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NASH: BEYOND THE
ACRONYM, CERTAINTIES
AND CLINICAL DILEMMAS
12-14 MAY 2016
RIGA, LATVIA
Scientific Organising Committee
Jean-François Dufour, Bern, Switzerland
Manuel Romero-Gomez, Sevilla, Spain
Vlad Ratziu, Paris, France
www.easl.eu
Specialties
Cirrhosis and
complications
General
hepatology
Metabolic,
alcohol
and toxicity
Liver tumours
Cholestatic and
autoimmune
Viral
hepatitis
Fields
Liver transplant and surgery
Public health
Basic and translational science
Imaging and interventional
What’s your colour?
Follow the colour codes and pictogrammes throughout this book
to find the sessions of interest to you!
CONTENTS
Welcome message.......................................................................................................................................................................................................................... 5
Committees.............................................................................................................................................................................................................................................6
Acknowledgements........................................................................................................................................................................................................................ 7
General information......................................................................................................................................................................................................................9
Scientific programme................................................................................................................................................................................................................ 13
ePoster sessions.............................................................................................................................................................................................................................19
Invited speakers’ abstracts..............................................................................................................................................................................................30
ePoster abstracts........................................................................................................................................................................................................................... 71
EASL Monothematic Conference • Riga, Latvia • 12-14 May, 2016
3
THE LEADING LIVER ASSOCIATION IN EUROPE
APPLY FOR AN EASL
FELLOWSHIP PROGRAMME!
EASL Physician Scientist Fellowship
Applications open from 30 April - 30 June 2016
APPLICATION CONDITIONS
• No restrictions on applicant’s nationality
• Leading European hosting institutions
• Open to all registered EASL members
As a continuation of the Dame Sheila Sherlock EASL Fellowship Programs, this initiative aims at enabling physician-scientists to take a leave from their clinical duties and
to spend 6 or 12 months in a research laboratory.
Physician Scientist Fellowship Program is open to all registered EASL members and
applicants can apply for either:
•
•
6-month research fellowship of €20,000
12-month research fellowship of €40,000
One 6-month and one 12-month fellowship will be awarded each year.
i For more information on application conditions, deadlines and details visit www.easl.eu
www.easl.eu
WELCOME MESSAGE
We are delighted to invite you to attend the EASL Monothematic Conference “NASH:
Beyond the acronym: certainties and clinical dilemmas” in Riga, Latvia.
COVERED TOPICS
NASH
Epidemiology
Disease History and Prognostic
Diagnosis Progress
Disease Management
TARGETED AUDIENCE
Hepatologists
Physicians with interest in Hepatology
Researchers in the field of NASH
Health professionals
Young researchers and trainees
WHY ATTEND?
The latest on NASH diagnosis and management
Cutting edge clinical research on NASH
Network with renowned specialists and leading experts
Prof. Jean-François Dufour
Bern, Switzerland
Prof. Manuel Romero-Gómez
Sevilla, Spain
Prof. Vlad Ratziu
Paris, France
5
SCIENTIFIC ORGANISING COMMITTEE
Prof. Jean-François Dufour, Bern, Switzerland
Prof. Manuel Romero-Gómez, Sevilla, Spain
Prof. Vlad Ratziu, Paris, France
EASL GOVERNING BOARD
SECRETARY GENERAL
Laurent Castera, Paris, France
VICE-SECRETARY
Tom Hemming Karlsen, Oslo, Norway
TREASURER
Mauro Bernardi, Bologna, Italy
SCIENTIFIC COMMITTEE MEMBERS
Annalisa Berzigotti, Bern, Switzerland
Alejandro Forner, Barcelona, Spain
Marco Marzioni, Ancona, Italy
Philip N. Newsome, Birmingham, United Kingdom
Frank Tacke, Aachen, Germany
EDUCATIONAL COUNCILLORS
Massimo Pinzani, London, United Kingdom
Francesco Negro, Geneva, Switzerland
EU POLICY COUNCILLORS
Helena Cortez-Pinto, Lisbon, Portugal
EXECUTIVE DIRECTOR
Gregoire Pavillon, Aclens, Switzerland
6
Programme & Abstracts • NASH: Beyond the acronym, certainties and clinical dilemmas
ACKNOWLEDGEMENTS
PREMIUM SPONSORS
EASL thanks its Premium Sponsors for their generous contributions and support
of the EASL Monothematic Conference: "NASH: Beyond the acronym, certainties
and clinical dilemmas" with an unrestricted educational grant.
7
LIVER FIBROSIS:
THE NEXT GOAL OF
TARGETED THERAPY?
17-18 JUNE 2016
PORTO, PORTUGAL
Sophie Lotersztajn, Creteil, France
Massimo Pinzani, London, UK
Christian Trautwein, Aachen, Germany
JOIN US IN PORTO
REGISTER TODAY!
www.easl.eu/_events
www.easl.eu
GENERAL
INFORMATION
GENERAL INFORMATION
GENERAL INFORMATION
CONFERENCE VENUE
CLIMATE
Radisson Blu Hotel Latvija,
Elizabetes 55 LV-1010,
Riga, Latvia
Riga has a humid continental climate with
warm summers and no dry season. The
month of May is characterized by rising
daily high temperatures, with daily highs
increasing from 16°C to 20°C over the
course of the month, exceeding 25°C or
dropping below 9°C only one day in ten.
DISCOVER RIGA
City website:
http://www.latvia.travel/en/city/riga-8
Riga, the capital of Latvia, is the pearl
both of Latvia and the whole of the
Baltics. Riga is included in the UNESCO
World Cultural and Natural Heritage
list. It is located in the central part of the
country, on the South coast of the Gulf
of Riga, at the mouth of the largest river,
the Daugava. Riga is home for more than
700,000 inhabitants and is the largest city
in the Baltic States.
As Riga has developed at the crossroads
of trade, the metropolis has become a
multicultural city in which one can always
find a large number of things that are of
interest. Each century has left its mark in
the city’s features. They can be seen in the
architecture of the Old Town and the City
Centre. This cultural heritage coexists
harmoniously with the quick pace of
modern living.
All participants are kindly requested to
wear their name badges throughout the
EASL Monothematic Conference in
order to be admitted to the lecture halls
and other scheduled activities.
REGISTRATION AND ACCOMMODATION
All participants are invited to register
online in order to save time upon their
arrival at the conference.
Hotel accommodation for the EASL
Monothematic Conference will be
offered to participants during the online
registration process. Detailed information,
as well as access to the online registration
is available on the website. Registered
participants are entitled to reduced rates
in the conference hotel.
REGISTRATION DESK
LANGUAGE
The official language of the conference is
English.
10
NAME BADGES
The on-site registration desk at the
conference venue will be open at the
following times:
Thursday 12 May 2016 12:00 – 19:30
Friday 13 May 2016 08:30 – 18:00
Saturday 14 May 2016 08:30 – 11:30
The European Association for the Study
of the Liver (EASL) is accredited by
the European Accreditation Council
for Continuing Medical Education
(EACCME) to provide the following
CME activity for medical specialists.
The EACCME is an institution of the
European Union of Medical Specialists
(UEMS), www.uems.net. The EASL
Monothematic Conference Conference:
“NASH: Beyond the acronym,
certainties and clinical dilemmas” is
designated for a maximum of (or ‘for up
to’) 12 hours of European external CME
credits. Each medical specialist should
claim only those hours of credit that he/she
actually spent in the educational activity.
Through an agreement between the
European Union of Medical Specialists
and the American Medical Association,
physicians may convert EACCME credits
to an equivalent number of AMA PRA
Category 1 Credits™. Information on
the process to convert EACCME credit
to AMA credit can be found at http://
www.ama-assn.org/go/internationalcme Live
educational activities, occurring outside
of Canada, recognized by the UEMSEACCME for ECMEC credits are
deemed to be Accredited Group Learning
Activities (Section 1) as defined by the
Maintenance of Certification Program
of The Royal College of Physicians and
Surgeons of Canada. EACCME credits.
Each medical specialist should claim only
those hours of credit that he/she actually
spent in the educational activity. The
EACCME credit system is based on 1
ECMEC per hour with a maximum of 3
ECMECs for half a day and 6 ECMECs
for a full-day event.
ACCESS RIGA
Direct flights are available from the European airports listed below to the Riga International
Airport (RIX):
AUSTRIA
BELGIUM
FRANCE
GERMANY
IRELAND
Vienna
Brussels
Charleroi
Paris
Berlin
Bremen
Cologne
Dusseldorf
Frankfurt
Dublin
ITALY
NETHERLANDS
NORWAY
SWITZERLAND
UNITED KINGDOM
Milan
Amsterdam
Oslo
Basel
Zurich
Geneva
Doncaster
East Midlands
Glasgow
Leeds London
11
GENERAL INFORMATION
CME ACCREDITATION
GENERAL INFORMATION
GENERAL INFORMATION
TRANSPORT TO THE VENUE
BANKING, SAFETY AND SECURITY
The conference venue, Radisson Blu
Hotel Latvija, is 20 minutes by taxi from
Riga International Airport (RIX).
The currency used in Latvia is the EURO.
Foreign currency can be exchanged at
banks, bureau de change and automatic
currency exchange machines.
By public transport
Take the bus 22 from Abrenes iela to
Melnsila iela. Then, take the bus 53 to
Esplan de. Walk 200 meters to Elizabetes
iela, the Radisson Blu Latvija is across the
street.
By car
Take along the P133 motorway, then take
the A10 in direction of the centre. Turn
left on Lielirbes iela, then keep on for
1 Km and then turn right on Elizabetes
iela, the Radisson Blu Hotel Latvija is on
your right-hand side.
Please do not leave bags or suitcases
unattended at any time, whether inside or
outside the session halls. Hotels strongly
recommend that you use their safety
deposit boxes for your valuables.
LIABILITY AND INSURANCE
The EASL Office cannot accept liability
for personal accidents or loss of or damage
to private property of participants.
Participants are advised to take out their
own personal travel and health insurance
for their trip.
DRESS CODE AND SMOKING POLICY
Dress code is informal for all occasions.
This will be a non-smoking event.
12
SCIENTIFIC
PROGRAMME
SCIENTIFIC PROGRAMME
DAY 1 – THURSDAY 12 MAY 2016
12:00 – 14:00
Registration
13:00 – 14:00
ePoster presentations 1
1. EPIDEMIOLOGY
Chair: Vlad Ratziu, France
14:00 – 14:30
CURRENT EPIDEMIOLOGICAL TRENDS IN THE WEST,
EAST AND DEVELOPING COUNTRIES
Jorn Schattenberg, Germany
14:30 – 15:00
2. ASSESSING INDIVIDUAL RISK
Chair: Fabio Marra, Italy
15:00 – 15:30
ALCOHOL CONSUMPTION: BETWEEN HARM AND
BENEFIT. HOW MUCH, IF ANY, ALCOHOL ARE
PATIENTS ALLOWED TO DRINK?
Ramón Bataller, United States
15:30 – 16:00
NASH AFTER NAP: COFFEE AND CANNABIS
Rodolphe Anty, France
16:00 – 16:30
CLINICAL CASE 1. DIFFERENTIAL DIAGNOSIS
NASH – DILI
Raúl Andrade, Spain
16:30 – 17:00
GENES AND miRNAs:
BIOLOGY AND CLINICAL ASSOCIATIONS
Quentin Anstee, United Kingdom
14
17:00 – 17:30
ePoster presentations 3 and coffee break
3. NATURAL HISTORY AND PROGNOSTIC STUDIES
17:30 – 18:00
RISK OF PROGRESSION IN EARLY DISEASE
Raluca Pais, France
18:00 – 18:30
NATURAL HISTORY OF NASH
Leon Adams, Australia
18:30 – 19:00
CIRRHOSIS AND LIVER RELATED MORTALITY IN NASH
Matias Ekstedt, Sweden
19:00 – 19:30
HEPATOCELLULAR CARCINOMA: CURRENT TRENDS
IN NAFLD
Helen Reeves, United Kingdom
19:30
ePoster presentations 4 and cocktail reception
DAY 2 – FRIDAY 13 MAY 2016
08:30 – 09:00
4. ASSOCIATED PATHOGENIC CONDITIONS IN NAFLD
Chair: Ramón Bataller, United States
09:00 – 09:30
DIAGNOSIS AND NATURAL HISTORY: WHAT SHOULD
THE HEPATOLOGIST KNOW ABOUT DIABETES?
Amalia Gastaldelli, Italy
09:30 – 10:00
GUT MICROBIOTA & NASH
Herbert Tilg, Austria
10:00 – 10:30
METABOLICALLY HEALTHY OBESE INDIVIDUALS:
FACT OR FICTION?
