 ± 12.5 years; Child-
Pugh A/B/C: 25/87/34, MELD: 14.4 ± 7.6] consecutively hospitalized
from January 2009 to March 2015. Bacteria isolates were clas-
sified in sensitive (SI), multi-drug-resistant (MDR), extensively
drug-resistant (XDR) and pandrug-resistant (PDR). Clinical and lab-
oratory features associated to EAT failure, mortality at 1-month
(M-1) and 3-months (M-3) were evaluated.
Results: Cultures tested positive in 81/157 (51.6%) of BIs
episodes. Thirty-five of 81 (43.2%) isolates were SI, 39 (48.1%)
MDR, 6 (7.4%) XDR, and 1 (1.8%) PDR. EAT was changed accord-
ing to antibiogram in 26/81 (32%) of the cases. MDR were more
frequently isolated in patients who changed EAT than in those who
did not (5/26 vs. 30/55, respectively, p = 0.003). BIs with EAT failure
had longer duration of antibiotic therapy (13.1 ± 6.1 vs. 6.1 ± 2.8
days, p < 0.001), longer in-hospital-stay (19.6 ± 11.6 vs. 11.4 ± 6.1,
p = 0.002), higher MELD (15.35 ± 7.40 vs. 12.06 ± 4.12, p = 0.012)
and MELD-Na scores (18.12 ± 7.45 vs. 14.24 ± 5.51, p = 0.01), higher
bilirubin (3.9 ± 6.8 vs. 1.8 ± 3.4, p = 0.025), C-reactive protein (c-
RP) (2.41 ± 1.44 vs. 1.74 ± 0.73, p = 0.007), higher white blood cells
count (WBC) (9196 ± 7737 vs. 4651 ± 2239, p = 0.007) and lower
albumin (2.99 ± 0.53 vs. 3.32 ± 0.55, p = 0.014). M-1 and M-3 was of
13.6% and 25.9%, respectively and it was not statistically different
in patients who changed EAT and those who did not.
Conclusions: EAT was not confirmed in about one third of cases
of positive cultures mainly due to selection of MDR isolates. The
change of EAT was associated to a longer antibiotic-therapy, longer
in-hospital-stay, higher MELD, c-RP, WBC count, but did not affect
short term mortality.
http://dx.doi.org/10.1016/j.dld.2017.01.116
F-29
Liver Stiffness Based Model (LSPS) predictsportal hypertension (PH), esofageal varices (EV)and HCC in Caucasian patients with HBV-relatedcirrhisis responsive to antiviral therapy
A. Tucci, W. Debernardi Venon, C. Chialà,
M. Fadda, G.M. Saracco, A. Marzano
Department of Gastroenterology and Hepatology,
San Giovanni Battista Hospital, Città della Salute e
della Scienza, University of Torino, Turin, Italy
Introduction and aims: Antiviral therapy reduces but does not
eliminate the risk of HCC in HBV-related cirrhosis. Endoscopic mon-
itoring of EV remains controversial in responsive patients. LSPS has
been correlated with PH, EV and risk of HCC [1].
Methods: A longitudinal study was performed in 121 cirrhotics
(median age 54, median fu 8 years, M/F 100/21, HBeAg/antiHBe
5/116, no HCV, HIV or HDV) responsive to antiviral therapy
who underwent HVPG and LS measurement. Sixty-one (50.4%)
had clinical PH (cPH) (US, EV, ascites and/or LS > 11 KPa and/or
plts < 100,000) at baseline.
Results: LSPS ≤0.62 and <1.4 identified all patients without
measured PH (HVPG <6 mmHg, NPV 100%) and EV (PPV 63.3%,
NPV 93.7%), respectively. After antiviral therapy LSPS ≤0.62 was
detected in 51.3% of the patients (16.4% and 76.6% with and with-
out cPH at baseline, p < 0.0001). Overall median LS decreased from
16.1 to 9.5 KPa (p < 0.0001). HCC developed in 26 patients (21.5%,
2.6% year) with a higher incidence in patients with LSPS > 0.62 after
antiviral therapy (36% vs. 7%, 7.1% vs. 0.75% year, p < 0.001), without
difference in lamivudine-exposed patients. On univariate and mul-
tivariate analysis patients with HCC had a higher LSPS after therapy
and cPH baseline (p < 0.001). Quantitative HBsAg was not different.
Conclusions: LSPS is useful to identify patients with PH and EV,
avoiding endoscopy. LSPS ≤0.62 baseline or inducted by antiviral
therapy (regression of cirrhosis) is associated with a lower risk of
HCC. This goal is obtainable in 75% and 20% of patients without and
with cPH baseline. These results support early antiviral treatment
of CHB in order to maintain or to induce LSPS ≤0.62 and the use
of the score to define the HCC risk and the individual endoscopic
surveillance in treated patients.
Reference
[1] Abreldes JG. Hepatology 2016.
http://dx.doi.org/10.1016/j.dld.2017.01.117
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e59
F-30
HBV reactivation in pOBI is influenced bydetectable viremia at baseline rather thanduration of prophylaxis with lamivudine
F. Cavallo 1, P. Ghione 1, M. Battaglini 1, B. Botto 2,
D. Caracciolo 1, S. Ferrero 1, R. Passera 3,
U. Vitolo 2, M. Boccadoro 1, A. Marzano 4
1 Department of Molecular Biotechnologies and
Health Sciences, Division of Hematology, University
of Torino, Torino, Italy2 Citta’ della Salute e della Scienza, Division of
Hematology, Torino, Italy3 Citta’ della Salute e della Scienza, Division of
Nuclear Medicine, Torino, Italy4 Division of Gastro-Hepatology, San Giovanni
Battista Hospital, University of Torino, Torino, Italy
Introduction: Non Hodgkin Lymphoma (NHL) patients under-
going chemo-immunotherapy are at risk of HBV reactivation (HR)
and clinical events which can be life-threatening and compro-
mise treatment. HR can develop in both overt (HBsAg-positive) and
Occult B Infected (OBI; HBsAg-negative) carriers. AntiHBc positive
patients are defined as potential OBI (pOBI). Antiviral prophylaxis
in pOBI is effective in preventing HR, but its use and timing remain
controversial.
Materials and methods: All the patients with NHL treated with
Rituximab (R) in the period 2007–2016 at our institution were ana-
lyzed (inclusion criteria: 18 years or older, positive for anti-HBc
or HBsAg; exclusion criteria: HIV, chronic lymphocytic leukemia,
Lymphoblastic and T cell lymphoma). HR was defined by the reap-
pearance of HBsAg (Sieroreversion, SR), and clinical reactivation
(ALT > 1.5ULV).
Results: Among 2063 patients screened, 154 pOBI were ana-
lyzed (excluded: 550 R−; 26 HIV+; 1333 HBV−, 18 HBsAg+). POBI
characteristics: 90% Caucasian; median age 68 y (39–85), M/F ratio
1.17; HBV-DNA positive baseline 5/97 (3%); Lymphoma: DLBCL 76
(49%), FL 35 (23%), MCL 12 (8%), other 31 (20%). Patients received
one (109, 71%) or more lines of R (44, 29%), 9 (5, 9%) autologous
transplantation (ASCT). 139 (90%) patients received Lamivudine
(LAM) prophylaxis, and the drug was stopped in 45%. After R, pro-
phylaxis was maintained for <6, 6–12, 12–24 and >24 months in 7%,
17%, 43% and 32% of cases. HR developed in 5 (3.6%) cases (3/139
LAM+, 2.2%; 2/15 LAM−, 13.3%; p = 0.07). In LAM+ HR occurred 2 and
5 months after the discontinuation and in one case (with HBV-DNA
baseline >1500 IU) during prophylaxis. The number of chemother-
apy lines (p = 0.024) and detectable HBV-DNA baseline (p = 0.006)
were associated with HR.
Conclusions: (1) Antiviral prophylaxis is effective in preventing
>95% reactivation of HBV in NHL treated with R; (2) HR is more fre-
quent after LAM discontinuation than during antiviral treatment;
(3) detectable HBV-DNA baseline in pOBI and number of therapy
lines received were correlated with HR; (4) lymphoma subtype,
ASCT and duration of prophylaxis did not influence HR.
http://dx.doi.org/10.1016/j.dld.2017.01.118
F-31
Risk of hepatocellular carcinoma (HCC)recurrence in HCV cirrhotic patients treatedwith Direct Acting Antivirals (DAAs)
G. Cabibbo, I. Cacciola, M.R. Cannavò, S. Madonia,
V. Calvaruso, S. Petta, M. Distefano, L. Larocca,
T. Prestileo, F. Tinè, A. Digiacomo, G. Bertino,
L. Giannitrapani, F. Benanti, A. Davì, R. Volpes,
I. Scalisi, C. Iacobello, G. Mazzola, F. Cartabellotta,
L. Guarneri, V. Portelli, A. Averna, M. Russello,
G. Scifo, G. Squadrito, G. Raimondo, A. Craxì,
V. Di Marco, C. Cammà, on behalf of RESIST-HCV
(Rete Sicilia Selezione Terapia – HCV)
Rete Sicilia Selezione Terapia – HCV (RESIST-HCV),
Italy
Background and aims: Conflicting data exists regarding the
impact of Direct Acting Antivirals (DAAs) on early recurrence in
successfully treated HCV-related HCC. With this aims, we analysed
the on-going dataset of RESIST-HCV.
Methods: We evaluated 185 cirrhotic patients with complete
radiological response after curative treatment of HCC (mean age
70 ± 9 years, 63.8% males, 41% naïve to antiviral therapy, 156
(84.3%) Child-Pugh A and 29 (1.7%) Child-Pugh B) who completed
the treatment between March 2015 and October 2016 in 22 centers
of RESIST-HCV. Each physician established DAA regimens and use
of Ribavirin. Seventy-nine patients received 12 weeks of therapy,
while 106 received a DAA regime of 24 weeks. All patients received
HCC surveillance according to the clinical practice policy. The pri-
mary endpoint of the analysis was the rate and the time of HCC
recurrence from the start of DAAs.