Konstantinos Kantartzis, Germany
15
Chair: Jean-François Dufour, Switzerland
10:30 – 11:00
11:00 – 11:30
OBSTRUCTIVE SLEEP APNEA - AN OVERLOOKED
DIAGNOSIS THAT CAN WORSEN NASH
Judith Aron-Wisnewski, France
11:30 – 12:00
ASSOCIATION OF NAFLD WITH CHRONIC KIDNEY
DISEASE
Sven Francque, Belgium
12:00 – 12:30
NASH & CARDIOVASCULAR DISEASE
Javier Ampuero, Spain
12:30 – 13:00
CLINICAL CASE 2: PREDICTING OUTCOMES IN NASH
Jean-François Dufour, Switzerland
13:00 – 14:00
Lunch
13:30 – 14:00
5. PROGRESS IN DIAGNOSIS
Chair: Elisabetta Bugianesi, Italy
HISTOLOGY
14:00 – 14:30
CURRENT CLASSIFICATIONS AND THEIR LIMITATIONS
Dina Tiniakos, United Kingdom
14:30 – 15:00
NASH WITH ADVANCED FIBROSIS AND HCV AND
WILSON’S DISEASE MASQUERADING NASH
Carolin Lackner, Austria
NON-INVASIVE ASSESSMENT OF STEATOSIS, NASH AND FIBROSIS
15:00 – 15:30
SERUM MARKERS
Emmanuel Tsochatzis, United Kingdom
15:30 – 16:00
ELASTOMETRY
Salvatore Petta, Italy
16
16:30 – 17:00
NEW IMAGING TECHNIQUES
Rohit Loomba, United States
17:00 – 17:30
METABOLOMIC
Malu Martínez-Chantar, Spain
17:30 – 18:00
THE SEARCH FOR INNOVATIVE MARKERS:
FROM IMAGING TO EPIGENETIC BIOMARKERS
Manuel Romero-Gómez, Spain
16:00 – 16:30
DAY 3 – SATURDAY 14 MAY 2016
08:30 – 09:00
6. MECHANISMS OF NASH PROGRESSION
Chair: Manuel Romero-Gomez, Spain
09:00 – 09:30
CARCINOGENESIS IN NAFLD: MECHANISMS
Mathias Heikenwälder, Germany
09:30 – 10:00
FIBROGENESIS IN NAFLD: MECHANISM
Fabio Marra, Italy
10:00 – 10:30
CHEMOKINES, MYOKINES AND ADIPOKINES IN NASH
Carmelo García-Monzón, Spain
10:30 – 11:00
CLINICAL CASE 3: THE CHALLENGES OF MONITORING
NAFLD
Helena Cortez-Pinto, Portugal
11:00 – 11:30
17
7. MANAGEMENT OF NAFLD
Chair: Manuel Romero-Gomez, Spain
11:30 – 12:00
INTRODUCTION TO BARIATRIC SURGERY:
TECHNIQUES, SHORT TERM AND LONG-TERM
RESULTS AND COMPLICATIONS
Salvador Morales, Spain
12:00 – 12:30
MACRO AND MICRONUTRIENTS IN NASH
Shira Zelber-Sagi, Israel
12:30 – 13:00
THE BENEFITS OF EXERCISE: HOW TO PRESCRIBE?
Mike Trenell, United Kingdom
13:00 – 13:30
WEIGHT LOSS IN NASH:
MANAGEMENT AND BENEFICIAL ASPECTS
Eduardo Vilar, Spain
13:30 – 14:00
CURRENT INSULIN SENSITIZING AGENTS IN NASH
Philip Newsome, United Kingdom
14:00 – 14:30
THE PROMISE OF FUTURE DRUGS IN NASH
Vlad Ratziu, France
14:30
CONCLUDING REMARKS
Jean-Francois Dufour, Switzerland
Manuel Romero-Gómez, Spain
Vlad Ratziu, France
18
ePoster
SESSIONS
THURSDAY 12 MAY 2016
ePOSTER SESSIONS
ePoster presentations 1: 13:30 – 14:00
Screen Title
Abstract Presenter
1
DYSMETABOLIC IRON OVERLOAD
SYNDROME IN NON-ALCOHOLIC FATTY
LIVER DISEASE PATIENTS
MR-146 Claudia
Oliveira
2
EVALUATION OF HEPATOCELLULAR
CARCINOMA (HCC) BY 18 FDG MICROPET-CT
ON EXPERIMENTAL MIXED RODENT MODEL
OF NONALCOHOLIC STEATOHEPATITIS
(NASH)-RELATED HCC
MR-102 Leila
Mouelhi
3
PNPLA3 AND TNF-α G238A GENETIC
POLYMORPHISMS IN EGYPTIAN PATIENTS
WITH DIFFERENT GRADES OF SEVERITY OF
NAFLD.
MR-163 Mona
Hegazy
4
THE CONTROLLED ATTENUATION
MR-117 Rosa Coelho
PARAMETER (CAP) IN NAFLD AND OTHER
NON-ALCOHOLIC CHRONIC LIVER DISEASES:
SHOULD IT BE CONSIDERED A DIAGNOSTIC
CRITERIA FOR METABOLIC SYNDROME?
5
REFRACTORY SUBACUTE STEATOHEPATITIS
AFTER BILIOPANCREATIC DIVERSION: A
CASE REPORT
MR-124 Sander
Lefere
6
CONTROLLED ATTENUATION PARAMETER
AND LIVER STIFFNESS MEASUREMENTS
BY FIBROSCAN FOR THE DETECTION OF
NON-ALCOHOLIC FATTY LIVER DISEASE IN
PATIENTS WITH TYPE 2 DIABETES: RESULTS
FROM A PILOT STUDY
MR-106 Yusuf Yilmaz
20
Abstract Presenter
1
CORONARY ARTERY CALCIUM SCORE
MR-103 Claudia Oliveira
(CACS) AND FRAMINGHAM SCORE (FS) IN
EVALUATION OF CARDIOVASCULAR RISK
AFTER LIVER TRANSPLANTATION.
2
PREVALENCE AND CHARACTERISTICS
OF PATIENTS WITH OBESE VERSUS NONOBESE NON-ALCOHOLIC FATTY LIVER
DISEASE (NAFLD) IN THAILAND
MR-133 Chalermrat
Bunchorntavakul
3
CHANGES OF THE GUT MICROBIOTA IN
PATIENTS WITH OBESITY, METABOLIC
SYNDROME AND NONALCOHOLIC
FATTY LIVER DISEASE (NAFLD) VERSUS
HEALTHY CONTROLS
MR-160 María Teresa
Arias Loste
4
INTERVENTION WITH THE CCR2
INHIBITOR PROPAGERMANIUM
ATTENUATES INSULIN RESISTANCE,
ADIPOSE TISSUE INFLAMMATION AND
DEVELOPMENT OF NASH
MR-161 Petra Mulder
5
NORUDCA IMPROVES LIVER INJURY
AND GLUCOSE SENSITIVITY IN MOUSE
MODELS OF OBESITY AND STEATOSIS
MR-164 Daniel Steinacher
6
ASSOCIATION BETWEEN LEFT
VENTRICULAR MASS AND HEPATIC FAT
CONTENT IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE
MR-178 Daniele Pastori
21
ePOSTER SESSIONS
Screen Title
ePOSTER SESSIONS
Screen Title
Abstract Presenter
1
EVALUATION OF HEPATOCELLULAR
CARCINOMA (HCC) BY 18 FDG MICROPET-CT
ON EXPERIMENTAL MIXED RODENT MODEL
OF NONALCOHOLIC STEATOHEPATITIS
(NASH)-RELATED HCC
MR-102 Claudia
Oliveira
2
HIGH INCIDENCE OF NON-ALCOHOLIC
FATTY LIVER DISEASE IN FIRST EPISODE
SCHIZOPHRENIA SPECTRUM PATIENTS:
A 3 YEARS PROSPECTIVE STUDY
Arias Loste
3
OBETICHOLIC ACID ATTENUATES FIBROSIS
DEVELOPMENT IN A HIGH-FAT DIET
INDUCED NASH MODEL (LDLR-/-.LEIDEN
MICE)
MR-167 Petra Mulder
4
EXERCISE THERAPY IN PATIENTS
CONSUMING MODERATE ALCOHOL:
A RANDOMISED CONTROL TRIAL
MR-105 David
Houghton
5
FATTY LIVER INDEX (FLI) AS A
MR-130 Diego Caroli
MULTIDISCIPLINARY SCORE NOT ONLY FOR
A CORRECT DIAGNOSIS OF NONALCOHOLIC
FATTY LIVER DISEASE (NAFLD) BUT ALSO TO
IMPROVE ACCURACY IN CARDIOVASCULAR
DISEASE IN DIABETIC TYPE 2 PATIENTS
6
TM6SF2 KO AND PNPLA3 I148M KNOCKIN
MICE AS NAFLD ANIMAL MODELS:
SIMILAR BUT NOT THE SAME.
22
MR-109 Eriks
Smagris
Screen Title
Abstract Presenter
1
IMPACT OF AEROBIC EXERCISE IN
POSTMENOPAUSAL WOMEN WITH
NONALCOHOLIC FATTY LIVER DISEASE:
A 24 - WEEK RANDOMIZED CLINICAL TRIAL
MR-108 Claudia
Oliveira
2
THE FTO RS1421085 T>C POLYMORPHISM IS
ASSOCIATED WITH THE SEVERITY OF
NON-ALCOHOLIC FATTY LIVER
Arias Loste
3
SILIBININ EXERTS BENEFICIAL EFFECTS ON
GUT-LIVER AXIS IN MURINE AND HUMAN
NON-ALCOHOLIC FATTY LIVER DISEASE
MR-192 Federico
Salomone
4
MOLECULAR CHARACTERIZATION OF
THE FECAL MICROBIOME IN BRAZILIAN
NASH OBESE AND OBESE WITHOUT NASH
PATIENTS COMPARED TO LEAN HEALTHY
CONTROLS
MR-115 Hugo Brito
5
SMOKING IS ASSOCIATED WITH FIBROSIS
BUT NOT WITH NAFLD ACTIVITY
MR-134 Isabelle
Munsterman
6
CIRCULATING MICRORNAS IN PATIENTS
WITH NON-ALCOHOLIC FATTY LIVER
DISEASE IN TAIWAN
MR-143 Jee-Fu
Huang
23
ePOSTER SESSIONS
FRIDAY 13 MAY 2016
ePOSTER SESSIONS
Screen Title
Abstract Presenter
1
HYPOLACTASIA (LCT-13910CC GENOTYPE) IS MR-110 Claudia
ASSOCIATED WITH INSULIN RESISTANCE IN
Oliveira
BRAZILIAN PATIENTS WITH NONALCOHOLIC
STEATOHEPATITIS (NASH)
2
POSSIBILITY OF GHRELIN AS NON-INVASIVE
MARKER FOR NAFLD/NASH DIAGNOSIS
MR-126 Nazarii
Kobyliak
3
SECRETOME PROFILES OF HUMAN
MESENCHYMAL STEM CELLS BEFORE AND
AFTER HEPATOCYTIC DIFFERENTIATION –
IDENTIFICATION OF PATHWAYS IMPACTING
ON POTENTIAL TREATMENT OF NASH
MR-129 Sandra
Winkler
4
MELANIN PRODUCED BY YEAST
NADSONIELLA NIGRA AS NOVEL
THERAPEUTICS AGENTS IN NAFLD/NASH
MANAGEMENT
MR-181 Savytska
Maryana
5
THE BERLIN QUESTIONNAIRE SCREENS
AND EPWORTH SLEEPINESS SCALE FOR
OBSTRUCTIVE SLEEP APNEA IN NONALCOHOLIC FATTY LIVER DISEASE.