Results: At the end of October 2106, 145 patients (78.4%) com-
pleted the DAA regime and 40 were still on treatment. During the
follow-up (mean 24 weeks, range 8–60) 24 patients had a recur-
rence of HCC with a crude rate of 13%.
Pattern of HCC recurrence was nodular in 83% patients (20/24)
and infiltrative in 17% (4/24).
The 6- and 12-mo HCC recurrence rates by Kaplan–Meier
method were 7.9% and 16.3%, respectively. One patient died during
follow-up.
Conclusions: In patients with HCV-related successfully treated
HCC DAAs does not increase the risk of HCC recurrence. More-
over, potential benefit of DAA on preservation of liver function,
resulting in a lower cirrhosis-related mortality and a greater
change of receiving curative treatments, should improve survival of
patients with HCV-related HCC who achieved complete radiological
response after curative treatment.
http://dx.doi.org/10.1016/j.dld.2017.01.119
e60 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
F-32
Early occurrence of hepatocellular carcinoma(HCC) in patients with HCV cirrhosis treatedwith direct-acting antivirals (DAAs)
V. Calvaruso, G. Cabibbo, I. Cacciola, S. Petta,
S. Madonia, A. Bellia, F. Tinè, M. Distefano,
L. Giannitrapani, T. Prestileo, G. Mazzola, A. Davì,
L. Larocca, A. Ardiri, A. Digiacomo, M. Gussio,
L. Guarneri, A. Magro, A. Averna, C. Iacobello,
I. Scalisi, F. Cartabellotta, F. Savalli, M. Russello,
G. Scifo, G. Squadrito, C. Cammà, G. Raimondo,
A. Craxì, V. Di Marco, on behalf, RESIST-HCV (Rete
Sicilia Selezione Terapia – HCV)
Rete Sicilia Selezione Terapia – HCV (RESIST-HCV),
Italy
Background and aims: The risk of HCC occurrence during and
after DAA based treatment is still debated. The aims of this analysis
were to evaluate the early HCC occurrence and to analyse the HCC
pattern in a large cohort of treated cirrhotic patients.
Methods: We evaluated 2684 cirrhotic patients (mean age
65.3 ± 10.8 years, 58.4% males, 45.8% naïve to antiviral therapy,
2,364 (88%) Child-Pugh A and 320 (12%) Child-Pugh B) who com-
pleted the treatment between March 2015 and October 2016 in
22 centers of RESIST-HCV. Ribavirin was associated to DAAs in
1354 patients (50.4%), 1537 patients (57.3%) received DAAs for
12–14 weeks and 1147 (42.7%) for 24 weeks. Patients received HCC
surveillance as indicate by guidelines.
Results: During the observation (mean 34.2 weeks, range 4–72)
55 patients (2.0%) developed HCC. The rate was 1.73% in Child-
Pugh A and 4.37% in Child-Pugh B cirrhosis (p = 0.004). HCC met
Milan criteria in 29 patients (52.7%) while 26 (47.3%) were Milan-
out. Seven of 29 patients with Milan-in criteria developed HCC on
therapy and 22 out therapy, while 3 of 26 patients with Milan-
out criteria developed HCC on therapy and 23 out therapy (p = 0.3).
The evaluation of SVR was available in 1628 patients. By intention
to treat analysis, 1435 patients (88.1%) achieved a SVR and 193
(11.9%) no obtained SVR. The HCC occurrence was 1.88% (27/1435)
in patients whit SVR and 5.2% (10/193) in patients without SVR
(p = 0.008).
Conclusions: The occurrence of “de novo” HCC during the first
year of observation in our cohort of cirrhotic patients treated with
DAAs remained similar to that reported in historical cohorts of
untreated patients. The risk of HCC was higher in patients with
Child-Pugh B cirrhosis and in patients without SVR. The presenta-
tion pattern of HCC was no different on- and out therapy.
http://dx.doi.org/10.1016/j.dld.2017.01.120
F-33
HLA-G is highly expressed by plasma cellsinfiltrating hepatic tissue of patients affected byautoimmune hepatitis
S. Onali 1, F. Figorilli 1, E. Sanna 1, C. Balestrieri 2,
G. Serra 2, M. Conti 2, F. Alba 3, M. Trucas 4,
D. Fanni 5, G. Senes 5, A. Mereu 5, G. Faa 5,
C. Carcassi 3, R. Littera 4, L. Chessa 1,2
1 Department of Medical Sciences and Public Health,
University of Cagliari, Cagliari, Italy2 Liver Unit, Department of Internal Medicine,
Azienda Ospedaliera-Universitaria di Cagliari,
Cagliari, Italy3 Medical Genetics, Department of Medical Sciences,
University of Cagliari, Cagliari, Italy4 Bone Marrow Transplantation Centre, Binaghi
Hospital, Cagliari, Italy5 Division of Pathology, Department of Surgical
Sciences, University of Cagliari, Italy
Introduction: Human leukocyte antigen G (HLA-G) is an HLA
class Ib molecule with immunomodulatory, immunosuppressive
and tolerance-inducing functions. Altered HLA-G expression has
been observed in various autoimmune diseases but no data exist in
autoimmune hepatitis.
Aims: To analyse the frequency of HLA-G 14-bp inser-
tion/deletion polymorphism, known to have a functional effect on
HLA-G mRNA stability, and HLA-G hepatic expression in a cohort
of patients affected by autoimmune hepatitis type 1.
Methods: The frequencies of HLA-G 14-bp insertion/deletion
(rs371194629) polymorphism were determined by polymerase
chain reaction amplification in each patient and compared to those
of healthy individuals extracted from the Sardinian bone marrow
donor registry. Hepatic HLA-G expression was analysed on liver
biopsy samples using an immunohistochemistry staining with a
murine anti-human monoclonal antibody. HLA-G expression was
graded according to the proportion of cells displaying anti-HLA-G
positivity.
Results: Liver biopsy samples were available for immunohis-
tochemistry staining in 13 patients (female 85%, mean age 50 y).
Homozygosis for HLA-G 14-bp insertion/insertion (ins/ins) poly-
morphism was observed in 19% of patients while heterozygosis
(ins/del) was found in 47% and no significant difference was
observed between AIH and healthy group. On evaluation of hepatic
HLA-G expression, we found that 7 (54%) patients showed a marked
positivity (from 50% to 100%) for HLA-G both in the cytoplasm
and on the surface of plasma cells. Interestingly, only the plasma
cells were labelled, while hepatocytes and other cells, such as
macrophages, did not display any positivity. Three (23%) patients
were negative and showed only a mild inflammatory response at
histological examination.
Conclusions: Our study showed a strong HLA-G expression by
plasma cells infiltrating the liver of patients affected by AIH type-1.
Absence of HLA-G expression was observed only in 3 patients who
had a mild inflammatory damage, suggesting a possible correlation
between HLA-G and severity of liver inflammation.
http://dx.doi.org/10.1016/j.dld.2017.01.121
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e61
F-34
Survival and recurrences after curativetreatments of HCV-related early hepatocellularcarcinoma. A meta-analysis of single armstudies
G. Cabibbo 1, S. Petta 1, M. Barbàra 1, G. Missale 2,
R. Virdone 3, E. Caturelli 4, F. Piscaglia 5,
F. Morisco 6, A. Colecchia 7, F. Farinati 8,
E. Giannini 9, F. Trevisani 10, A. Craxì 1,
M. Colombo 11, C. Cammà 1, on behalf of the
ITA.LI.CA study group
1 Section of Gastroenterology, Biomedical
Department of Internal and Specialized Medicine,
University of Palermo, Italy2 Unit of Infectious Diseases and Hepatology,
Teaching Hospital-University of Parma, Italy3 Division of Internal Medicine 2, Ospedali Riuniti
Villa Sofia-Cervello, Palermo, Italy4 Division of Gastroenterology, Belcolle Hospital,
Viterbo, Italy5 Division of Internal Medicine, Department of
Medical and Surgical Sciences, Alma Mater
Studiorum, University of Bologna, Italy6 Division of Gastroenterology, Department of
Medicine and Surgery, University of Naples Federico
II, Italy7 Department of Medical and Surgical Sciences,
University of Bologna, Italy8 Department of Surgery, Oncology and
Gastroenterology, University of Padua, Italy9 Gastroenterology Unit, Department of Internal
Medicine, IRCCS Azienda Ospedaliera Universitaria
San Martino IST, University of Genoa, Italy10 Division of Semeiotics, Department of Medical and
Surgical Sciences, Alma Mater Studiorum, University
of Bologna, Italy11 A.M.&A. Migliavacca Center for Liver Disease, 1st
Division of Gastroenterology, Fondazione IRCCS Ca’
Granda Maggiore Hospital, University of Milan, Italy
Background and aims: Knowing risk for recurrence and
survival after curative resection or ablation in patients with HCV-
related hepatocellular carcinoma (HCC) is important for stratifying
patients according to expected outcomes in future studies of adju-
vant therapy in the era of direct acting antivirals (DAA). The aims of
this meta-analysis were to estimate recurrence and survival prob-
ability of HCV-related early HCC who achieved complete response
after curative treatments and to identify predictors of recurrence
and survival.
Methods: Studies reporting time-dependent outcomes (HCC
recurrence or death) after curative treatment of HCV-related early
HCC were identified on MEDLINE through May 2016. Data on the
patient populations and outcomes were extracted from each study
by three independent observers and combined by a distribution-
free summary survival curve. Primary outcomes were actuarial
probability of recurrence and survival.
Results: Eleven studies met the inclusion criteria. The pooled
estimates of actuarial recurrence rates were 7.4% at 6 months and
47.0% at 2 years. The pooled estimates of actuarial survival rates
were 79.8% at 3 years and 58.6% at 5 years. Heterogeneity among
studies was highly significant for all outcomes. By univariate meta-
regression analyses, lower serum albumin, study design and follow-
up were independently associated with higher risk of recurrence,
while tumor size and alpha-fetoprotein with higher mortality.
Conclusions: This meta-analysis showed that recurrence risk
and survival are extremely variable in patients with successfully
treated HCV-related HCC, providing a useful benchmark for indirect
comparisons of the benefit of DAA and for a correct design of RCT
in the adjuvant setting.
http://dx.doi.org/10.1016/j.dld.2017.01.122
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Are detectable sofosbuvir troughconcentrations predictive of virological failureduring anti-HCV treatment? Preliminaryevidences from the KINETI-C study
A. De Nicolò, L. Boglione, C. Carcieri, J. Cusato,
S. Mornese Pinna, F. Favata, A. Ariaudo,
G. Di Perri, A. D’Avolio
Unit of Infectious Diseases, Department of Medical
Sciences, University of Turin, Turin, Italy
Introduction: In the current standard of care for HCV infection,
sofosbuvir (SOF) represents the backbone of several therapeutic
regimens. Up to now, pharmacokinetic/pharmacodynamic prop-
erties of SOF, as well as other DAAs, have been poorly studied in
“real-life” settings. SOF is a prodrug, which is firstly converted in
its active metabolite and is then measurable in plasma as its main
metabolite GS-331007. In fact, the fast conversion of SOF makes
GS-331007 the best marker of SOF exposure.
Aim: The aim of this study was to investigate pharmacokinetic
data in a real-life clinical context to identify possible predictors of
virological failure.
Materials and methods: HCV infected patients in treatment
with SOF-based regimens were enrolled in “Kineti-C” clinical study.
SOF, GS-331007 and concomitant drug concentrations were mea-
sured at 1, 3, 7, 30 and 60 days of treatment, through validated
methods in UHPLC–MS/MS. Statistical analysis was performed
through SPSS 22.0 statistical software. P values lower than 0.05
were considered as statistically significant.
Results: 95 patients who received SOF in their anti-HCV ther-
apy were enrolled: 37.9% (36) with SOF/DCV; 27.4% (26) with
SOF/SMV; 23.2% (22) with SOF/LPV; 9.5% (9) with SOF/RBV; 2.1%
(2) with SOF/RBV/PEG-IFN.SOF Ctrough was detectable at least at
one timing for 6 patients. Detectable SOF concentrations resulted
significantly associated to the onset of breakthrough (2 cases out of
3; P-value = 0.000013). GS-331007 and other drugs concentrations
resulted not significantly correlated with treatment response.
Conclusions: A residual Ctrough of SOF might underlie an incom-
plete conversion of SOF to its active metabolites: this could lead to
a lower activity than expected. Further studies are needed to clarify
the reasons behind the SOF detectable determinations and conse-
quent clinical implications. Anyway, this tool could be useful to the
clinicians for the early identification of the residual rare cases of
virological failure.
http://dx.doi.org/10.1016/j.dld.2017.01.123
e62 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
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Prevalence and characteristics of resistanceassociated substitutions in DAA-naive andDAA-failed HCV-3 patients in Italy
V.C. Di Maio 1, S. Barbaliscia 1, I. Lenci 2, E. Teti 3,
F.P. Antonucci 1, V. Cento 1, M. Aragri 1,
S. Paolucci 4, B. Bruzzone 5, N. Coppola 6,
T. Ruggiero 7, T. Pollicino 8, E. Polilli 9,
C. Pasquazzi 10, V. Pace Palitti 11, C.F. Magni 12,
V. Micheli 13, A. Di Biagio 14, L. Sticchi 5,
M. Melis 15, S. Francioso 2, C. Masetti 2,
L. Foroghi 3, C. Sarrecchia 3, L. Baiocchi 2,
S. Landonio 12, A. Bertoli 1, V. Calvaruso 16,
F. Morisco 17, I. Maida 15, S. Marenco 18, A. Leo 19,
V. Ghisetti 7, A. Ciancio 20, P. Sacchi 21, S. Novati 22,
G. Brancaccio 6, A. Pieri 9, M. Puoti 23,
P. Toniutto 24, V. Vullo 25, A. Aghemo 26,
G. Di Perri 27, S. Babudieri 15, G. Rizzardini 12,
S. Bruno 19, A. Pellicelli 28, G. Taliani 29,
G. Raimondo 8, F. Baldanti 4, G.B. Gaeta 6,
A. Craxì 16, G. Parruti 9, M. Andreoni 3,
M. Angelico 2, C.F. Perno 1,
F. Ceccherini-Silberstein 1, on behalf of HCV
Virology Italian Resistance Network Group
(Vironet C)
1 Department of Experimental Medicine and Surgery,
University of Rome Tor Vergata, Rome, Italy2 Hepatology Unit, University Hospital of Rome Tor
Vergata, Rome, Italy3 Infectious Diseases, University Hospital of Rome Tor
Vergata, Rome, Italy4 Virologia Molecolare, Fondazione IRCCS Policlinico
San Matteo, Pavia, Italy5 Hygiene Unit, IRCCS AOU San Martino-IST, Genoa,
Italy6 Infectious Diseases and Viral Hepatitis Unit, Second
University of Naples, Naples, Italy7 Unit of Infectious Diseases, Laboratory of
Microbiology and Virology, “Amedeo di Savoia”
Hospital, Turin, Italy8 Department of Internal Medicine, University
Hospital of Messina, Messina, Italy9 Infectious Disease Unit, Pescara General Hospital,
Pescara, Italy10 Infectious Diseases, Sant’Andrea Hospital–“La
Sapienza” University, Rome, Italy11 Hepatology Unit, Pescara General Hospital,
Pescara, Italy12 Division of Infectious Disease, ASST
Fatebenefratelli Sacco, Milan, Italy13 Clinical Microbiology, Virology and
Bioemergencies, ASST Fatebenefratelli Sacco, Milan
Italy14 Infectious Disease, IRCCS AOU San Martino - IST,
Genova, Italy15 Infectious Diseases Unit, University of Sassari,
Sassari, Italy16 Gastroenterology, “P. Giaccone” University
Hospital, Palermo, Italy17 Department of Clinical Medicine and Surgery,
University “Federico II” of Naples, Naples, Italy18 Division of Hepatology, IRCCS San Martino, IST
Genova, Genoa, Italy
19 Department of Internal Medicine, Humanitas
University, Rozzano, Milan, Italy20 Unit of Gastroenterology, University of Turin,
Department of Medical Sciences, Città della Salute e
della Scienza di Torino Molinette Hospital, Turin,
Italy21 Division of Infectious and Tropical Diseases,
Fondazione IRCCS Policlinico San Matteo, Pavia, Italy22 Institute of Infectious Diseases, University of
Pavia, Pavia, Italy23 Department of Infectious Diseases, Hospital
Niguarda Ca’Granda, Milan, Italy24 Department of Medical Sciences Experimental and
Clinical, Medical Liver Transplant Section, Udine,
Italy25 Department of Public Health and Infectious
Diseases, Sapienza University of Rome, Rome, Italy26 UO Gastroenterologia ed Epatologia, Fondazione
IRCCS Ca’ Granda Ospedale Maggiore Policlinico di
Milano, Milan, Italy27 Unit of Infectious Diseases, Department of Medical
Sciences, Amedeo di Savoia Hospital, University of
Turin, Turin, Italy28 Hepatology Unit, San Camillo Forlanini Hospital,
Rome, Italy29 Infectious and Tropical Diseases Unit, Department
of Clinical Medicine, Sapienza University of Rome,
Rome, Italy
Introduction and aim: Aim of this study was to investigate
the prevalence and characteristics of resistance-associated-
substitutions (RASs) in HCV-3 infected patients, naïve to direct-
acting antivirals (DAA) and/or failing an interferon-free regimen in
Italy.
Materials and methods: Sanger-sequencing of NS5A +
NS5B + NS3-protease was performed in 204 HCV-3 infected
patients (150 DAA-naïve and 75 DAA-failures, of them, 21 at both
baseline and DAA-failure).
Results: The majority of patients were male (86.3%) and
cirrhotic (60.3%). 18 patients (8.8%) were HIV-coinfected. Further-
more, 89.5% of patients with known risk-factor of HCV-infection,
were injection-drug-users. HCV-sequencing identified two spe-
cific subtypes (HCV-3a, 99.5% and HCV-3 h, 0.5%), though 15/204
(7.3%) patients were previously misclassified as infected with
indeterminate-genotype (N = 4), non-3 genotype (N = 10), or mixed
(N = 1).
Overall, 75 patients experienced a virologic-failure to an
interferon-free-regimen: 61.3% to sofosbuvir + ribavirin and 30.7%
to daclatasvir + sofosbuvir ± ribavirin. Notably, 8.0% were treated
with 3D ± ribavirin (paritaprevir/r + ombitasvir + dasabuvir), due to
a wrong-genotype 1 assignment. A different distribution of RASs
was observed between DAA-naïve and DAA-failing patients. The
NS3-Q80K was mainly detected in the 3D-failures (33% vs. 0.7%
DAA-naïve, p = 0.004). In NS5A-experienced patients, the Y93H
was the most prevalent RASs: 5/6 (83.3%) 3D-failures, 17/23
(78.2%) daclatasvir + sofosbuvir-failures, vs. 5/130 (3.8%) DAA-naïve
patients (p < 0.0001). 2/5 DAA-naïve patients with natural Y93H
were treated with daclatasvir + sofosbuvir + ribavirin for 24 weeks
and 1/2 (50%) reached SVR. Interestingly, also 3/46 (6.5%) sofosbu-
vir + ribavirin failing-patients showed natural NS5A-RASs (2 = Y93H
and 1 = A30K + L31F). In NS5B, sofosbuvir RASs L159F and S282T
were both detected only at virologic-failures of a sofosbuvir-
containing regimen (5.8% and 2.9%, respectively).
Conclusions: HCV-sequencing at failure is useful for identi-
fying RASs and revealing previously misinterpreted genotypes
in order to select the best DAA-regimen for retreatment option.