MR-195 Bochra
Bouchabou
6
AN OPEN LABEL RANDOMIZED
CONTROLLED TRIAL OF VITAMIN D VS
PENTOXIFYLLINE IN NON-DIABETIC
PATIENTS OF NAFLD
MR-149 Sanchit
Budhiraja
24
Abstract Presenter
1
MOLECULAR CHARACTERIZATION OF
THE FECAL MICROBIOME IN BRAZILIAN
NASH OBESE AND OBESE WITHOUT NASH
PATIENTS COMPARED TO LEAN HEALTHY
CONTROLS
MR-115 Claudia
Oliveira
2
SYNERGISTIC EFFECT OF ALIVE PROBIOTIC MR-171 Nazarii
AND ABSORBENT SMECTITE GEL FOR
Kobyliak
NAFLD/NASH PREVENTION: EXPERIMENTAL
STUDY
3
LIVER AND SYSTEMIC IRON LOADING
CHARACTERISE INITIAL DISEASE
PROGRESSION IN NAFLD
4
DIAGNOSTIC ACCURACY OF SHEAR WAVE
MR-174 Matteo
ELASTOGRAPHY FOR THE ASSESSMENT OF
Garcovich
LIVER STIFFNESS IN CHILDREN WITH FATTY
LIVER DISEASE
5
ADIPOSE TISSUE INSULIN RESISTANCE
IS ASSOCIATED WITH MACROPHAGE
ACTIVATION IN NON-DIABETIC PATIENTS
WITH NON ALCOHOLIC FATTY LIVER
DISEASE
MR-150 Milena
Marietti
6
PATATIN-LIKE PHOSPHOLIPASE DOMAINCONTAINING PROTEIN 3 POLYMORPHISM
AND THE RISK OF HEPATOCELLULAR
CARCINOMA DEVELOPMENT IN RELATION
TO UNDERLYING LIVER DISEASES
MR-152 Pisit
Tangkijvanich
ePOSTER SESSIONS
Screen Title
MR-184 John Ryan
25
ePOSTER SESSIONS
Screen Title
Abstract Presenter
1
COMPARATIVE ANALYSIS OF ONLINE
PATIENT EDUCATION RESOURCES
PERTAINING TO NASH OR NAFLD
MR-172 Rishabh
Gulati
2
IMPACT OF GWAS-IDENTIFIED COMMON
VARIANTS ON HISTOPATHOLOGICAL
FEATURES OF NAFLD PATIENTS
MR-159 Rocío
GallegoDurán
3
NASH: AN UNDERECOGNIZED CAUSE OF
CRYPTOGENIC CIRRHOSIS
MR-182 Rym
Ennaifer
4
HIGH RISK POPULATIONS: ATTITUDES TO
NAFLD AMONG DIABETOLOGISTS
MR-136 Thomas
Marjot
5
THE RECOGNITION OF OXIDIZED LIPIDS
BY IGM ANTIBODIES IS AN EARLY EVENT
IN THE PATHOGENESIS OF HUMAN NONALCOHOLIC FATTY LIVER DISEASE
MR-154 Tim
Hendrikx
6
ASSOCIATION OF PRO12ALA
POLYMORPHISM OF PPAR-γ GENE WITH
BIOCHEMICAL MARKERS OF LIVER INJURY
IN NONALCOHOLIC FATTY LIVER DISEASE
PATIENTS
MR-104 Vasyl
Prysyazhnyuk
26
Abstract Presenter
1
ELAFIBRANOR, A LIVER TARGETED PPARα/δ
AGONIST FOR GLOBAL MANAGEMENT OF
NASH
MR-210 Dean Hum
2
VALIDATION OF NON-INVASIVE METHODS
FOR ADVANCED FIBROSIS DETECTION IN
NAFLD PATIENTS
MR-169 Rocío
GallegoDurán
3
ARE FEMALES REALLY MORE PROTECTED
THAN MALES IN THE PROGRESSION FROM
NAFLD TO NASH?
MR-144 Veronica
Marin
4
REGENERATE: A PHASE 3, DOUBLE-BLIND,
RANDOMIZED, PLACEBO-CONTROLLED
MULTICENTER STUDY OF OBETICHOLIC
ACID THERAPY FOR NONALCOHOLIC
STEATOHEPATITIS
MR-147 Vlad Ratziu
5
SARCOPENIA IS AN INDEPENDENT RISK
MR-180 Won Kim
FACTOR FOR BIOPSY-PROVEN NONALCOHOLIC STEATOHEPATITIS IN A KOREAN
POPULATION
6
LEAN VERSUS OVERWEIGHT/OBESE
NONDIABETIC NONALCOHOLIC
FATTY LIVER DISEASE (NAFLD) – A
CLINICOPATHOLOGICAL COMPARATIVE
STUDY
ePOSTER SESSIONS
Screen Title
MR-120 Sanchit
Budhiraja
27
SATURDAY 14 MAY 2016
ePoster presentations 08:30 – 09:00
ePOSTER SESSIONS
Screen Title
Abstract Presenter
1
HEPATOCELLULAR CARCINOMA IN NON- MR-125 Claudia Oliveira
ALCOHOLIC STEATOHEPATITIS (NASH)
– HISTOPATHOLOGICAL ASPECTS
2
LIVER STIFFNESS VALUES MEASURED
BY SHEAR WAVE ELASTOGRAPHY
DEPENDING ON TRANSAMINASE
ACTIVITY IN PATIENTS WITH
NONALCOHOLIC FATTY LIVER DISEASE
MR-121 Nazarii Kobyliak
3
LYSOSOMAL ACID LIPASE ACTIVITY IS
ASSOCIATED WITH AST TO PLATELET
RATIO INDEX IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE
MR-173 Francesco Baratta
4
PATIENT’S PROFILE IN LATVIA
MR-137 Jekaterina Kucina
5
RESVERATROL IMPROVES HEPATIC
NITRIC OXIDE SYNTHESIS AND
ATTENUATING ENDOTHELIAL
DYSFUNCTION IN NON-ALCOHOLIC
FATTY LIVER DISEASE
MR-128 Balasubramaniyan
Vairappan
6
SPLEEN DIMENSIONS EVALUATED
BY ULTRASOUND ARE INVERSELY
ASSOCIATED WITH LYSOSOMAL ACID
LIPASE ACTIVITY IN PATIENTS WITH
MR-179 Licia Polimeni
28
Screen Title
Abstract Presenter
1
CYTOKERATIN 18 FRAGMENT LEVEL IS
A USEFUL BIOMARKER IN PREDICTING
STEATOSIS AND NASH BUT NOT FIBROSIS
MR-148 Sanchit
Budhiraja
2
NATURAL EXTRACTS ABOLISH LIPID
ACCUMULATION IN CELLS HARBOURING
NON-FAVOURABLE PNPLA3 GENOTYPE
MR-165 Ángela Rojas
3
PRIMARY CARE SEQUENTIAL USE OF FIB4 AND THE ENHANCED LIVER FIBROSIS
TEST TO STRATIFY PATIENTS WITH NAFLD
DOUBLES CIRRHOSIS DETECTION AND
REDUCES REFERRALS OF PATIENTS WITH
MILD DISEASE
MR-132 Ankur
Srivastava
4
TOWARDS A NON-INVASIVE DIAGNOSIS
OF NON-ALCOHOLIC STEATO HEPATITIS
(NASH)
MR-145 Carla M.
Chackelevicius
5
ANGIOPOIETIN-LIKE4 IS ASSOCIATED WITH
LIPID METABOLISM AND SEVERE FIBROSIS
IN NON-DIABETIC PATIENTS WITH NON
ALCOHOLIC FATTY LIVER DISEASE
MR-151 Chiara Rosso
6
ASSOCIATION BETWEEN SEVERITY OF
NONALCOHOLIC FATTY LIVER DISEASE
AND THE RATIOS OF CHOLESTEROL AND
TRIGLYCERIDES
MR-135 Chia-Yen
Dai
29
ePOSTER SESSIONS
INVITED SPEAKERS’
ABSTRACTS
NASH AFTER NAP: COFFEE AND CANNABIS
Rodolphe Anty* 1
Hepatology unit, Digestive department, University Hospital of Nice, INSERM U1065, Nice,
France
1
The impact of coffee and cannabis on Non-alcoholic fatty liver diseases (NAFLD) differ.
In the case of coffee consumption-a legal substance- numerous epidemiological studies
have studied the impact of various coffee preparations on NAFLD, NASH and liver
fibrosis. In the case of cannabis –an illegal substance in most countries (at least for
recreational purpose)- very few epidemiological studies assessing cannabis consumption
on liver diseases are available.
Coffee consumption seems to be protective for liver fibrosis during NAFLD [1-3].
While cannabis consumption seems to be deleterious in chronic hepatitis C and may be
deleterious during NAFLD, however little epidemiological data are available [4].
A substantial number of compounds are contained in coffee and cannabis and the number
of studies in the literature concerning these two products is very different [5, 6]. In the
case of coffee consumption, potential beneficial compounds and mechanisms for fatty
liver protection remain speculative [7]. In contrast, the discovery of the endocannabinoid
system has lead to a lot of research into many organs (from the brain to the adipose tissue)
due to the fact that it is implicated in many physiological pathways [8]. The discovery of the
cannabinoid receptors 1 (CB1) and 2 (CB2), which have opposite effects in many organs,
came as a breakthrough in the understanding of this system. In the liver, stimulation of
CB1 may impair liver fibrosis while stimulation of CB2 may improve inflammation and
fibrosis [9]. While the first patented drug rimonabant –an inverse agonist of CB1- given
to lose weight and improve the metabolic profile has been removed from the market due
to adverse effects on the central nervous system, the modulation of the endocannabinoid
system by organ specific drugs could be a new way of treatment for patients with NAFLD
[9].
In summary, cannabis users are exposed to potential beneficial or deleterious substances.
New research into agonists/inverse agonists of endocannabinoid receptors is promising.
Identification of the beneficial compounds and a better the understanding of their
signaling pathways could be helpful in the field of the NAFLD/NASH. In the meantime,
patients should be advised to drink regularly coffee without sweetener and to restrain from
smoking cannabis (or tobacco).
31
SPEAKERS’ ABSTRACTS
Corresponding author’s email: rodolphe.anty@laposte.net
References
[1] Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, Harrison SA. Association of coffee and caffeine
consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology
2011;10:24731.
[2] Anty R, Marjoux S, Iannelli A, Patouraux S, Schneck AS, Bonnafous S, et al. Regular coffee but not espresso
drinking is protective against fibrosis in a cohort mainly composed of morbidly obese European women with
NAFLD undergoing bariatric surgery. J Hepatol 2012;57:1090-1096.
[3] Shen H, Rodriguez AC, Shiani A, Lipka S, Shahzad G, Kumar A, et al. Association between caffeine
consumption and nonalcoholic fatty liver disease: a systemic review and meta-analysis. Therap Adv
Gastroenterol 2016;9:113-120.
[4] Hezode C, Roudot-Thoraval F, Nguyen S, Grenard P, Julien B, Zafrani ES, et al. Daily cannabis smoking as a
risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 2005;42:63-71.
[5] Muriel P, Arauz J. Coffee and liver diseases. Fitoterapia 2010;81:297-305.
[6] Andre CM, Hausman JF, Guerriero G. Cannabis sativa: The Plant of the Thousand and One Molecules. Front
Plant Sci 2016;7:19.
[7] Saab S, Mallam D, Cox GA, 2nd, Tong MJ. Impact of coffee on liver diseases: a systematic review. Liver
international : official journal of the International Association for the Study of the Liver 2014;34:495-504.
[8] Mouslech Z, Valla V. Endocannabinoid system: An overview of its potential in current medical practice. Neuro
Endocrinol Lett 2009;30:153-179.
[9] Mallat A, Teixeira-Clerc F, Lotersztajn S. Cannabinoid signaling and liver therapeutics. J Hepatol 2013;59:891896.
Disclosure of Interest: None Declared
32
CLINICAL CASE 1.