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e63
NS5A-failing HCV-3 patients (including the 3D-failures) showed
a high frequency of Y93H, in some cases in association with
NS3 and/or NS5B-RAS. The clinical relevance of baseline Y93H in
genotype 3 deserves further investigation.
http://dx.doi.org/10.1016/j.dld.2017.01.124
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Evaluation of mild cognitive dysfunction byMontreal Cognitive Assessment test in patientswith chronic HCV infection treated with directantiviral agents
S. Onali 1, D.G. Pacini 1, C. Balestrieri 2, F. Figorilli 1,
G. Serra 2, L. Chessa 1,2
1 Department of Medical Sciences and Public Health,
University of Cagliari, Cagliari, Italy2 Liver Unit, Department of Internal Medicine,
Azienda Ospedaliera-Universitaria di Cagliari,
Cagliari, Italy
Introduction: Cognitive impairment is frequently observed in
HCV patients, leading to impaired daily activities, adherence to
therapy and quality of life.
Aim: To investigate changes in neurocognitive status of HCV
patients undergoing antiviral treatment using the Montreal Cogni-
tive Assessment (MoCA) test.
Methods: Our single-centre prospective study included con-
secutive HCV patients treated with direct antiviral agents (DAAs)
between 2015–2016. The MoCA test was performed at baseline and
6 months after end of treatment. Various cognitive functions such
as attention, memory, language, orientation, executive and visual-
spatial skills, were evaluated. The result of MoCA was the sum of
the scores in each area for a maximum of 30 points. A score ≥26/30
was considered normal.
Results: Out of 118 patients evaluated at baseline, 31 repeated
the MoCA after therapy. All of them achieved a sustained virological
response (SVR). Male 15 (48%), mean age 58 (±11) years, geno-
type 1 23 (74%), naïve to previous treatment 14 (45%). 17 patients
(55%) had a compensated cirrhosis. Post-treatment MoCA score
improved in 26 patients (p < 0.001) with 61% of patients achiev-
ing the normal threshold vs. 26% (p = 0.003) at baseline. Execution
and memory areas, which were the most affected at baseline, sig-
nificantly improved after SVR: 81% of patients achieved a score of
at least 3/4 in execution vs. 48% at baseline (p = 0.013) while 35% of
patients had a score of at least 3/5 in memory vs. 19% at baseline
(p = 0.003). Good performances were reported in the area of orien-
tation and language with no difference before and after treatment.
Conclusions: MoCA was a simple and easy test to administer.
Although limited by the small number of cases, our results suggest
that successful treatment with DAAs could improve neurocognitive
functions, such as execution and memory, in patients affected by
HCV infection and advanced liver fibrosis.
http://dx.doi.org/10.1016/j.dld.2017.01.125
F-38
Comparative antiviral efficacy with higher ALTnormalization of tenofovir alafenamide (TAF)versus tenofovir disoproxil fumarate (TDF) inHBeAg-negative, genotype D chronic hepatitis B
G. Ricco 1, M. Buti 2, M. Omata 3, Y.J. Kim 4,
B. Coco 1, D. Samuel 5, J.F. Flaherty 6, L. Lin 6,
A. Gaggar 6, E. Ceausu 7, U.S. Akarca 8, M.J. Tong 9,
H.L. Chan 10, M.R. Brunetto 1,11
1 Hepatology Unit and Laboratory of Molecular
Genetics and Pathology of Hepatitis Viruses,
Reference Center of the Tuscany Region for Chronic
Liver Disease and Cancer, University Hospital of Pisa,
Pisa, Italy2 Vall d’Hebron Hospital, Barcelona, Spain3 Yamanashi Prefectural Central Hospital, Kofu-shi,
Japan4 Seoul National University Hospital, Seoul, Republic
of Korea5 Hôpital Paul-Brousse, Villejuif, France6 Gilead Sciences, Inc., Foster City, CA, United States7 Spitalul Clinic de Boli Infectioase si Tropicale Dr.
Victor Babes, Bucuresti, Romania8 Ege University Medical Faculty Hospital, Izmir,
Turkey9 Huntington Medical Research Institutes, Pasadena,
CA, United States10 Prince of Wales Hospital, Hong Kong11 Department of Clinical and Experimental
Medicine, University of Pisa, Pisa, Italy
Background: TAF, a TDF prodrug, has been shown in chronic
hepatitis B (CHB) patients to have noninferior week (W) 48 efficacy
to TDF. We evaluated TAF efficacy compared to TDF in HBeAg-
negative CHB patients according to genotype (GT) D or non-D
infection.
Methods: 425 patients were randomized to receive TAF 25 mg
QD (n = 285) or TDF 300 mg QD (n = 140) for 144W; thereafter
patients receive open label TAF through 8 years. The endpoints for
this subanalysis were virologic (HBV-DNA <29 IU/mL, log10 IU/mL
changes in HBV-DNA and HBsAg levels), and biochemical (ALT nor-
malization) W48 responses.
Results: At baseline 90/285 (32%) TAF and 42/140 (30%) TDF
patients were GT-D. Within GT-D vs. non-GT-D patients baseline
characteristics were similar between the TAF and TDF arms, GT-
D patients being more likely to be male (68 vs. 58%), White (71 vs.
4%), without cirrhosis (8 vs. 13%) and have higher baseline BMI (25.8
vs. 24.2). In addition, GT-D patients had higher HBV DNA, HBsAg,
and serum ALT levels compared with non-GT-D patients. At W48,
the proportion of subjects with HBV-DNA <29 IU/mL was similar
between TAF and TDF arms for GT-D (92% vs. 95%) and non-GT-
D (95% vs. 92%) patients. Over 48 weeks declines in HBsAg were
minimal (mean change at W48 was −0.09 vs. −0.06 log10 IU/mL for
the TAF and TDF; p = 0.59) independently of GT-D or non-GT-D. ALT
normalization rates were higher in TAF vs. TDF arms when assessed
by both central laboratory (83 vs. 75%, p = 0.076) and AASLD (50 vs.
32%, p < 0.001) criteria independently of genotype.
Conclusions: In HBeAg-negative patients high rates of W48
HBV-DNA suppression were seen in TAF- and TDF-treated patients
independently of the genotype; whereas W48 HBsAg declines were
minimal in both treatment arms. Rates of ALT normalization were
higher in TAF versus TDF without any impact of HBV genotype.
http://dx.doi.org/10.1016/j.dld.2017.01.126
e64 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
F-39
Daclatasvir/sofosbuvir and ribavirin 800 mg flatdose is highly efficacy and safe in genotype 3compensated and decompensated cirrhoticpatients: The CLEO experience
A. Pellicelli 1, V. Messina 2, P. Tarquini 3,
V. Pace Palitti 4, F. Ceccherini Silberstein 5,
M. Pompili 6, R. Gulminetti 7, G. Cerasari 1,
C. D’Ambrosio 1, R. Villani 1, L. Fondacaro 1,
S. Dell’isola 8, S. Babudieri 9, V. Iovinella 10,
F. Di Candilo 11, F. Chiesara 12, V.C. Di Maio 5,
F.R. Ponziani 6, R. Sacco 13, A. Izzi 14, A. Moretti 12,
V. Giannelli 1, C.F. Perno 5, G. Barbarini 7, for the
CLEO Group
1 Liver and Transplant Unit, Azienda Ospedaliera San
Camillo Forlanini, Rome, Italy2 Infectious Disease, San’Anna and San Sebastiano
Hospital, Caserta, Italy3 Infectious Disease, G Mazzini Hospital, Teramo,
Italy4 Liver Unit, Department of Medicine, Pescara, Italy5 Virology Chair, Department of Experimental
Medicine and Surgery, “Tor Vergata” University of
Rome, Rome, Italy6 Internal Medicine, Catholic University, Rome, Italy7 Infectious Disease, IRCCS San Matteo, Pavia, Italy8 Infectious Disease, Belcolle Hospital, Viterbo, Italy9 Infectious Disease, University of Sassari, Sassari,
Italy10 Internal Medicine, San Paolo Hospital, Naples, Italy11 Infectious Disease, Azienda Ospedaliera, Perugia,
Italy12 Gastroenterology, San Filippo Neri Hospital, Rome,
Italy13 Liver Unit, Azienda Ospedaliero Universitaria
Pisana, Pisa, Italy14 Infectious Disease, Cotugno Hospital, Naples, Italy
Introduction: Genotype 3 cirrhotic patients are a difficult pop-
ulation to treat, with lower virological response rate than other
HCV genotypes (G). We aimed to explore the efficacy and safety
of SOF-DCV plus 800 mg flat dose RBV regimen in G3 naive and
experienced cirrhotic patients respect to pts treated with SOF-DCV-
weight-based RBV and SOF-DCV without RBV for 24 w.
Material and methods: We analysed the data of 140 G3 cir-
rhotic pts. 20.7% (29 pts), 46.4% (65) and 32.9% (46) received
respectively SOF-DCV, SOF-DCV-800 mgRBV, SOF-DCV-weight-
based RBV. Treatment duration was 24 weeks in all the pts.
Results: 87.9% (123 pts) were in class A Child-Pugh (CP) while
11.4% (16 pts) were in class CP-B and 0.7% (1 pts) in class CP-C.
52.1% (73 pts) were naive and 47.9% (67 pts) were experienced.
Overall SVR 12 was reached in 133 pts (95%). SVR 12 rate was
86.2% (25 pts) in pts treated with SOF-DCV, 98.5% (64 pts) in pts
treated with SOF-DCV-800 mg flat dose RBV and 95.7% (44 pts) in
pts treated with SOF-DCV-weight-based dose RBV. No significant
difference in SVR12 was found between patients treated with a flat
dose RBV respect to weight-based RBV dose, while a statistically
significant difference was disclosed in patients treated with reg-
imen containing RBV (97.2%) respect to pts treated without RBV
(86.2%) (p < 0.03). Grade II anemia was disclosed more frequently
in patients treated with weight-based dose RBV (39.1%) respect to
patients treated with a flat dose RBV (23.1%) (p < 0.05) and without
RBV (7.1%) (p < 0.003).
Conclusions: SOF-DCV plus 800 mg flat dose RBV is safe and
highly efficacy in term of SVR 12. This regimen presents less grade
2 anemia respect to other regimens. SOF-DCV without RBV regimen
presents a low SVR12 and should be prescribed only in cirrhotic pts
with a clear contraindications to the use of RBV.
http://dx.doi.org/10.1016/j.dld.2017.01.127
F-40
Emerging players in liver fibrosis regression in achronic murine model of hepatic injury
M. Crescenzi 1, C. Frasson 2, D. Gabbia 3,
S. De Martin 3, M.T. Conconi 3, G. Basso 2,
P. Burra 1, F.P. Russo 1
1 Gastroenterology Section, Department of Surgery,
Oncology and Gastroenterology, University Hospital
Padova, Italy2 Department of Woman and Child Health,
University of Padova, Institute of Pediatric Research
Città della Speranza – IRP, Padova, Italy3 Department of Pharmaceutical and
Pharmacological Sciences, University of Padova,
Padova, Italy
Aim: To verify if gender-dependent mechanisms are responsible
for liver fibrosis establishment and regression.
Materials and methods: Balb/cJ mice were intra-peritoneally
treated with CCl4 and sacrificed at week (wk) 2, 6, 12 and after
8 weeks from the cessation of the damage. We used different
techniques to analyse the mechanisms involved: H&E, immunohis-
tochemistry, Sirius Red staining, Western Blot, and flow cytometry.
Results: A significant difference in fibrotic areas at wk2
between treated mice (mean ± ds females vs. males: 5.52 ± 1.01 vs.
8.4 ± 2.02, p = 0.021) was observed. In the recovery group fibrosis
was higher in females with respect to males (mean ± ds females
vs. males: 4.48 ± 1.39 vs. 2.46 ± 0.53, p = 0.032). Alpha-SMA+ areas
significantly differed between female and male mice at wk2
(mean ± ds females vs. males: 8.52 ± 0.7 vs. 5.47 ± 0.88, p = 0.009),
with an overall decrease over time (mean ± ds females at wk2 vs.
wk12 and males wk2 vs. wk12: 8.52 ± 0.7 vs. 2.72 ± 0.24, p < 0.001
and 5.47 ± 0.88 vs. 1.58 ± 0.68, p = 0.004, respectively). Collagens I,
III and IV were found lower in females than in males at wk2, and
a reversal of the trend in the recovery group was observed. IL-6
and IL-10 were found lower in females at wk2. Interestingly, male
mice showed a significant increase of IL-6 along with a significant
decrease of IL-10 during the recovery period. Androgen Receptor+
macrophages, were found higher in females than in males both at
wk2 and in the recovery group, while GAT6+ macrophages were
present in both control mice and were found higher in females at
wk2 and showed a reversion in their abundance in the recovery
group.
Conclusions: The higher amount of fibrosis found in females
after the recovery period suggests that a molecular mechanism, not
CYP2E1-mediated, is defective in females. Female mice inflamma-
tory status preliminary analysis could explain, in part, their defects
in fibrosis regression, in respect to male mice.
http://dx.doi.org/10.1016/j.dld.2017.01.128
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e65
F-41
Portosystemic shunts in cirrhosis are associatedto more complications and deteriorated qualityof life. An international cohort study
M. Simón-Talero 1, D. Roccarina 2, A. Majumdar 2,
E.A. Tsochatzis 2, J. Martínez 3, C. Picón 4,
A. Albillos 3, K. Lampichler 5, D. Toth 5,
T. Reiberger 5, A. Baiges 6, A. Darnell 7,
V. Hernandez-Gea 6, G. Low 8, J.G. Abraldes 9,
P. Tandon 9, E. Llop 10, M. Lopez 10, J.L. Calleja 10,
M. Praktiknjo 11, G. Kukuk 12, J. Trebicka 11,
M. Maurer 13, A. Berzigotti 14, A. Zipprich 15,
C. Ripoll 15, M. Triolo 16, V. La Mura 16,
G. Vangrinsven 17, W. Laleman 17,
R. Garcia-Martinez 18, R. Banares 18, A. Dam 19,
A. Krag 19, S. Augustin 1, J. Genescà 1, the Baveno
VI-SPSS group
1 Liver Unit, Department of Internal Medicine,
Hospital Universitari Vall d’Hebron, VHIR,
Universitat Autònoma de Barcelona, CIBERehd,
Barcelona, Spain2 Sheila Sherlock Liver Unit and UCL Institute for
Liver and Digestive Health, Royal Free Hospital and
UCL, London, United Kingdom3 Department of Gastroenterology and Hepatology,
Hospital Universitario Ramón y Cajal, IRICYS,
Universidad de Alcalá, CIBERehd, Spain4 Department of Radiology, Hospital Universitario
Ramón y Cajal, IRICYS, Universidad de Alcalá,
Madrid, Spain5 Division of Gastroenterology and Hepatology,
Vienna Hepatic Hemodynamic Lab, Medical
University of Vienna, Vienna, Austria6 Hepatic Hemodynamic Laboratory, Liver Unit,
Hospital Clinic, IDIBAPS, Universitat de Barcelona,
CIBERehd, Spain7 Department of Radiology, Hospital Clinic, IDIBAPS,
Universitat de Barcelona, Barcelona, Spain8 Department of Radiology, University of Alberta,
Edmonton, Canada9 Cirrhosis Care Clinic, University of Alberta,
Edmonton, Canada10 Liver Unit, Hospital U. Puerta de Hierro,
Universidad Autónoma de Madrid, CIBERehd,
Madrid, Spain11 Department of Internal Medicine I, University of
Bonn, Germany12 Department of Radiology, University of Bonn,
Bonn, Germany13 Department of Radiology, Inselspital, University of
Berne, Switzerland14 Hepatology, Inselspital, University of Berne, Berne,
Switzerland15 First Department of Internal Medicine, Martin
Luther University Halle-Wittenberg, Halle (Saale),
Germany16 First Division of Internal Medicine, IRCCS
Policlinico San Donato, University of Milan, Milan,
Italy17 Department of Gastroenterology and Hepatology,
University Hospitals Leuven, Leuven, Belgium18 Liver Unit, Hospital General Universitario Gregorio
Maranón, Universidad Complutense, CIBERehd,
Madrid, Spain
19 Department of Gastroenterology and Hepatology,
Odense University Hospital, Odense, Denmark
Introduction: Spontaneous porto-systemic shunts (SPSS) have
been reported in hepatic-encephalopathy (HE). However, their
prevalence in cirrhosis and association with any decompensation
are not known.
Aim: determining the prevalence of SPSS in cirrhosis and the
impact on clinical outcome.
Methods: Retrospective, multicenter, international study of
consecutive cirrhotic patients submitted to abdominal-imaging
(angioCT/angioMR) (years: 2010–2015). Advanced hepatocellular
carcinoma, psychiatric or terminal illness were exclusion criteria.
Patients were classified into large SPSS (L-SPSS ≥ 8 mm), small SPSS
(S-SPSS < 8 mm), without SPSS (W-SPSS).
Results: 1785 of 2978 patients were included, median follow-
up: 19.4 months (IR 7.9–34.9), Child-Pugh A/B/C distribution:
42/38/20%. Prevalence of shunts: 26% L-SPSS, 30% S-SPSS, 44%
W-SPSS. L-SPSS/S-SPSS/W-SPSS distribution by Child: Child A
24/30/46%; B 35/33/32%; C 41/38/21% (p < 0.001). Patients with L-
SPSS had the highest prevalence of HE (prior abdominal-imaging, at
time of abdominal-imaging and during the follow-up): L-SPSS 58%,
S-SPSS 42%, W-SPSS 27% (p < 0.001) and recurrent/persistent HE:
L-SPSS 50%, S-SPSS 40%, W-SPSS 13% (p < 0.001) with differences in
quality of life (QoL, autonomy according to mRS): L-SPSS 76%, S-
SPSS 81%, W-SPSS 91% (p < 0.001). L-SPPS significantly influenced
the presence of HE in Child A and B (p < 0.001) and the presence of
recurrent/persistent HE in each Child class. Child A patients with
SPSS had more ascites and bleeding (p = 0.03). However, transplant-
free survival was no different according to the presence of SPSS in
the 3 Child classes.
Conclusions: SPSS are common in cirrhosis and their prevalence
increases with liver function deterioration. SPSS are associated
with frequent and severe HE-episodes, poorer QoL and more
ascites/bleeding in Child A. No association with mortality was
observed.
http://dx.doi.org/10.1016/j.dld.2017.01.129
F-42
High rate of misclassification of fibrosis stageusing transient elastography thresholds toprioritize HCV patients for antiviral treatment
V. Calvaruso 1, F. Bronte 1, B. Magro 1, E. Conte 1,
S. Petta 1, D. Cabibi 2, A. Craxì 1, C. Cammà 1,
V. Di Marco 1
1 Sezione di Gastroenterologia e Epatologia,
Dipartimento Biomedico di Medicina Interna e
Specialistica (Di.Bi.M.I.S.), University of Palermo,
Palermo, Italy2 Istituto di Anatomia Patologica, Scienze per la
Promozione della Salute e Materno Infantile “G.
D’Alessandro”, University of Palermo, Palermo, Italy
Background: Transient elastography (TE) is largely used to stage
fibrosis in patients with Hepatitis C Virus (HCV) infection and
recently the threshold of 10 kPa, as marker of severe fibrosis, has
been considered as a criteria to prioritize HCV patients to therapy
with Direct Antiviral Agents (DAAs).
Aims: To assess diagnostic reliability of TE in identifying severe
fibrosis or cirrhosis and in ruling out patients with mild-moderate
fibrosis in a large cohort of patients with histological diagnosis of
HCV chronic hepatitis.
e66 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
Methods: We included in this analysis 716 consecutive HCV
patients who underwent liver biopsy (METAVIR score) within 1
months of TE.
Results: TE was not reliable in 20 patients (2.8%) due to obesity.
TE < 10 kPa was found in 461 patients (66.2%), 49 of them had a
METAVIR stage ≥3 (F ≥ 3) with a false negative rate (FNR) of 10.6%
(sensitivity 82.2%, NPV 89.4%) and 89 patients had a F ≤ 2 (false
positive rate-FPR: 37.9%, specificity 74.9, PPV 62.1%) with a misclas-
sification rate of 48.5%. Reducing the TE cut off to 8 kPa the rate of
patients with F ≥ 3 and TE < 8kPa (FNR) was 7.4% (28/379 patients)
with a FPR (patients with F0-2 and TE ≥ 8 kPa) of 47.3% (150/317
patients) increasing the misclassification rate to 54.7%.