DIFFERENTIAL DIAGNOSIS NASH – DILI
Raul J. Andrade* 1, 2, 3 on behalf of Spanish DILI Registry and Spanish DILI Registry
1
Medicine, UNIVERSITY OF MÁLAGA, 2IBIMA,Virgen de la Victoria University Hospital,
3
CIBERehd, Málaga, Spain
A 44-year-old-woman started tamoxifen on January 2003 after breast cancer surgery. Her
baseline liver biochemistry showed, AST 68 U/L (normal < 35), ALT 86 U/L (normal<43),
and GGT 280 U/L (normal < 35), whereas TB (0.47 mg/dL) and ALP (80 U/L) where
within normal range. She had no other underlying diseases or was taking concomitant
treatments, except for lorazepam for insomnia during several years. On July 2003 she
noticed jaundice and her liver profile was TB 1.85 mg/dL, AST 186 U/L, ALT 112 U/L,
and GGT 446 U/L, with normal within ALP values. The liver enzymes improved except
for TB that reached 3.68 mg/dL after five months and the treatment was discontinued in
December 2003. The patient voluntary decided to reintroduce tamoxifen treatment three
months later and on April 2004 was admitted to hospital with jaundice. The analytical
values were TB 10.83 mg/dL, AST 154 U/L, ALT 47 U/L, ALP 132 U/L (normal < 100)
and GGT 351 U/L. Serology ruled out viral causes and screening for autoantibodies was
negative. Abdominal ultrasound showed a heterogeneous liver and hepatomegaly. A liver
biopsy showed chronic liver disease with regenerative liver nodules and fibrosis, as well
as mild steatosis.Idiosyncratic drug-induced liver injury (DILI) is a complex and multilayered disorder that affects susceptible subjects exposed to therapeutic doses of drugs
whose diagnosis remains largely of exclusion. While DILI is uncommonly diagnosed, nonalcoholic fatty liver disease (NAFLD) is highly prevalent due to the widespread occurrence
of obesity and the metabolic syndrome in western countries. Because of this, distinguishing
DILI from non-alcoholic fatty liver disease (NAFLD) and NASH is often a difficult task
in the evaluation of suspected cases of hepatotoxicity. Actually, the growing prevalence of
NAFLD recently led to a consensus group to raise the cut-off point of transaminases from
> 2 X upper limit of normal (ULN) to 5 X ULN for consider a case as possible DILI in
order to avoid the inclusion of many false positive cases of minor increases in transaminases
of uncertain meaning. On the other hand, yet rarely, drugs can cause fat accumulation in
the liver. Approximately 2% of NAFLD instances are believed to be caused by drugs. In
contrast, some degree of liver steatosis is frequently encountered in liver biopsy specimens
of DILI cases. Thus, a recent review of 249 of biopsies from the Drug Induced Liver
Injury Network DILIN) indicated that although this is rarely described as the dominant
pattern, 26% of cases showed some degree of steatosis, with macrovesicular steatosis as the
dominant pattern in over 70% of the cases. However, it is difficult to ascertain the extent
33
Corresponding author’s email: andrade@uma.es
to which fat accumulation in many of these cases is a hepatotoxic effect of the drug or it
is simply a pre-existing liver lesion. Indeed, an interaction between DILI and NAFLD
probably occurs in many instances, is complex and bidirectional. Although, whether
NAFLD/NASH are risk factors for DILI is yet unproven, hepatotoxicity produced by
drugs such as tamoxifen or methotrexate can aggravate underlying NAFLD and vice
versa. Several components of the metabolic syndrome can influence DILI outcome. For
example, diabetes mellitus was a risk factor for DILI severity in the DILIN experience, as
was also for chronic outcome in the Spanish DILI Registry survey along with hypertension
and hyperlipidemia. In contrast, hyperlipidemia was protective for the development of
acute liver failure in Spanish DILI patients this effect probably being mediated by the
use of statins. In the causality assessment of suspected DILI cases with known NAFLD,
or risk factor for it such as obesity or metabolic syndrome the adjudication would be
particularly difficult if the resulting pattern is hepatocellular because there is no specific
biomarker to distinguish true DILI from a flare of transaminases typical of the natural
course of NAFLD. The height of transaminase values along a rapid improvement after
dechallenge with the suspected drug can be an important clue. For other phenotypes such
as cholestasis or mixed injury the diagnosis of DILI can be more evident.
34
NAFLD NATURAL HISTORY: RISK OF PROGRESSION IN
EARLY DISEASE
Raluca Pais* 1
1
Hepatogastroenterology, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpétrière –
Université Pierre et Marie Curie, UMR_S 938, INSERM – CDR Saint Antoine, Institute of
Cardiometabolism and Nutrition (ICAN), Paris, France
The spectrum of NAFLD (non alcoholic fatty liver disease) encompasses two entities with
distinct histological features: isolated steatosis (NAFL) with no/minimal inflammation
and steatohepatitis (NASH). While lipid droplet accumulation within hepatocyte is the
defining histological feature for NAFLD, the long-term outcomes seem to be determined
by other histological lesions (lobular/portal inflammation, hepatocyte ballooning and
fibrosis), which accompany steatosis in various degrees1.
The current concept is that triglyceride (TG) storage as lipid droplets in the liver is an
adaptive response to adipose tissue insulin resistance and has no harmful effect. Instead
non-TG metabolites of fatty acids are responsible for lipotoxic liver injury and disease
progression2. Blocking DGAT2 (diacylglycerol acyltransferase 2), the final enzyme
catalyzing TG formation, results in less steatosis but more inflammation and fibrosis.
These data suggests that there should be little or no transition from steatosis to NASH.
Earlier studies failed to demonstrate any significant histological changes in patients with
bland steatosis. Later studies confirmed that patients with bland steatosis have similar
survival with general population while patients with NASH have increased overall, liverrelated and CV mortality (Figure). However isolated cases of progression from steatosis to
advanced fibrosis have been previously described. In the study of Ekstedt et al., among 36
patients with bland steatosis, 47% had fibrosis progression with 3 patients (8%) developing
bridging fibrosis over 13 years of follow-up3.
Recently, two studies with paired liver biopsies specifically analysed the evolution of
patients with NAFL. Progression to bridging fibrosis occurred in almost one quarter of
patients (24% over 3.7 years of follow-up in the French study and 22% over a median of
8 years of follow-up in the British study)4, 5. Although sampling error and interobserver
variability are possible confounders, the striking reproducibility of the results of these
two studies, most probably reflect unambiguous disease progression. Remarkably, fibrosis
progression occurred together with the development of ballooning and transition to
NASH. This highlights the prognostic significance of the histological lesions on the baseline
biopsy, especially steatosis and inflammation. Fibrosis progression was associated with the
persistence/aggravation of metabolic risk factors. In a recent meta-analysis, among 133
patients with NAFL, fibrosis progression occurred in 39% of patients at a mean rate of 1
35
Corresponding author’s email: ralu_pais@yahoo.com
stage over 14 years. Rapid fibrosis progression (from none to bridging fibrosis of cirrhosis)
occurred in 17% of patients with NAFL over a short follow-up period of 6 years. When
only patients with stage 0 or 1 fibrosis were analysed, fibrosis progression rate was similar
between patients with NAFL and NASH6. This suggests that additional physiopathologic
pathways might drive fibrosis progression in the “fast progressors” group.
In conclusion, NAFL is not such a benign condition as initially believed and some patients
are at risk for disease progression. Patients with NAFL might justify of similar surveillance
rate as patients with NASH, at least in case of aggravation of metabolic risk factors. We
should also keep in mind that if fibrosis is associated with long-term clinical outcomes,
inflammation and ultimately NASH are the main drivers that precedes and play a key role
in fibrosis progression. This justifies the current focus of clinical trials on the resolution of
NASH. It also raises the question if pharmacological treatment should not be considered
in earlier stages of the disease.
References
1.
2.
3.
4.
5.
6.
Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but no Other Histologic Features, Associates with
Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2015;149:389-97.
Neuschwander-Tetri BA. Nontriglyceride hepatic lipotoxicity: the new paradigm for the pathogenesis of
NASH. Curr Gastroenterol Rep 2010;12:49-56.
Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver
enzymes. Hepatology 2006;44:865-73.
Pais R, Pascale A, Fedchuck L, et al. Progression from isolated steatosis to steatohepatitis and fibrosis in
nonalcoholic fatty liver disease. Gastroenterol Clin Biol 2010.
McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to fibrosingsteatohepatitis using paired biopsies: Implications for prognosis and clinical management. J Hepatol
2015;62:1148-55.
Singh S, Allen AM, Wang Z, et al. Fibrosis Progression in Nonalcoholic Fatty Liver vs Nonalcoholic
Steatohepatitis: A Systematic Review and Meta-analysis of Paired-Biopsy Studies. Clin Gastroenterol Hepatol
2015;13:643-654.e9.
Figure:
36
NATURAL HISTORY OF NASH
Leon Adams* 1
The University of Western Australia, Crawley, Australia
1
Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum from
non-alcoholic fatty liver (NAFL), which is characterized by steatosis without significant
liver injury, to nonalcoholic steatohepatitis (NASH) where inflammation and ballooning
is present, with or without fibrosis. The natural history of NASH parallels its more
aggressive histological picture, with prospective cohort studies demonstrating a higher rate
of morbidity and mortality compared to NAFL, particularly when fibrosis is present. The
additional morbidity associated with NASH is not limited to liver disease, with an increase
in cardio-vascular events also described.
Longitudinal studies of NAFLD patients with paired liver biopsies, suggest that one third
of patients with NAFL and NASH have progressive fibrosis over an average follow-up
between 2.2-13.8 years, however the rate of progression is twice as high in NASH subjects.
Although fibrosis progression in NASH patients is characteristically indolent, some
patients may progress rapidly from no fibrosis to advanced fibrosis over an average 6 year
period, however this has been observed in both NASH and NAFL patients. In contrast
to fibrosis progression over time, features of steatosis, inflammation and ballooning tend
to reduce which is paralleled by reduction in amino-transaminase levels. Factors which
influence the histological progression of NASH are outlined below.
Predictors of progressive fibrosis in NASH
Sex
No consistent relationship between sex and fibrosis has been found in NASH, with crosssectional and longitudinal studies reporting conflicting findings. The relationship between
sex and fibrosis may be complicated by menopausal status, with one cross-sectional study
finding both men and post-menopausal women having a higher risk of fibrosis compared
with pre-menopausal women.
Race and Ethnicity
Although Hispanic patients have an increased prevalence of NAFLD compared to
Caucasians, there appears to be no difference in susceptibility to NASH or fibrosis.
Cohorts of patients undergoing bariatric surgery suggest Asian patients may be prone to
more severe histological changes, although potential confounding environmental factors
such as diet have not been assessed.
37
Corresponding author’s email: leon.adams@uwa.edu.au
Genetic Polymorphisms
Polymorphisms in the PNPLA3 and TM6SF2 genes are associated with an increased risk
of NAFLD as well NASH and fibrosis. A polymorphism in the IFNL4 gene, which is
associated with response to interferon based treatment in chronic hepatitis C, has also
been associated with fibrosis in NAFLD and has been amalgamated into a predictive score
in conjunction with other clinical factors.
Age
Cross-sectional studies have demonstrated increasing age to be consistently associated
with more severe fibrosis in NASH patients, however this may simply be a marker of
the cumulative exposure to other pathogenic factors. Longitudinal studies have not
consistently demonstrated age to impact the rate of fibrosis progression.
Metabolic Features
Diabetes, measures of insulin resistance (eg QUICKI) and obesity are risk factors for liver
fibrosis in cross-sectional cohorts of NASH patients. However, not all longitudinal studies,
have demonstrated these metabolic factors to be predictive of a higher rate of fibrosis
progression. An increase or decrease in body mass index over time, has been associated
with progression or resolution of liver fibrosis respectively in NAFLD patients and the
emergence of diabetes also appears to parallel fibrosis progression. One meta-analysis
examining the full spectrum of NAFLD found hypertension to be a risk factor for fibrosis
progression, however an earlier meta-analysis limited to NASH patients did not.
Histological Factors
The degree of hepatic steatosis does not appear to predict disease progression in NASH.
The degree of inflammation however, has been associated with progression to advanced
fibrosis in a meta-analysis, but not in any single cohort study. Two large studies published
in abstract form, have suggested that other histological features of NASH including
ballooning, portal inflammation and Mallory Denk bodies predict progression to advanced
fibrosis.
Molecular Factors
Activation of hepatic stellate cells (HSC) and deposition of fibronectin are early indicators
of a fibrogenic response to liver injury. Consequently, histological staining for HSC
activation using alpha-smooth muscle actin and fibronectin staining, has been shown to
accurately predict fibrosis progression in NAFLD patients.
Conclusion
A minority of NASH patients will develop progressive fibrosis over a 10 year period,
however the prediction of those patients who will progress remains difficult. Control of
metabolic risk factors is likely to be important to alter the natural history and genetic and
molecular markers may assist prognostication in the future.
38
GUT MICROBIOTA AND NASH
Herbert Tilg* 1
1
Medical University Innsbruck, Innsbruck, Austria
Gut microbiota and NASH
The human intestinal tract contains an enormous number of microorganisms i.e. the
microbiota consisting of more than 1014 bacteria, archaea and viruses. Importantly, the
microbiome exceeds the human genome more than 100-fold (1). Recent studies suggest
that the microbiota might regulate many metabolic and inflammatory pathways in very
diverse diseases including NAFLD.
Experimental studies
An association of an altered intestinal microbiota with NAFLD has been increasingly
described. An age-related increase in breath ethanol content had been demonstrated in
ob/ob mice and this effect was eliminated by antibiotic treatment with neomycin proving a
role for intestinal bacteria (2).Treatment with the probiotic VSL#3 improved liver histology,
reduced hepatic total fatty acid content, and decreased serum alanine aminotransferase
(ALT) levels (3). VSL’3 affected liver fibrosis but did not protect from inflammation and
steatosis in NASH. In ApoE-/- mice low grade intestinal inflammation drives development
of steatohepatitis and worsens the severity of atherosclerosis. Prebiotics also show efficacy
as mice treated with fructo-oligo-saccharides show less hepatic steatosis and a decrease
in fatty oxidation. Overall, animal studies support the concept for a role of the gut´s
microbiota in experimental NAFLD and interference with antibiotics, pre- and probiotics
may affect disease phenotype.