When the threshold of 8 kPa was used to identify patients with
METAVIR stage = 2 (F2), the rate of patients with F2 and TE < 8 kPa
(FNR) was 25.1% (95/379 patients), NPV: 74.9%; and the FPR was
17.4% (55/317 patients), NPV 82.6% and a misclassification rate of
42.5%.
Conclusions: In HCV patients, the use of TE threshold of 10 kPa
is related to a misclassification rate of the patients to prioritize
to DAAs in almost of 50% of cases with a significant risk to defer
antiviral therapy in patients with severe fibrosis. Moreover, the
low performance of TE for significant fibrosis do not allow to find
a reliable TE threshold which correctly select patients with Stage 2
fibrosis for DAAs.
http://dx.doi.org/10.1016/j.dld.2017.01.130
F-43
The prevalence of liver diseases due Hepatitis CVirus (HCV) in Sicily: A population-based survey
F. Cartabellotta 1, V. Calvaruso 1, C. Paci 2,
F. Magliozzo 2, V. Milazzo 2, C. Crisafulli 2,
C. Lo Curcio 2, M. Russello 1, A. Digiacomo 1,
L. Galvano 2, L. Spicola 2, V. Di Marco 1
1 RESIST-HCV (Rete Sicilia Selezione Terapia-HCV),
Italy2 Società Italiana di Medicina Generale (SIMG)
Sicilia, Italy
Background and aims: HCV therapies have transformed the
treatment landscape, but data on the prevalence of HCV infection
and related liver disease in Italy are out-dated. This survey assessed
the prevalence of HCV liver disease in a large number of Sicilian
citizens.
Methods: The first step of survey was carried-out in a country
with 10,449 inhabitants (Campobello di Licata) where 7 general
practitioners evaluating patients with chronic HCV disease regis-
tered in their database.
The second step evaluated the clinical database of 84,480 per-
sons managed by 70 general practitioners of several countries of
Sicily.
Results: In Campobello di Licata the prevalence of HCV chronic
disease was 1% (101 patients/10,447 inhabitants) with differ-
ence between women (0.77% of 5548) and men (1.18% of 4899)
(p = 0.042). The rate of HCV disease decreased from 3.29% in per-
sons over 70 years to 2.0% in persons with 60–70 years and fell to
0.67% between 50–60 years. The prevalence was highest between
40–50 years (1.13%) with a significant difference between women
(4/784, 0.51%) and men (13/713, 1.81%; p = 0.025) probably due to
the risk of past drug addiction. Only 4 men of 1309 people (0.3%)
aged 30–40 years and no persons under 30 years had HCV hepatitis.
In the second survey the prevalence of HCV chronic diseases was
0.96% with a range between 0.48% and 1.53% in different geographic
area. Among 800 persons with HCV chronic disease, 230 (28.7%)
had over 75 years, 317 (39.6%) 60–75 years and 210 (26.2%) 40–60
years. Only 47 persons (5.8%) were under 40 years.
Conclusion: Our survey shows that 1% of Sicilian citizens have
a known chronic liver disease due to HCV infection. These per-
sons need to be evaluated for antiviral therapy. In the coming
years, healthcare organizations must determine the need for a
population-based screening to identify all people with chronic HCV
infection.
http://dx.doi.org/10.1016/j.dld.2017.01.131
F-44
HCC onset and features among chronic hepatitisB patients treated with nucleos(t)ide analogues
M. Schranz 1, M. De Giorgio 1, G. Conte 2,
L. Pasulo 1, G. Magini 1, S. Fagiuoli 1
1 Department of Hepatology and Transplantology,
ASST Papa Giovanni XXIII, Bergamo, Italy2 Department of Surgery, Transplant Division, ASST
Papa Giovanni XXIII, Bergamo, Italy
Introduction: The impact of HBV antiviral treatment on HCC
occurrence is still debated.
Patients and methods: This study included 345 HBsAg positive
patients who were consecutively evaluated for the occurrence of
HCC at our centre since 2000. Patients with comorbidities like viral
co-infection, elevated alcohol consumption or metabolic syndrome
were excluded (n = 287). After removal of possible confounders,
remaining patients were divided into a study group (n = 25), includ-
ing patients who received nucleos(t)ide analogue (NA) treatment
for at least one year, and a treatment naïve (or NA experienced for
less than 1 year) control group (n = 33). The differences in features of
HCC between the two groups and the distribution of HCC according
to the duration of antiviral treatment were evaluated.
Results: Within the study group 11 (44%) patients were ini-
tially treated with lamivudine, 10 (40%) with entecavir and 3 (12%)
with tenofovir, while 1 (4%) patient received both lamivudine and
adefovir. In 12 patients treatment was subsequently modified.
No significant difference between the two groups was
found concerning number of cirrhotic patients, number of HCC
lesions, cumulative diameter, angioinvasion and histological grade
(p > 0.05).
Patients treated with NAs more frequently exceeded 400 ng/ml
alpha fetoprotein (AFP) serum concentration (24% vs. 6%, p = 0.05)
and had significantly more often tumour lesions without typical
hypervascular appearance in imaging (16% vs. 0%, p = 0.017).
Among NA treated patients the mean annual HCC occurrence
was 3 times higher during the first 7 years of therapy and decreased
subsequently to just 1 case per year.
Conclusions: In our study group (76% cirrhotic patients) the
effect of NAs on the reduction of HCC incidence becomes evident
after several years and correlates well with the expected effect on
the regression of cirrhosis. Moreover, HCC in NA treated patient
seems to show more aggressive tumour features.
http://dx.doi.org/10.1016/j.dld.2017.01.132
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e67
F-45
Effect of interferon free antiviral therapy onglomerular and tubular kidney involvement inHCV child-A cirrhosis
D. Palazzo 1, E. Biliotti 1, F. Tinti 1, A. Bachetoni 2,
L. Volpicelli 1, A. Cappoli 1, M.D. D’Alessandro 2,
R. Labriola 2, P. Perinelli 1, S. Grieco 1, M. Subic 3,
I. Umbro 1, P. Rucci 4, A.P. Mitterhofer 1,
G. Taliani 1
1 Department of Clinical Medicine, Sapienza
University of Rome, Rome, Italy2 Department of General Surgery Paride Stefanini,
Sapienza University of Rome, Rome, Italy3 Department of Internal Medicine, Sapienza
University of Rome, Rome, Italy4 Department of Biomedical and Neuromotor
Sciences, University of Bologna, Bologna, Italy
Background: Hepatitis C virus (HCV) infection is associated with
an increased risk of renal disease. The correlation between HCV
and glomerular damage is well recognized, but limited data are
available on HCV-mediated tubular damage. Recently, several novel
direct antiviral agents (DAAs) have been approved for HCV treat-
ment, but the effects of HCV clearance on renal involvement (RI)
has not been fully characterized.
Aim: The aim of this study was to evaluate the effect of viral
eradication, by means of DAAs, on renal glomerular (GI) and tubular
involvement (TI) in pts with HCV-related cirrhosis.
Materials and methods: 94 CPA cirrhotic pts treated with
DAAs were consecutively enrolled. Estimated glomerular filtration
rate (e-GFR) assessed by CKD-EPI equation, urinary albumin-
to-creatinine ratio (ACR), urinary �1-microglobulin-to-creatinine
ratio (�1MCR) and sodium fractional excretion (FeNa) were eval-
uated before starting therapy (T0) and six months after treatment
withdrawal (FU6). GI was defined as ACR > 30 mg/g, TI was defined
as �1MCR > 14 mg/g and/or FeNa > 1%.
Results: RI (glomerular and/or tubular) occurred in 39 pts
(41.5%). GI was found in 19 pts (20.2%), 6 of them (31.6%) had dia-
betes. TI was detected in 30 pts (31.9%). Pts with RI showed lower
e-GFR values than pts without RI (95.2 ± 15.2 mL/min/1.73 m2
vs. 85.1 ± 5.8 mL/min/1.73 m2, p = 0.07). In diabetic pts with GI,
ACR did not change after treatment (316.2 ± 406.7 mg/g vs.
321.3 ± 416.2 mg/g, p = 0.92), while a significant reduction of ACR
(73.5 ± 138.5 mg/g vs. 19.9 ± 12.3 mg/g, p = 0.019) occurred in non-
diabetic HCV cirrhotic pts and GI resolved in 11/13 (84.6%) pts
without diabetes. The proportion of pts with TI decreased sig-
nificantly after DAAs treatment, since in 14/25 (56%) patients TI
recovered.
Conclusions: Our study confirms a strong relationship between
HCV and GI and underlines significant occurrence of TI. In HCV
cirrhotic pts with diabetes the GI seems to be mainly driven by
the metabolic disorder rather than by HCV infection itself. This is
the first report demonstrating a significant improvement of either
non-diabetic glomerular, either tubular HCV-induced damage after
HCV clearance by DAAs therapy, emphasizing the importance of
antiviral treatment.
http://dx.doi.org/10.1016/j.dld.2017.01.133
F-46
The old patient in DAA era: Real life reports on5925 patients from the Lombardy HCV Network
L. Pasulo 1, A. Aghemo 2, S. Fargion 2, A. Spinetti 3,
G. Cologni 4, F. Maggiolo 4, G. Rizzardini 5,
M. Puoti 6, R. Bruno 7, L. Minoli 8, M. Zuin 9,
C. Uberti Foppa 10, T. Quirino 11,
A. D’Arminio Monforte 12, A. Colli 13, M.G. Rumi 14,
C. Iegri 1, S. Fagiuoli 1, M. Colombo 2
1 Gastroenterology, ASST Papa Giovanni XXIII,
Bergamo, Italy2 Gastroenterology, IRCSS Policlinico Milano, Milan,
Italy3 Infectious Disease, Spedali Civili, Brescia, Italy4 Infectious Disease, ASST PAPA GIOVANNI XXIII,
Bergamo, Italy5 Infectious Disease, Sacco Hospital, Italy6 Infectious Disease, Ca’ Granda Niguarda Hospital,
Milan, Italy7 Infectious Disease, Policlinico Pavia, Italy8 Infectious Disease, Policlinico Pavia, Pavia, Italy9 Gastroenterology, San Paolo Hospital, Italy10 Immunology and Infectious Disease, San Raffaele
Hospital, Milan, Italy11 Infectious Disease, Busto Arsizio Hospital, Varese,
Italy12 Infectious Disease, San Paolo Hospital, Milan, Italy13 Internal Medicine, Lecco Hospital, Lecco, Italy14 Hepatology, San Giuseppe Hospital, Milan, Italy
Background and aims: Since May 2015, 34 Prescribing Centers
from the Lombardia Region HCV Network (Northern Italy) col-
lected Real life data from DAA IFN-free treatments of older patients
(>70 yrs old) with chronic Hepatitis C (HCV).