Clinical studies
Substantial evidence has evolved in the last years suggesting that the intestinal microbiota
is involved in human NAFLD. NASH patients exhibit small intestinal bacterial overgrowth
(SIBO), an impaired intestinal permeability, and increased circulating endotoxin and
TNFa levels (4). Two recent clinical studies investigated the gut microbiome in NASH
patients. In these studies, differences were abundant at phylum, family, and genus levels
between healthy subjects and NASH patients. Importantly, fewer differences were
observed between obese and NASH microbiomes. Proteobacteria, Enterobacteriaceae, and
Escherichia were the only phylum, family and genus types exhibiting significant difference
between obese and NASH microbiomes (5). Another study showed that patients with
NASH had a lower percentage of Bacteroidetes compared to both simple steatosis and
healthy controls (6).
39
Corresponding author’s email: herbert.tilg@i-med.ac.at
Overall, evidence is evolving that there exists similar to obesity and type 2 diabetes a
“gut microbiotal signature” which has the potential in the future to differentiate between
patients with simply fatty liver and NASH and might furthermore allow to elucidate
underlying pathomechanisms in the development of NASH. NAFLD severity in humans
has been recently associated with gut dysbiosis and a shift of metabolic functions of the gut
microbiota (7). Gut microbiota analysis in humans therefore might be used in the future
to classify NAFLD and predict disease severity. Studies identifying how manipulation of
gut microbiota in NASH might prove beneficial are eagerly needed.
References
1.
2.
3.
4.
5.
6.
7.
Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol
Metab 2013;24:537-545.
Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for
fatty liver disease pathogenesis. Gastroenterology 2000;119:1340-1347.
Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, et al. Probiotics and antibodies to TNF inhibit
inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003;37:343-350.
Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small
intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the
pathogenesis of non-alcoholic steatohepatitis. Gut 2001;48:206-211.
Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, et al. Characterization of gut microbiomes in
nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH.
Hepatology 2013;57:601-609.
Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, et al. Intestinal microbiota in
patients with nonalcoholic fatty liver disease. Hepatology 2013;58:120-127.
Boursier J, Mueller O, Barret M, Machado M, Fizanne L, Araujo-Perez F, et al. The severity of nonalcoholic
fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota.
Hepatology 2016;63:764-775.
40
OBSTRUCTIVE SLEEP APNEA – AN OVERLOOKED
DIAGNOSIS THAT CAN WORSEN NASH
Judith Aron-Wisnewsky* 1
IHU ICAN, Pitié-Salpêtrière Hospital, Paris, France
1
Obstructive sleep apnea (OSA) and its hallmark chronic intermittent hypoxia (CIH) are
established factors involved in NAFLD pathogenesis and exacerbation. This has now
been demonstrated in rodents models exposed to intermittent hypoxia, both in paediatric
and adults populations. OSA and CIH induce insulin-resistance and dyslipidemia which
are involved in NAFLD physiopathogenesis. CIH is increasing HIF1α gene expression
and that of downstream genes involved in lipogenesis, therefore increasing β-oxydation
and subsequently exacerbating liver oxidative stress. OSA also disrupts the gut liver axis,
thus increasing intestinal permeability with a possible role of gut microbiota in the link
between OSA and NAFLD. OSA patients should be screened for NAFLD and conversely
those with NAFLD for OSA. To date there is no evidence that treating OSA with CPAP
will improve NAFLD exacerbation but might at least stabilize and slow its progression.
Anyhow, these multimorbid patients should be efficiently treated for all their metabolic
co-morbidities and involved in weight stabilization or weight loss programs and physical
activity life style interventions.
41
Corresponding author’s email: judith.aron-wisnewsky@aphp.fr
NAFLD AND CHRONIC KIDNEY DISEASE
Sven M. Francque* 1
Gastroenterology Hepatology, University Hospital Antwerp, Edegem, Belgium
1
Corresponding author’s email: sven.francque@uza.be
The prevalence of chronic kidney disease (CKD) is increasing in the Western adult
population, in relation to its riks factors ageing, smoking, arterial hypertension, overweight/
obesity and diabetes. As such, CKD shares several risk factors with non-alcoholic fatty
liver disease (NAFLD). It is hence not surprising to find an association between the two
conditions. Evidence is increasing, however, that points towards a cause-effect relationship
that goes beyond a simple association based on shared risk factors. Because of the large
overlap in risk factors and co-morbidities in NAFLD, CDK, metabolic syndrome and
cardiovascular disease, it is extremely difficult to analyse unilateral and unidirectional
cause-effect relationships based on clinical data, even if prospectively collected follow-up
data are available. Methodological issues, amongst others related to the mode of diagnosis
of NAFLD (for which liver biopsy is still the gold standard to accurately diagnose different
disease features) and CDK hamper the interpretation of the data. Nevertheless, there is
mounting evidence of an increased pervalence and incidence of CKD in patients with
NAFLD, with higher figures in patients with non-alcoholic steatohepatitis (NASH)
and in patients with significant fibrosis compared to patients with non-alcoholic fatty
liver (NAFL) and without fibrosis respectively. The potential mechanisms linking the 2
conditions are poorly understood, Production by the inflamed and steatotic liver in NASH
patients of pro-inflammatory mediators, prothrombotic factors, pro-fibrogenic and proatherogenic molecules have been postulated as potential factors involved. Impact of the
liver on endothelial function in several vascular beds may be a crucial factor in the complex
relationship between metabolic syndrome, NAFLD, cardiovascular disease and CKD. The
relation between NAFLD and CKD is probably not unidirectional, as, amongst others,
experimental data in nephrectomized animals also show an impact on the liver. The
association also has potential clinical implications, both for diagnosis (should we screen
for CKD in NAFLD?) and for treatment (e.g. the potential benefit of the use of sartans
on both NAFLD (sartans have been reported to impact on fibrogenesis in animal models)
and CKD, but also CVD; or the implications for management of renal problems in liver
transplantation for NASH-related end-stage liver disease or hepatocellular carcinoma).
42
NASH AND CARDIOVASCULAR RISK
Javier Ampuero* 1, 2
Unit For Clinical Management Of Digestive Diseases,VIRGEN DEL ROCIO UNIVERSITY
HOSPITAL, 2Instituto de Biomedicina de Sevilla, Sevilla, Spain
1
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple
steatosis to steatohepatitis (NASH) without excess alcohol intake and is considered to be
the hepatic manifestation of metabolic syndrome. Prevalence rates are rising because of
overweight and obesity. In fact, NAFLD is the most common cause of chronic liver disease
in Western countries with a prevalence of 20%>30%, which is increased up to 70% in
obese and diabetic subjects.
NAFLD is closely associated with abdominal obesity, atherogenic dyslipidemia,
hypertension, insulin resistance and impaired glucose tolerance, which are all features
of the metabolic syndrome. Recent studies indicate that NAFLD is closely related to
cardiovascular disease, especially to thickening of the intima-media layer of the carotid
artery (as the morphostructural manifestation of the presence of subclinical atheromatosis).
In addition, the presence of impaired carotid-femoral pulse wave velocity or left ventricular
dysfunction are frequently found in patients showing NAFLD. We should be alert about
an increased risk of coronary artery disease in subjects with NAFLD and to be more
aggressive in the searching of primary prevention with the performance of tests of detection
of subclinical atherosclerosis. The right management of this kind of patients will enable to
modify the natural history both liver and cardiovascular disease.
43
Corresponding author’s email: javi.ampuero@gmail.com
NAFLD: CURRENT CLASSIFICATIONS AND
THEIR LIMITATIONS
Dina G. Tiniakos* 1, 2
1
Institute of Cellular Medicine, Newcastle University, UK, Newcastle upon Tyne, United Kingdom,
2
Laboratory of Histology-Embryology, Medical School, National & Kapodistrian University of
Athens, Athens, Greece
Corresponding author’s email: dina.tiniakos@ncl.ac.uk
Steatosis, steatosis with inflammation, non-alcoholic steatohepatitis (NASH) and
cirrhotic nonalcoholic fatty liver disease (NAFLD) are generally considered components
of a continuous spectrum. Most experts agree that the minimal requirements for the
morphological diagnosis of NASH include hepatocyte ballooning in addition to steatosis
and inflammation. These key lesions are typically accentuated in zone 3 of the hepatic
acinus. Fibrosis is not required for the diagnosis of NASH as it is not required for the
diagnosis of chronic hepatitis of other etiology.1 Liver biopsy interpretation is still regarded
as the “gold” standard for making accurate diagnoses in NAFLD although sampling
limitations are recognized. Clear definitions for some of the key histopathological
components, such as ballooning, are lacking partly reflecting inter-observer variation in
making a diagnosis of steatohepatitis. Even the definition of steatosis itself, according
which presence of fat in >5% of hepatocytes is regarded as the cut-off for making a
diagnosis of NAFLD, is somewhat arbitrary since this is based on early biochemical
studies that indicated that normal liver contained 5% lipid by weight. Evaluation of
morphological features of NAFLD by semi-quantitative scoring is frequently performed
to provide standardized assessment of disease activity grade and fibrosis stage to support
clinical decision making and for use in clinical trials. One of the most widely used scores
for grading activity, the NAFLD activity score (NAS) developed by the NIH-sponsored
NASH Clinical Research Network, derives from the sum of semi-quantitative numerical
scores for steatosis, hepatocyte and acinar inflammation.2 This has been erroneously used
in the past to classify NAFLD as “NASH” or “not-NASH”. However, NAS was never
intended to and should not replace the histopathological classification of NAFLD types.3
Recently, a simple histological algorithm was developed to standardize and limit interobserver-related variation in the histological diagnosis of NASH.4 The European Fatty
Liver Inhibition of Progression (FLIP) algorithm informed by the scores for steatosis,
hepatocellular ballooning and inflammation allows for NAFLD stratification into two
main diagnostic categories: steatosis versus NASH. The FLIP algorithm can significantly
reduce the inter-observer bias of the diagnosis of NASH among expert hepatopathologists
as well as between general pathologists.4 The FLIP algorithm is accompanied by semiquantitative scoring of the key features of NASH, steatosis (S,0-3), activity (A, 0-4), and
44
fibrosis (F, 0-4), known as the SAF score. The main difference from previous histological
scoring systems, like the NAS, is that in SAF the severity of NAFLD activity is reflected by
the sum of scores for hepatocyte ballooning (0-2) and acinar inflammation (0-2) only and
steatosis is graded separately.5 Using the SAF score, NAFLD may be categorized as mild
disease (A<2 and/or F<2) or significant disease (A≥2 and/or F≥2) defined by hepatocyte
ballooning, acinar inflammation and fibrosis, parameters of known prognostic significance
in NAFLD, and not by steatosis that has no prognostic value. The prognostic relevance of
the dichotomous classification of mild and significant NAFLD remains to be evaluated in
further studies.
References
2.
3.
4.
5.
Burt AD, Lackner C, Tiniakos D. Diagnosis and assessment of NAFLD: definitions and histopathological
classification. Semin Liver Dis. 2015;35(3):207-20.
Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for
nonalcoholic fatty liver disease. Hepatology 2005;41:1313–21.
Brunt EM, Kleiner DE, Wilson LA, et al. Nonalcoholic fatty liver disease (NAFLD) activity score and the
histopathologic diagnosis in NAFLD: distinct clinico-pathologic meanings. Hepatology 2011;53(3):810-20.
Bedossa P, Poitou C, Veyrie N, et al. Histopathological algorithm and scoring system for evaluation of liver
lesions in morbidly obese patients. Hepatology 2012;56:1751-9.
Bedossa P & FLIP Pathology Consortium. Utility and appropriateness of the fatty liver inhibition of
progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of
nonalcoholic fatty liver disease. Hepatology 2014;60:565-75.
1.
45
NASH WITH ADVANCED FIBROSIS AND HCV AND
WILSONS DISEASE MASQUERADING NASH
Carolin Lackner* 1
1
Medical University of Graz, Institute of Pathology, Graz, Austria
Corresponding author’s email: karoline.lackner@medunigraz.at
Metabolic syndrome (MS)-associated NAFLD and chronic hepatitis C are among the
most prevalent liver diseases and thus the co-existence of both conditions is not an
infrequent setting in clinical practice. NAFLD comprises a spectrum of liver diseases
including non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH)
and NAFLD-associated cirrhosis. Among the NAFLD types, NASH is considered a
progressive lesion associated with the development of fibrosis, cirrhosis and eventually
hepatocellular carcinoma (HCC) in a subset of patients. The co-occurrence of both
diseases is clinically important owing to an apparently synergistical effect on the severity
of liver disease associated with higher fibrosis stage, and the development of cirrhosis and
HCC. While the clinical diagnosis of HCV infection and respective fibrosis stage can be
achieved by non-invasive molecular and radiological methods, the diagnosis of NASH
is dependent on a liver biopsy and histological evaluation. The histological changes of
NASH, in particular centrilobular accentuation of liver injury with steatosis, inflammation,
hepatocellular ballooning, Mallory Denk bodies (MDBs) and pericellular fibrosis, are
distinct from portal and periportal based inflammation and fibrosis in chronic hepatitis
C. However, some of the morphological hallmarks of NASH, especially hepatocelllular
ballooning and MDBs can be discrete changes and may even be missing in H&E stained
sections in advanced fibrosis or cirrhosis stages. The reliable and objective detection of
ballooned hepatocytes and/or MDBs can be facilitated by several recently described
immunohistochemical markers. The definition of advanced fibrosis stage by non-invasive
methods has not been evaluated in detail in a setting of combined NASH/HCV. Both,
histological stage and detection of pericellular fibrosis as a footprint of prior episodes of
NASH may have important implications for patient management.
Wilson´s disease (WD) is a hereditary disorder of copper metabolism due to mutations
in the copper-transporting P-type ATPase, ATP7B. The ATP7B protein mediates the
transport of copper from intracellular chaperone proteins for excretion into the bile and
incorporation of copper into apo-ceruloplasmin. Mutations in the ATP7B gene lead to
copper accumulation and liver injury due to impaired secretion of copper. Eventually
copper is released into the blood and is deposited in other organs like the brain, kidneys
and cornea. Most patients present between the ages 5 and 35 with either liver disease or
as a progressive neurological or psychiatric disorder. Without treatment WD is a fatal.
Most patients die from complications of liver disease and less frequently from progressive
46
47
neurological disease. The development of cirrhosis is associated with increased risk of
death. However, provided an early diagnosis, WD is a treatable and even preventable
condition. Patients who are diagnosed in a precirrhotic stage and receive adequate care
seem to enjoy good long-term prognosis and less frequent need for a liver transplant.
The clinical diagnosis of WD can be challenging. Therefore diagnostic algorithms based
on clinical symptoms and biochemical variables have been published by international
expert committees. Liver biopsy is required for the quantification of liver copper for
diagnostic purposes in patients in whom clinical signs and non-invasive tests do not allow
a definitive diagnosis or if additional causes for liver disease are suspected. On histology
any type of liver pathology may be encountered in WD. However, one of the manifestations
is with features of steatosis and steatohepatitis with morphological overlap with MSassociated fatty liver disease or resembling autoimmune hepatitis. Some of the features
of steatohepatitis may differ between WD and classical MS-associated NASH in adults
or type 1 NASH in children. In WD portal and periportal based liver injury with portal
inflammation and fibrosis, interphase activity, and ballooned hepatocytes with MDBs
prevail which is in contrast to the centrilobular accentuation of morphological changes
in MS-associated NASH. However, distinction of WD from type 2 paediatric NAFLD
may be impossible on morphological grounds. WD may be the underlying cause of liver
disease in an individual with biochemical abnormalities and/or metabolic risk factors for
NAFLD/NASH. Therefore, a high level of suspicion is important in order to meet the
diagnosis in a patient who has been biopsied for other reasons than WD. In particular,
WD should be suspected in the young or middle aged individuals who have unexplained
chronic liver disease, or no classical risk factors for MS-associated NASH and/or liver
disease and neurological or psychiatric symptoms. In some patients also the co-occurrence
of NAFLD/NASH and WD cannot be excluded.
NON-INVASIVE ASSESSMENT OF STEATOSIS, NASH
AND FIBROSIS: SERUM MARKERS
Emmanuel Tsochatzis* 1
Royal Free Hospital NHS Trust, London, United Kingdom
1
Corresponding author’s email: mtsochatzis@hotmail.com
NAFLD is a disease of high prevalence and relatively low severity in the majority of
patients. Although liver biopsy is the gold standard for diagnosing steatohepatitis and
assessing disease severity, it would be inappropriate to biopsy every patient diagnosed
with NAFLD, as it is a costly and invasive procedure, which is associated with patient
discomfort and potential side effects. In order to address this rising need, non-invasive
tests and strategies have been developed that attempt to diagnose NAFLD, NASH and
stage the disease. In this talk, I will review and critically appraise the evidence on the use
of non-invasive blood tests for diagnosing steatosis, NASH and staging fibrosis.
48
SARCOPENIA IS ASSOCIATED WITH SEVERE LIVER
FIBROSIS IN PATIENTS WITH NON-ALCOHOLIC FATTY
LIVER DISEASE
Salvatore Petta* 1, Stefania Ciminnisi, Vito Di Marco, Daniela Cabibi, Calogero
Cammà, Giulio Marchesini, Antonio Craxì
1
Section of Gastroenterology, DI.BI.MI.S University of Palermo, Palermo, Italy
We tested whether sarcopenia is associated with the severity of liver fibrosis(main outcome)
and with the entire spectrum of liver damage in patients with NAFLD.
We considered 225 consecutive patients with a histological diagnosis of NAFLD(Kleiner
score). The skeletal muscle index(SMI)[SMI(%)=total appendicular skeletal muscle
mass(kg)/weight(kg)×100] was measured by electrical bioimpedentiometry.
The lower SMI tertile was independently associated with male gender(p<0.001), visceral
obesity(p<0.001) and higher HOMA(p=0.002). The prevalence of severe fibrosis
progressively increased from 18.6% in patients in the upper, to 26.5% in those in the
middle and to 49.3% in those in the lower SMI tertile(p<0.001). This association was
maintained(OR 2.03,CI 1.21-3.39,p=0.007), together with older age(OR 1.11,CI 1.071.16, p<0.001), higher HOMA values(OR 1.33,CI 1.11-1.58, p=0.002) and NASH(OR
11.2,CI 1.33-94.6, p=0.02), after adjusting for these factors and for hypertension and
visceral obesity. Similarly, a significant association was found between lower SMI tertile
and NASH(p=0.005), the severity of steatosis(p=0.004), presence of ballooning(p=0.001)
and grade 2-3 lobular inflammation(p=0.07). After adjusting for metabolic and liver
confounders, the association was only maintained with the severity of steatosis(OR
1.53,CI 1.07-2.18, p=0.01) and ballooning(OR 2.19,CI 1.17-4.11, p=0.01).
In a cohort of patients with NAFLD, sarcopenia is a marker/risk factor for the entire
spectrum of liver damage, independently of well known liver and metabolic risk factors.
Studies are needed to assess the impact of sarcopenia correction on hepatic and metabolic
complications in NAFLD patients.
49
Corresponding author’s email: petsa@inwind.it
NEW IMAGING TECHNIQUES FOR THE NON-INVASIVE
ASSESSMENT IN NAFLD
Rohit Loomba* 1
1
Division of Gastroenterology, Department of MedicineDivision of Epidemiology, Department
of Family Medicine and Public Health, University of California at San Diego, San Diego, CA,
United States
Corresponding author’s email: roloomba@ucsd.edu
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver
disease in the United States (US).(1-4) NAFLD is characterized by presence of hepatic
steatosis in the absence of excessive alcohol use or other identifiable liver disease. It is
commonly classified into two main subtypes: non-alcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH).(5) Although these were previously considered to be
distinct entities with separate disease courses and prognoses, more recent literature has
demonstrated that NAFL and NASH actually represent points across a disease continuum
that ultimately culminates in progression to hepatic fibrosis and cirrhosis if not intervened
upon.(6-8) Approximately 20% of NAFLD patients may rapidly progress to advanced
fibrosis,(3, 9) and the development of advanced fibrosis is associated with an increased
risk for morbidity and mortality through hepatic (cirrhosis, hepatocellular carcinoma) and
non-hepatic (cardiovascular disease) complications.(7, 10-12) Thus, prompt diagnosis
and timely referrals for at risk patients is needed to off-set the natural progression of this
disease through the use of effective interventions.
In order to accurately detect presence of NAFLD, and to identify advanced fibrosis, the
points at which the maximal benefit may be achieved for interventions, providers must rely
heavily on liver biopsies and histologic assessment. Liver biopsies are, however, not without
cost or risk (bleeding and perforation), and the inter-provider variability in sampling along
with the inter-observer variability in scoring, creates a great deal of uncertainty when
attempting to use this diagnostic method for disease assessment.(13, 14) Furthermore,
serial liver biopsies for monitoring response to interventions is impractical and unlikely to
be well received by patients or providers alike. This growing appreciation for the limitations
of liver biopsy, coupled with the increase in potentially effective therapeutic interventions
for at risk patients,(6) has led to the development of several non-invasive techniques that
can be used to assess for the presence of NAFLD and help to differentiate between disease
activity states (NAFL, NASH, fibrosis and advanced fibrosis). Although these non-invasive
biomarkers and imaging techniques are appealing for the detection of hepatic fibrosis,
differentiation of NAFL from NASH, and for the monitoring of response to interventions,
they remain unable to obviate the need for liver biopsies given their limited sensitivity
and specificity with accompany false positive and false negative results.(14, 15) A need,
50
MRI based assessment of hepatic steatosis and quantitative changes in hepatic fat
– What is MRI-PDFF?
– Diagnostic accuracy and comparison to other non-invasive imaging techniques
– When to use MRI-PDFF?
– Why to use MRI-PDFF ?
– Advantages of MRI-PDFF over MRS or other ultrasound-based tests such as CAP or
novel QUS methods
–Protocol for assessment for treatment response (Examples colesevelam trial and
MOZART Trial)
o Importance of co-localization for assessing treatment response in NASH (figure 1)
MRE based assessment of hepatic fibrosis
– What is MRE?
– Diagnostic accuracy and comparison to other non-invasive imaging techniques
– When to use MRE?
– Why to use MRE?
– Advantages of MRE over VCTE or other ultrasound-based methods
– Utility of liver multiscan
– Protocol for assessment for treatment response? (How to assess treatment response in
NASH E.g. MOZART Trial)
o Importance of co-localization for assessing disease progression (see figure 1)
51
therefore, remains for a non-invasive approach to assessing hepatic steatosis and fibrosis in
patients at risk for NALFD or those who have already developed NALFD where response
to interventions need to be monitored to optimize disease outcomes.
Magnetic resonance imaging including MRI-proton density fat fraction (MRI-PDFF)
has recently been demonstrated to be a highly accurate diagnostic tool for the detection
and quantification of hepatic steatosis and, MR elastography (both 2D and 3 D MRE)
for the detection and quantification of hepatic fibrosis, and for differentiating between
disease states among NALFD patients.(16-22) It may, therefore, potentially be used in
place of liver biopsy for diagnosing NAFLD and for assessing response to certain types of
therapies as newer interventions become available. MRI-PDFF is an accurate, robust and
quantitative biomarker for the detection of hepatic steatosis as well as quantification of
the amount of fat in the liver. It has emerged as a key adjunct endpoint for assessment of
treatment response in early phase trials in which the therapies have a proposed mechanism
of action that lowers liver fat. MRE is the most accurate, reproducible and quantitative
biomarker for the diagnosis of advanced fibrosis in NAFLD(22). It is not affected by
obesity, ascites or advanced stage of disease. The results are comparable across various
platforms. However, generalizability is limited compared to VCTE or other ultrasound
based methods. Following issues would be discussed in details during the presentation.
Figure 1. Co-localization protocol for assessment of treatment response by MRI-PDFF
and MRE in NASH trials
Future studies and considerations
In this presentation, we will summarize the currently available evidence regarding the
use of advanced imaging methods and their utility among patients with NAFLD. The
advantages each imaging technique over other non-invasive assessment techniques, and
how it may be used for the assessment of disease activity and response to therapy in
both clinical trials and clinical practice will be discussed with special emphasis on MRIPDFF for steatosis quantification and MRE for liver stiffness quantification. This will
have considerable implications on the evolving clinical trial atmosphere in NALFD and
on clinical practice where the growing burden of NAFLD in the community will need
to be met with an enhanced monitoring protocol geared towards early diagnosis and
intervention among at risk individuals.
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52
Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013;10:686-690.
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic
fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34:274-285.
Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, et al. Prevalence of
nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population
utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011;140:124-131.
Rinella ME. Nonalcoholic fatty liver disease: a systematic review. Jama 2015;313:2263-2273.
Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, et al. The diagnosis and
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Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology.
Gastroenterology 2012;142:1592-1609.
Spengler EK, Loomba R. Recommendations for Diagnosis, Referral for Liver Biopsy, and Treatment of
Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Mayo Clin Proc 2015;90:1233-1246.
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Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty
liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin
Gastroenterol Hepatol 2015;13:643-654 e641-649; quiz e639-640.
Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease:
a spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413-1419.
Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, Chim AM, et al. Disease progression of nonalcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 2010;59:969-974.
Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G, Adams LA, et al. The natural history
of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study.
Hepatology 2011;54:1208-1216.
Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of
nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113-121.