Methods: We retrospectively/prospectively analyzed the data
of 5925 patients affected by HCV infection treated with DAA accord-
ing to the EASL and AISF guidelines. The data were stratified for
age.
Results: At the time of the analysis, 3067 patients had com-
pleted the treatment, and 2987 could be evaluated for SVR 12;
of these, 2396 (78.12%) were younger than 70 yrs (group 1) and
582 (21.87%) were older than 70 yrs (group 2). Baseline character-
istics: in group 1, higher rates of both male and HIV co-infections
were reported; the distribution of genotypes was significantly dif-
ferent among the two groups: Genotype 1b 68.6% vs. 38.5% and
Genotype 2 28.4% vs. 9% respectively in Group 2 and 1. Only 2 pts
Fig. 1.
e68 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
Fig. 2.
with Genotype 3 were present in group 2. By ITT analysis, over-
all SVR12 was 95% (2834/2978) (the results are shown in Fig. 1).
Among the cirrhotic patients SVR12 was 94% and a MELD score
improvement was observed (44,6% in group 1 vs. 32.4% in group 2:
p < 0.002); no differences in MELD variation emerged when pts ≥70
y.o. were stratified by 5-year blocks. SAEs were observed in 1.8% (n.
56) during treatment or follow-up.
Conclusions: In our cohort, overall SVR12 was 95%. No sig-
nificant differences in SVR were observed between patients with
age greater or lower than 70 yrs (Figs. 1 and 2). Among cirrhotic
patients, a MELD score improvement was observed in 44.6% of
younger patients vs. 33.5% of elder patients. Comorbidities, age-
related metabolic events and/or longer disease duration might play
a role in preventing liver function restoration after HCVRNA eradi-
cation in elder patients.
http://dx.doi.org/10.1016/j.dld.2017.01.134
F-47
Genotype 3 infection in DAA era: Reports of areal life Northern Italy Network for viralhepatitis after 2 years by the start
L. Pasulo 1, A. Aghemo 2, T. Quirino 3, P. Viganò 4,
P. Bonfanti 5, E. Buscarini 6, M. Strazzabosco 7,
M. Puoti 8, M. Vinci 8, P. Perini 9, M. Colpani 1,
M. Colombo 2, S. Fagiuoli 1
1 Gastroenterology, ASST Papa Giovanni XXIII,
Bergamo, Italy2 Gastroenterology, IRCSS Policlinico Milano, Italy3 Infectious Disease, Busto Arsizio Hospital, Italy4 Infectious Disease, Legnano Hospital, Italy5 Internal Medicine, Lecco Hospital, Italy6 Gastroenterology Department, Crema Hospital,
Italy7 Gastroenterology Department, San Gerardo
Hospital, Monza, Italy8 Infectious Disease, Ca Grande Niguarda Hospital,
Milan, Italy9 Internal Medicine, Ponte San Pietro San Marco
Hospital, Italy
Background and aims: In this new era, HCV genotype 3 has
emerged as a difficult-to-treat viral strain, achieving response rates
lower than other genotypes. The Lombardy Region Network col-
lected data on HCV Gen3 treatments since May 2015.
Aim: To explore the real life outcome of g3infected patients
treated with DAAs.
Fig. 1.
Methods: 806 g3 infected pts were prospec-
tively/retrospectively. 30%, 66% and 4% of pts received respectively:
SOF + RBV, SOF + DAC ± RBV, PEG + SOF + RBV. Treatment duration
was 24 weeks in 85%.
Results: 85.8% of patients were cirrhotic of whom 82% were
well compensated and the remaining were waitlisted for LT. Pts
treated with DAC + SOF + RIBA were older, with a higher rate of
cirrhosis. Overall, 21 SAEs (3.28%), unrelated to therapy, were
observed during treatment or follow-up. 1 pt died for heart attack
and Another one for end stage liver disease. At the time of the
analysis, 639 pts had completed the treatment and 433 could be
evaluated for SVR 12. The overall SVR12 was 88.4%. No differences
were observed in SVR rate by stratifying the patients according
to: presence/absence of cirrhosis, HIV coinfection and treatment
duration. SVR rates in pts treated with SOF + RBV (81%) were sig-
nificantly lower (p < 0.005) than in pts treated with SOF + DAC
(89%), SOF + DAC + RBV (97%) and PEG + SOF + RBV (90%). In cir-
rhotic patients SVR12 was 87.54%: a significant MELD improvement
was observed (median EOT MELD: 6 vs. median baseline MELD:
9: p < 0.005); the patients which presented a MELD improvement
were statistically younger (median age 51 yrs vs. 54 yrs) (p < 0.005)
(Fig. 1).
Conclusions: In our cohort the highest SVR rates were achieved
with SOF + DAC + RIBA. No significant differences were observed in
SVR rate by stratifying Genotype 3 patients according to the pres-
ence or absence of cirrhosis (94% in F4 patients vs. 100% in F3) for
DAC + SOF + RIBA. Among cirrhotic patients, a MELD score improve-
ment was observed in 49.3% of patients.
http://dx.doi.org/10.1016/j.dld.2017.01.135
Abstracts / Digestive and Liver Disease 49S (2017) e43–e70 e69
F-48
Pre-emptive post-liver transplant (LT) HCVtreatment with DAAs: Proof of concept from apilot study
L. Pasulo 1, C. Mazzarelli 2, C. Iegri 1, L. De Carlis 3,
R. Viganò 2, F. Donato 4, G. Rossi 5, A. Zanetto 6,
S. Shalaby 6, S. Fagiuoli 1, L. Belli 2
1 Gastroenterology, ASST Papa Giovanni XXIII,
Bergamo, Italy2 Gastroenterology, Ca Granda Niguarda, Italy3 Surgery, Ca Granda Niguarda, Italy4 Gastroenterology, IRCSS Policlinico Milano, Milan,
Italy5 Surgery Department, IRCSS Policlinico Milano,
Milan, Italy6 Multivisceral Transplant Unit, University Hospital
of Padua, Padova, Italy
Background and aims: The adoption of a “true” pre-emptive
treatment with DAA has never been explored so far. In our pilot
study, SOF + RIBA were administered starting on the day of trans-
plant surgery.
Aim: To evaluate feasibility, safety and efficacy of a Sofosbuvir
plus ribavirin post-LT preemptive regimen.
Methods: 45 consecutive HCV positive patients undergoing LT
were prospectively enrolled for a 24 weeks SOF + RBV treatment.
The first dose of SOF + RIBA was administered at graft implant,
through N-G tube; HCV-RNA was tested at 1st, 2nd, 4th wk and
then every 4 weeks until 24th weeks post-treatment.
Results: The baseline features of recipients/donors are shown in
Table 1. At the time of the analysis, 24/45 reached SVR 12. At week
1, in 9% HCV-RNA was undetectable (NR), in 75% the viral load was
<3 log. All patients achieved EOT response. At univariate analysis,
advanced donor age showed a statistically significant correlation
with viral load decay (slope: −0.02; correlation: −0.34; r-squared:
−0.12; p = 0.04). By ITT analysis, SVR12 was 92% (2 relapses, both
due to RBV withdrawal during treatment: 1 voluntary and 1 due
to anemia). Five patients died for complications unrelated to DAA
treatment during the post-operative period and 1 patient died
for fibrosing cholestatic hepatitis after relapse. Acute rejection
occurred in 12.1%. The peak of incidence of anemia (Hb < 9 g/dl)
occurred at week 2 in 23% of patients); Blood transfusions (BT) were
the first supportive care option followed by erythropoietin; from
treatment week 12 no more transfusion were needed.
Table 1Baseline features of recipients.
Age 52 [50–57]
Male sex (N%) 88%
BMI (kg/m2) 24.5 [22.7–27]
Indication for LT
ESLD 55%
HCC 45%
Median MELD at the time of LT 17 (14–22)
Median HCV-RNA at the time of LT 4.8 (4–5.1)
Genotype
1a 16%
1b 23%
3 26%
4 35%
Experienced (%) 52%
Donors features
Median age [95% UCL-LCL] 57 (52–71)
Anti-Hbc+ (N%) 16%
Median cold ischemia time 467 (360–506 min)
Immunosuppression regimen
FK 45%
Cyclosporine 55%
Median ribavirin dose at the start 1000 mg/day
Conclusions: Our pilot study shows that a preemptive treat-
ment strategy is a feasible strategy: adopting a “sub-optimal” RBV
containing regimen, SVR 12 was obtained in 92% (failures due to
RBV-related anaemia). Based upon this data, a RBV-free regimen
could warrant excellent result. By the time of the EASL meeting,
more patients will have reached the end-point for SVR.
http://dx.doi.org/10.1016/j.dld.2017.01.136
F-49
Early changes in non invasive assessment ofliver fibrosis in hepatitis C virus-infectedpatients treated with DAAs: Preliminary reports
C. Iegri, L. Pasulo, M. Colpani, L. Sangiovanni,
G. Rizzatti, M. Schranz, G. Magini, M. De Giorgio,
M.G. Lucà, G. Gaffuri, S. Fagiuoli
Gastroenterology Department, ASST PAPA GIOVANNI
XXIII, Bergamo, Italy
Background and aims: Early identification of potential cirrhosis
reverser is a key-point for a personalized risk stratification of liver
related complications.