Arulanandan A, Ang B, Bettencourt R, Hooker J, Behling C, Lin GY, Valasek MA, et al. Association Between
Quantity of Liver Fat and Cardiovascular Risk in Patients With Nonalcoholic Fatty Liver Disease Independent
of Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol 2015;13:1513-1520 e1511.
Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD, American Association for the Study of Liver
D. Liver biopsy. Hepatology 2009;49:1017-1044.
Asrani SK. Incorporation of Noninvasive Measures of Liver Fibrosis Into Clinical Practice: Diagnosis and
Prognosis. Clin Gastroenterol Hepatol 2015.
Papagianni M, Sofogianni A, Tziomalos K. Non-invasive methods for the diagnosis of nonalcoholic fatty liver
disease. World J Hepatol 2015;7:638-648.
Cui J, Ang B, Haufe W, Hernandez C, Verna EC, Sirlin CB, Loomba R. Comparative diagnostic accuracy
of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced
fibrosis in biopsy-proven non-alcoholic fatty liver disease: a prospective study. Aliment Pharmacol Ther
2015;41:1271-1280.
Singh S, Venkatesh SK, Wang Z, Miller FH, Motosugi U, Low RN, Hassanein T, et al. Diagnostic performance
of magnetic resonance elastography in staging liver fibrosis: a systematic review and meta-analysis of individual
participant data. Clin Gastroenterol Hepatol 2015;13:440-451.e446.
Idilman IS, Keskin O, Celik A, Savas B, Halil Elhan A, Idilman R, Karcaaltincaba M. A comparison of liver
fat content as determined by magnetic resonance imaging-proton density fat fraction and MRS versus liver
histology in non-alcoholic fatty liver disease. Acta Radiol 2015.
Tang A, Desai A, Hamilton G, Wolfson T, Gamst A, Lam J, Clark L, et al. Accuracy of MR imaging-estimated
proton density fat fraction for classification of dichotomized histologic steatosis grades in nonalcoholic fatty
liver disease. Radiology 2015;274:416-425.
Permutt Z, Le TA, Peterson MR, Seki E, Brenner DA, Sirlin C, Loomba R. Correlation between liver histology
and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease – MRI accurately
quantifies hepatic steatosis in NAFLD. Aliment Pharmacol Ther 2012;36:22-29.
Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, Valasek M, et al. Magnetic resonance
elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study.
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53
7.
THE SEARCH FOR INNOVATIVE MARKERS: FROM
IMAGING TO EPIGENETIC BIOMARKERS
Manuel Romero-Gómez* 1
1
Digestive Diseases,Virgen Macarena-Virgen del Rocío University Hospital, Seville, Spain
Corresponding author’s email: mromerogomez@us.es
Liver biopsy remains as the gold standard for the diagnosis of NAFLD. Steatosis,
steatohepatitis and fibrosis stage have to be described as histological features of this
disease. Limitations of liver biopsy include: morbimortality associated with the procedure
and cost together with sample error . Distribution of lesions in the liver is heterogeneous
and concordance between two liver biopsies done at the same time is suboptimal.
Besides, longitudinal studies demonstrated that simple steatosis is not a benign and nonprogressive disease . Non-invasive methods spectrum ranged from serum to imaging,
genes and epigenetic biomarkers. From an etiological point of view, a combination of
biochemical parameters and anthropometric data (fatty liver index, hepatic steatosis index,
lipid accumulation product) together with ultrasonography are able to confirm steatosis
in the majority of patients. Magnetic Resonance spectroscopy could be included as gold
standard for steatosis diagnosis in patients with previous controversial results .
Histological features related to prognosis are presence of steatohepatitis and fibrosis stage.
In general, no imaging examinations have been found to accurately diagnose steatohepatitis
using ultrasonography, computed tomography or magnetic resonance. Steatohepatitis is
defined by lobular inflammation and ballooning. Optical analysis of MR images of the
liver (DeMILI®) generates an output (NASH-MRi) able to predict steatohepatitis with
high accuracy (AUROC: 0.83) . Owl-liver® a metabolomic approach corrected by body
mass index could also accurately predict steatohepatitis (AUROC: 0.85) . Serum-based
method (mainly FGF21 (AUROC: 0.62), CK-18 (0.70), AFABP (AUROC: 0.69) and
NASH-test (AUROC: 0.77) did not reach strong validation in external studies and have
not been incorporated in clinical practice.
Fibrosis is the last histological feature that has to be diagnosed for therapeutic decision
making together with prognosis impact. Non-invasive methods like NAFLD-Fibrosis score
and FIB-4, a non-invasive method developed in Hepatitis C sitting but has demonstrated
to be useful for fibrosis prediction on NAFLD. Both methods accurately confirmed
advanced fibrosis and excluded fibrosis, but the main limitation is the wide gray zone for
intermediate results. Fibrotest® and Enhanced Liver Fibrosis panel® seems not add value
to free-of-charge serum-based methods. In patients with inconclusive results imagingbiomarkers could be useful: transient elastography, Fibro-MRI and Magnetic Resonance
Elastography have demonstrated high accuracy for the diagnosis of fibrosis stage1,4.
PNPLA3 and TM6SF2 are two key genes in the pathogenesis of NAFLD. Both genes
predict risk of developing NAFLD and disease progression to liver-related complication
54
Figure:
55
and cardiovascular disease. A strong interaction between miRNA (small, noncoding
RNA molecules that regulate gene expression) involved in NAFLD and these two genes
remained elusive in the last years. Some miRNAs play a key role in disease progression
from healthy liver to steatosis, steatohepatitis, and fibrosis progression to cirrhosis and
liver cancer. Indeed, the relatively stable and multicellular nature of circulating miRNA,
combined with the noninvasive manner in which they can be measured, has positioned
miRNAs as potential biomarkers for NAFLD. Validation process has been unsuccessful
for many of the previously identified miRNAs. A few studies have reported that some
miRNAs appear to be associated with different histopathological stages of NAFLD. In
mice, plasma miRNAs (miR-34a, miR-122, miR-181a, miR-192 and miR-200b) are
sensitive indicators of inter-strain differences in the severity of liver injury induced by a
choline- and folate-deficient diet, with the strongest correlation occurring with miR-34a.
Serum concentrations of miR-21, miR-34a, miR-122, miR-16 and miR-451 are higher in
patients with NAFLD than in healthy controls. Moreover, serum levels of miR-122, miR34a and miR-200b correlate with disease severity from steatosis to NASH, supporting
the potential value of these miRNAs to serve as noninvasive biomarkers for NAFLD
progression. In the future, the identification of serum panels of miRNAs that can predict
the transition across different stages of NAFLD with a high degree of accuracy is clearly
needed, however, their potential utility could be limited by a number of factors relevant
to NAFLD, including the lack of cell-type specificity and the complexity of contributions
from co-morbid conditions as obesity, type 2 diabetes and dyslipidemia with which a
significant number of miRNAs have been associated.
ON THE ROLE OF IMMUNE CELLS IN THE
DEVELOPMENT OF NAFLD, NASH AND SUBSEQUENT
HEPATOCELLULAR CANCER
Mathias Heikenwälder* 1
1
Institute of Virology, TU Munich, Munich, Germany
Corresponding author’s email: heikenwaelder@helmholtz-muenchen.de
Overweight and metabolic syndrome are reaching pandemic dimensions in industrialized
countries and are rising in developed countries. Non-alcoholic fatty liver disease (NAFLD),
the most frequent liver disease world-wide, is a clinical manifestation of overweight and
metabolic syndrome. A significant number of NAFLD patients develop non-alcoholic
steatohepatitis (NASH), fibrosis and subsequent hepatocellular carcinoma (HCC), thus
contributing that HCC currently is the most rapidly increasing cancer in the USA and
Europe.
Although HCC is the second most common cause of cancer related mortality, the
exact mechanisms triggering NASH and subsequent HCC are poorly understood and
efficacious therapies are lacking. Our group has longstanding expertise in inflammationdriven HCC. Recently, we have established a mouse model of NASH-driven HCC
fully recapitulating human pathophyisology in the context of metabolic syndrome. We
demonstrated that CD8+ and NKT cells become activated during metabolic syndrome,
interact with hepatocytes through cytokines and alter hepatic lipid metabolism causing
NASH and HCC. An identical profile of CD8+ and NKT cell activation was found in
human NASH livers underlining the clinical relevance of our model.
Based on this but other model systems we further tried to elucidate the exact cellular
and molecular mechanisms that drive NASH and NASH driven liver cancer, which I will
report on.
56
HYPOXIA ACCELERATES FATTY ACID UPTAKE
LEADING TO INCREASED FAT ACCUMULATION AND
INFLAMMATION IN MICE AND IN CULTURED HUMAN
HEPATOCYTE-DERIVED CELLS
Carmelo Garcia-Monzon* 1, Águeda González-Rodríguez1, Gloria Mateo1, Ines
Soro-Arnáiz1, Mar Torres-Capelli1, Julian Aragonés1
1
Liver Research Unit, Santa Cristina University Hospital, Madrid, Spain
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver
disease in Western countries. NAFLD is strongly associated with overweight/obesity,
insulin resistance, type 2 diabetes (T2DM) and cardiovascular complications; therefore, it
is considered the hepatic component of the metabolic syndrome. NAFLD is characterized
by the progression from a benign steatosis to more severe liver injuries directly associated
with lipotoxicity such as nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular
carcinoma in 10% of NAFLD patients. Recent evidence indicates that NAFLD severity
is affected by obstructive sleep apnoea syndrome (OSAS), a recurrent upper-airway
obstruction during sleep, leading to periods of chronic intermittent hypoxia (CIH).
In this regard, dysregulation of the normal oxygen gradient in the liver that promotes
the stabilization of the hypoxia-inducible factors (HIFs) can induce liver steatosis and
inflammation. However, the pathogenic mechanisms underlying the progression of
NAFLD to NASH in the context of CIH featuring OSAS are not fully understood.
As working hypothesis, the more pronounced the CIH is, the more pronounced the
progression to NASH and fibrosis. AIM: The purpose of this study was focused on the
molecular mechanisms linking hypoxia to NAFLD/NASH setup. METHODS: HIF
system, CD36 content and liver damage markers were analyzed in livers from conditional
Von Hippel-Lindau knockout (VHL-KO) mice, which display an overexpression of HIFs
after VHL gene deletion induced by tamoxifen, and in HepG2 human hepatocytes loaded
with palmitic acid submitted to an hypoxic environment (1% O2). RESULTS: As expected,
HIF1 and HIF2 were overexpressed in livers from VHL-KO mice compared to control
mice. Remarkably, hepatic features of NAFLD and NASH were found in livers from VHLKO mice together with increased lipid content. Accordingly, CD36 levels were upregulated
in these mice after VHL deletion. In human hepatic cells, HIFs were stabilized under
hypoxic conditions. Interestingly, hypoxia itself enhanced fatty acid uptake monitored by
Nile Red staining due to the increase of CD36 translocation to the plasma membrane.
This event was parallel to an increase of inflammatory markers. Noteworthy, palmiticinduced lipotoxicity was more pronounced under hypoxic conditions. CONCLUSIONS:
57
Corresponding author’s email: cgmonzon@salud.madrid.org
Hypoxia accelerates fatty acid uptake, largely due to CD36 translocation to the plasma
membrane of hepatocytes, leading to increased fat accumulation and inflammation in
mice and in cultured human hepatocyte-derived cells. These results suggest that hypoxia
could have a key pathogenic role in the progression of NAFLD to NASH.
58
CLINICAL CASE 3.
THE CHALLENGES OF MONITORING NAFLD
Helena Cortez-Pinto* 1
Gastroenterology, Faculdade de Medicina de Lisboa, Hospital De Santa Maria, Lisbon, Portugal
1
NAFLD is a chronic disease for which there is no approved treatment, thus often needing
long-term follow-up.
It is very frequent, and not all NAFLD patients need to be followed on a Hepatology
specialized clinic. Decision regarding who should be followed on a specialist consultation,
depend on several factors. Since the degree of fibrosis is the most important prognostic
factor in NAFLD, correlating with liver-related outcomes and mortality (1, 2), if there is
evidence of significant fibrosis, more deep investigation is needed, that may include liver
biopsy. Patients with evidence of fibrosis should be followed in a specialist consultation,
and periodic evaluation of fibrosis should be done. The best timing of follow-up is still not
defined, since the risk and speed of progression are unclear. In the majority of cases routine
biochemistry, assessment of co-morbidities and non-invasive monitoring of fibrosis should
be done in a yearly or 6 months basis, depending on the severity. Regarding what is the best
non-invasive method for monitoring fibrosis, it will probably depend on local availabilities
and expertise. Transient elastometry if available, should be performed, although it has
several shortcomings, mostly related to high BMI. Numerous serum markers as well as
combinations of them, such as the NAFLD fibrosis score, FIB-4, and BARD, as well as
commercially panels such as FibroTest, FibroMeter and the ELF test can also be used,
with acceptable diagnostic accuracy.