Aim: To evaluate early changes of fibrosis by liver stiffness mea-
surement and early identification of potential “cirrhosis reverser”
in patients treated with DAAs.
Methods: 88 HCV pts were treated prospectively with DAAs. LS
was measured at baseline and 24 weeks after EOT. LSM was not
reliable in 8 patients (excluded from the final analysis).
Results: Well compensated cirrhosis was present in 85%;
median MELD score was 8 [7–9]. Median baseline LS values in over-
all population (OP) were 20.4 kPa [17.3–21.5]; median LSM was
21.4 kPa in cirrhotics [18.8–22.8] vs. 10.1 kPa in non cirrhotics (95%
CI: 7.3–10.5) (p = 0.0001). SVR 24 rate was 97.5%. The median LS
value 24 wks after EOT was 13.7 kPa [10.5–16.2] in OP, significantly
lower compared to baseline (p = 0.002). The decrease was statisti-
cally significant among cirrhotics (LS24 wks: 15.6 kPa [12.6–16.9];
p < 0.05) but not in non-cirrhotics (LS24 wks: 8.2 kPa [4.7–10.4];
p = 0.17). Cirrhotic patients with ALT < 2 ULN who showed a non-
invasive “downstaging” of at least one corresponding Metavir stage
were defined “early reverser”: 14 pts reversed to a precirrhotic
stage (6 pts-F3; 6 pts-F2 and 2 pts-F1). At univariate analysis: lower
PLT count, higher MELD score, higher APRI and Liver Stiffness val-
ues were significantly associated to failure of reversing cirrhosis
(p = 0.009; p = 0.01; p = 0.04 and p = 0.001, respectively). The pres-
ence of metabolic disorders (MD) and/or clinically significant portal
hypertension was significantly higher in non-reverser (MD: 46%
and CSPH: 74%) compared to reverser (MD: 7%; p < 0.001; CSPH:
20%; p < 0.0001). At multivariate analysis, none of these variables
emerged as independent predictors of failure to reverse cirrhosis.
Conclusions: A significant decrease in LSM was observed in SVR
patients. Among cirrhotic patients, 17.5% were identified as early
reverser according with serial LSM. These initial results need to be
confirmed after longer follow-up.
http://dx.doi.org/10.1016/j.dld.2017.01.137
e70 Abstracts / Digestive and Liver Disease 49S (2017) e43–e70
F-50
Treatment of chronic hepatitis C in Lombardia:An analysis on the safety and efficacy of DAAtherapy in 5457 patients
A. Aghemo 1, L. Pasulo 2, M. Puoti 3, S. Zaltron 4,
F. Maggiolo 5, G. Rizzardini 6, S. Fargion 7,
R. Bruno 8, M. Zuin 9, T. Quirino 10, M.G. Rumi 11,
A. Pan 12, P. Grossi 13, A. Rossini 14, A. Corbellini 15,
S. Fagiuoli 2
1 Gastroenterology and Hepatology, IRCSS Policlinico
Milano, Milan, Italy2 Gastroenterology, ASST Papa Giovanni XXIII, Italy3 Infectious Disease Ca’ Granda Niguarda Hospital,
Milan, Italy4 Infectious Disease, Spedali Civili, Brescia Bergamo,
Italy5 Infectious Disease, ASST PAPA GIOVANNI XXIII,
Bergamo, Italy6 Infectious Disease, Sacco Hospital, Italy7 Internal Medicine, IRCSS Policlinico Milano, Milan,
Italy8 Infectious Disease, Policlinico Pavia, Italy9 Gastroenterology, San Paolo Hospital, Milan, Italy10 Infectious Disease, Busto Arsizio Hospital, Varese,
Italy11 Hepatology, San Giuseppe Hospital, Milan, Italy12 Infectious Disease Cremona Hospital, Italy13 Infectious Disease Varese Hospital, Italy14 Hepatology, Spedali Civili, Brescia Bergamo, Italy15 Infectious Disease Vizzolo Pradabissi Hospital,
Italy
Background: Directly acting antivirals have allowed safe and
effective treatment in patients with chronic hepatitis C infection.
Real life data in Italian patients with advanced fibrosis and older
age are still few.
Methods: The Lombardia Hepatitis Networks created in 2015
included 19 liver centers and 2 macro-area networks.
Results: From December 2014 till November 2016, 5457
patients have received treatment with DAAs and have been
included in the analysis. The mean age was 59.3 years, 23% of
patients were older than 70 years of age, 64% were male. The most
prevalent genotypes were HCV-1 (61.2%) and HCV-3 (15.1%). 908
(17.5%) patients were HIV coinfected. Advanced fibrosis/Cirrhosis
(F3–F4) was present in 74.3%, the mean Child-Pugh was 5.4 ± 0.9,
the mean MELD was 8.5 ± 3.1. The most prescribed regimens
were SOF/LED ± RBV (30%), 3D ± RBV (18.6%), SOF + RBV (16%),
SOF + DAC ± RBV (15.6%) and SOF + SIM ± RBV (15.5%). Only 1% of
patients received a PEG-IFN containing regimen. At the time of the
analysis 3067 patients have completed treatment and 12 weeks
of follow-up and could be assessed for SVR. Overall the SVR rate
was 95%, being 97.3% in HCV-1a, 96.8% in HCV-1b, 94.7% in HCV-2,
88.4% in HCV-3 and 93.6 in HCV-4 (p = 0.0001). The disappointing
SVR rates in HCV-3 were the consequence of suboptimal efficacy
of SOF + RBV (SVR 82%). In HCV-3 patients the combination of
SOF + DAC ± RBV achieved SVR rates of 94%. Serious adverse events
(SAE) were observed in 115 patients (2.1%), and were deemed to be
probably or certainly related to DAA therapy in 40.3% of cases. The
incidence of SAEs was not associated with gender or patients age,
in patients over 70 years old the SAE incidence was 2.9%.
Conclusions: In a large cohort of Italian patients with advanced
fibrosis and older age, DAAs were safe and effective in all genotypes.
http://dx.doi.org/10.1016/j.dld.2017.01.138
Digestive and Liver Disease 49 (2017) e71
http://dx.doi.org/10.1016/j.dld.2017.01.160
1590-8658/
A.I.S.F. 2017: Abstracts Evaluation Procedure
Contents lists available at ScienceDirect
Digestive and Liver Disease
journal homepage: www.elsevier .com/locate/dld
Thanks to experts evaluating all the abstracts according to predetermined Clinical and Experimental categories.
The experts for the 2017 Annual Meeting are listed below:
Category A. “EXPERIMENTAL VIRAL HEPATITIS” B. Coco, Pisa - C. Ferrari, Parma – P. Pontisso,
Padua - F.P. Russo, Padua - A.L. Zignego, Florence
Category B. “HEPATITIS B & DELTA CLINICAL” B. Coco, Pisa - V. Di Marco, Palermo - C. Ferrari,
Parma - A. Marzano, Turin – M. Masarone, Salerno - F.P. Russo, Padua - G. Taliani, Rome
Category C. “HEPATITIS C CLINICAL” A. Aghemo, Milan - P. Andreone, Bologna - D. Bitetto,
Gemona del Friuli (UD) - S. Bruno, Rozzano (MI) - V. Di Marco, Palermo - A. Mangia, S.G. Rotondo (FG) - F. Morisco, Naples - G. Taliani, Rome - A.L. Zignego, Florence
Category D. “NAFLD & ALD EXPERIMENTAL” A. Alisi, Rome - P. Dongiovanni, Milan - C. Loguercio,
Naples - S. Petta, Palermo
Category E. “NAFLD & ALD CLINICAL” A. Fracanzani, Milan - C. Loguercio, Naples - S. Petta,
Palermo - C. Puoti, Grottaferrata (RM) - E. Vanni, Turin
Category F. “AUTOIMMUNE HEPATITIS & BILIARY DISEASE” V. Cardinale, Rome - A. Floreani, Padua - L. Muratori,
Bologna - C. Rigamonti, Novara - F. Rosina, Turin - C. Spirli, New Haven, CT (USA)
Category H. “EXPERIMENTAL LIVER DAMAGE, FIBROSIS, CIRRHOSIS & PORTAL HYPERTENSION”
M. Fraquelli, Milan - F. Marra, Florence – M. Parola, Turin - G. Svegliati-Baroni, Ancona
Category I. “FIBROSIS, CIRRHOSIS & PORTAL HYPERTENSION CLINICAL”
A. Berzigotti, Bern (Switzerland) - F. Campagna, Padua - P. Caraceni, Bologna - A. Dell’Era, Milan - V. La Mura, Milan - F. Schepis, Modena
Category L. “HEPATOCELLULAR CARCINOMA EXPERIMENTAL” F. Farinati, Padua - L. Gramantieri, Bologna - G. Missale,
Parma - E. Villa, Modena
Category M. “HEPATOCELLULAR CARCINOMA CLINICAL” A. Cucchetti, Bologna - F. Farinati, Padua - M. Iavarone,
Milan - G. Missale, Parma - F. Piscaglia, Bologna - G.L. Rapaccini, Rome - E. Villa, Modena
Category N. “LIVER FAILURE, HEPATOBILIARY SURGERY & TRANSPLANTATION”
M. Angelico, Rome - L. Baiocchi, Rome - P. Burra, Padua - M.F. Donato, Milan - S. Fagiuoli, Bergamo - E. Gringeri, Padua - M. Strazzabosco, Milan, New Haven, CT (USA)
Category O. “MISCELLANEOUS: GENETIC, PEDIATRIC, NUTRACEU-TICALS, DILI, OTHER”
A. Cappon, Padua - S. Fargion, Milan - A. Gasbarrini, Rome – G. Germani, Padua – F. Giannone, Bologna - A. Lleo, Rozzano (MI) - G. Svegliati Baroni, Ancona