On the opposite, the absence of fibrosis is rather reassuring, and after counseling on
lifestyle changes, it is possible to discharge the patient from specialized care. The patient
should then be reevaluated in a 5-year time.
For those patients remaining on follow-up, a very important point is the need of a
multidisciplinary team (3). In fact, since NAFLD is usually associated with obesity as
well as other aspects of the metabolic syndrome, there is need to implement and survey
weight loss and exercise. Several recent studies were able to demonstrate that intensive
lifestyle interventions (4, 5), such as the 12-month program reported by Vilar-Gomez et
al, resulted in a significant percentage of resolution of NASH, reduction of the NAFLD
Activity Score, and regression of fibrosis, (5). However, weight regain is very common. In
2008, Bellentani et al., advocated that NAFLD patients should be preferentially referred
to multidisciplinary teams, including physicians, dietitians, psychologists, and physical
activity supervisors (6). However, even in very good programs, such as the Diabetes
Prevention Program, only 38% maintained weight loss after about 3 year follow-up (7).
59
Corresponding author’s email: hlcortezpinto@netcabo.pt
Also, in relation with the increased risk of cardiovascular disease, monitoring of the
associated risk factors, such as lipid profile, blood pressure, and cardiovascular status is
mandatory and in the absence of fibrosis, focus should be on these factors.
One very controversial issue is the need to screen for hepatocellular carcinoma (HCC).
There is strong evidence of an increased risk of HCC in NAFLD and NASH, even in the
absence of cirrhosis (8). However, the systemic surveillance for HCC in unfeasible due
to the large number of NAFLD cases at risk, unless it will be possible to define a highrisk group. It is of course mandatory to screen for HCC, in the presence of cirrhosis, and
6-month scheduled surveillance with ultrasound is recommended.
References
1.
2.
3.
4.
5.
6.
7.
8.
Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is Associated
With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology
2015;149:389-397 e310.
Ekstedt M, Hagstrom H, Nasr P et al. Fibrosis stage is the strongest predictor for disease-specific mortality in
NAFLD after up to 33 years of follow-up. Hepatology 2015;61:1547-1554.
Centis E, Moscatiello S, Bugianesi E, et al. Stage of change and motivation to healthier lifestyle in nonalcoholic fatty liver disease. J Hepatol 2013;58:771-777.
Lassailly G, Caiazzo R, Buob D, et al. Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in
Morbidly Obese Patients. Gastroenterology 2015;149:379-388
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight Loss Through Lifestyle Modification
Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology 2015;149:367-378 e365
Bellentani S, Dalle Grave R, Suppini A et al. Behavior therapy for nonalcoholic fatty liver disease: The need for
a multidisciplinary approach. Hepatology 2008;47
Marchesini G, Mazzella N, Forlani G. Weight Loss for a Healthy Liver. Gastroenterology 2015;149:274-278
Dyson J, Jaques B, Chattopadyhay D, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a
multidisciplinary team. J Hepatol 2014;60:110-117
Disclosure of Interest: H. Cortez-Pinto: Consultant/ Advisor: Conflict with: Intercept,
Sponsored Lectures: National or International: Conflict with: Intercept
60
INTRODUCTION TO BARIATRIC SURGERY: TECHNIQUES,
SHORT-TERM AND LONG-TERM RESULTS AND
COMPLICATIONS
Salvador Morales* 1
Sevilla, Spain
1
OVERVIEW
Bariatric surgery appears in the 50s as a promising treatment in cases where
the classical approach is not effective and allows, by reducing intake, with or without
malabsorption, gets a negative energy balance that facilitates weight loss and longterm maintenance. Currently, he has not only proved this weight loss, but a reduction
in comorbidities associated with obesity and reduction in overall mortality in patients
undergoing bariatric surgery compared with traditional nonsurgical approach.
SURGICAL TECHNIQUE FOR OBESITY
Bariatric surgery techniques achieve weight loss through restrictive, malabsorptive or
a combination of both procedures. Each type of technique has its inherent advantages
and disadvantages, although there is not enough scientific evidence to recommend one
procedure over another in a particular patient. To choose the technique is usually consider
the eating habit, BMI, age, comorbidities and surgical risk, among other factors.
Pure restrictive techniques reduced the gastric capacity, with the aim of achieving a feeling
of fullness and satiety, which decreases energy intake. The techniques of this type most
commonly performed today are:
– Vertical banded gastroplasty (GVA) : This technique began in 1982, after publishing
his experience Mason. Using this technique the stomach is surgically modified in a
vertical way compiling a proximal pouch parallel to the lesser curvature, divided from
the remainder of the gastric cavity by mechanical sutures.
– Adjustable Gastric Banding (AGB) : In 1985, Kuzmak placed first an adjustable
band. This author modified the orinal technique with a new silicone ring provided with
an expandable interior cavity connected to a subcutaneous reservoir, allowing regulating
the internal passage.
– Sleeve Gastrectomy: This technique is described in the late 80s as the restrictive part
of the duodenal switch, being subsequently carried out as a single procedure, as a first
time part of the duodenal switch, or as a one step technique. It represents a special
case, since not only produces a significant restriction (with new volumes of the stomach
of 60-100 cc), since it has been also demonstrated changes in the levels of intestinal
61
Corresponding author’s email: smoralesc@gmail.com
hormones after performing this technique, which may be related to more effectively
against other pure restrictive techniques.
In the combined technique there is a restrictive component and a malabsorptive
component, performing an intestinal bypass. Depending on the extent of the gastrectomy
and common loop length predominates restriction or malabsorption. Combined
techniques most commonly performed are:
- Roux-en-Y Gastric Bypass: the type of bariatric surgery most commonly used
worldwide. This technique consist in creating a small gastric pouch (20-50 cc) to limit
food intake, associated with a Roux-Y gastrojejunal anastomosis with a jejunal loop of
variable length, which causes the malabsorptive component.
- Biliopancreatic diversion: the malabsorptive component is larger and involves a
gastrectomy, with larger capacity than in previous technique, with a Roux-Y gastrojejunal
anastomosis and a biliodigestive diversi�n creating a common limb 50- 75 cm from the
ileocecal valve.
- Duodenal Switch: it is a technique similar to that described by Scopinaro but transverse
gastrectomy is replaced for a vertical one, maintaining full gastric pyloric innervation
and function, with the same distances of the alimentary limb and increasing the common
limb.
Currently most of procedures that are being performed worldwide are Sleeve
gastrectomy and Roux-en-Y Gastric Bypass, both laparoscopically, and in some
centers the adjustable gastric band. The biggest obstacle of gastric banding is that it
requires a high fulfillment by the patient and a very close control, reducing the acceptance
of the technique. But, the Sleeve gastrectomy is booming, because of its simplicity and
effectiveness.
SAFETY AND COMPLICATIONS OF BARIATRIC SURGERY
Regarding the mortality associated with surgery, a decade ago early mortality (perioperative and
up to 30 days) in the US was up to 2%, and a year was up to 5%. With the advancement of
technology and the experience of surgeons, this risk has been greatly reduced in recent years, and
today you can do the surgery as safely as cholecystectomy, with Intraoperative mortality of 0.1%.
Nutritional complications depend on the type of surgery, diet and fulfillment, thereby being
necessary the existence of a multidisciplinary team. The same mechanisms that produce weight
loss can lead to its development. The most common are excessive weight loss, protein malnutrition
and micronutrient deficiency. One of the most common deficiencies after bariatric surgery is the
vitamin B12. Also iron deficiency and anemia are very prevalent, particularly if the duodenum
is excluded.
62
MACRO AND MICRONUTRIENTS IN NASH
Shira Zelber-Sagi* 1
1
Liver Unit, Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
Lifestyle change, including dietary habits, is a modifiable risk factor and thus represents a
main target for the primary prevention and treatment of NAFLD and NASH. Although
weight reduction is the most established treatment for both NAFLD and NASH (1), it is
hard to achieve and maintain in the long term. Therefore, changing dietary composition
without reducing caloric intake, may offer a more feasible alternative to treat NAFLD
patients. Furthermore, an increasing number of NAFLD patients have normal body
mass index (2-5), the so called “lean NAFLD” (6). Several epidemiological studies (7-9)
indicate that normal weight NAFLD patients in particularly consume an unhealthy diet
as compared to controls, and therefore reveals the importance of dietary composition
regardless of obesity.
Similarly to cardiovascular disease, different types of dietary fat have different effects
in NAFLD and NASH. Omega-3 fatty acids and their subtypes seem to be a potential
promising treatment due to their favorable effect on lipid metabolism and antiinflammatory effect. Recent RCTs, assessed their effect on NASH and fibrosis, yielding
conflicting results with regard to liver fat reduction and disappointing results with regard
to NASH or fibrosis (10-12).
Monounsaturated-fat (MUFA), which characterizes the Mediterranean diet, was
demonstrated to have a favorable effect on lipid profile (13,14). It has been suggested
that adherence to the Mediterranean diet pattern leads to a significant decrease in liver fat
(15). This was supported by two randomized short term trials in NAFLD patients with or
without type-2 diabetes assigned to either low fat (30% of calories as fat) or high-MUFA
diet/Mediterranean diet (40% of calories as fat) for a 6-8-week period. Liver fat content
decreased more in the MUFA/Mediterranean diet despite stable weight in both groups
(16, 17). It should be noted that the Mediterranean diet is also characterized by reduced
carbohydrates intake (40% of the calories vs. 50-60% in a typical low fat diet), especially
reduced sugars and refined carbohydrates, which may account, at least partially, for its
success.
There is overwhelming evidence with regard to the association between added sugars and
NAFLD. The association is more prominent with sugar-sweetened beverages (SSBs) (7,
18-20), but not with diet beverages (21). In addition, cola beverages contain caramel
coloring, which is rich in advanced glycation end products (AGEs) that may increase
insulin resistance and inflammation (22, 23). These findings are supported by a 6
month RCT in which only regular cola but not isocaloric semi skim milk or aspartame-
63
Corresponding author’s email: zelbersagi@bezeqint.net
sweetened diet cola led to increased liver fat (24). Fructose-containing beverages were also
demonstrated to be associated with a more severe fibrosis in NAFLD patients if consumed
on a daily basis (25), perhaps since fructose increases uric acid levels which is related to
oxidative stress and insulin resistance (26). Therefore, like alcohol, questions regarding
SSBs consumption should routinely be include as part of the patient’s history.
After the elimination of SSBs from the diet, patients may be encouraged to drink coffee.
Studies in NAFLD patients repeatedly suggested an inverse association between coffee
consumption and liver fibrosis (27-30) and HCC (31). However, with regard to steatosis
the results are conflicting (27, 28, 30, 32, 33). The hepatoprotective effects of coffee may
be linked not only to caffeine but also to its polyphenolic fraction (34, 35).
In spite of the evidence supporting the association of oxidative stress with NASH and the
efficacy of antioxidants in animal models, the efficacy of antioxidant therapy in humans
has not been demonstrated or properly tested (36), with the exception of vitamin E (37).
Choline is an essential component of cell membranes and is required for the synthesis of
phospholipids. In a cross-sectional analysis, postmenopausal women with deficient choline
intake had worse fibrosis and a similar trend was noted in both premenopausal women
and men (38). Choline is particularly abundant in egg yolks and animal sources of protein.
Emerging evidence suggests that vitamin D may play a role in the pathogenesis of NAFLD.
In support of that, a meta-analysis of observational studies demonstrated that compared
to controls, NAFLD patients were more likely to be vitamin D deficient (39). However,
a study carefully adjusting for adiposity, suggests that there is no relationship between
vitamin D levels and insulin resistance, the amount of liver fat, or the severity of NASH
(40).
Shifting the focus of goal setting from just weight reduction to dietary change goals may
help in our patient’s empowerment and enhancement of self-efficacy. The diet of choice
should be the one which individuals are able to adhere for years rather than weeks, with
the help of educational and behavioral strategies.
References
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4.
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7.
64
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, GonzalezFabian L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic
Steatohepatitis. Gastroenterology. 2015;149(2):367-78 e5; quiz e14-5.
Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al. NASH and insulin
resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology.
2002;35:373-9.
Pagano G, Pacini G, Musso G, Gambino R, Mecca F, Depetris N, et al. Nonalcoholic steatohepatitis, insulin
resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology. 2002;35:367-72.
Lee JH, Rhee PL, Lee JK, Lee KT, Kim JJ, Koh KC, et al. Role of hyperinsulinemia and glucose intolerance
in the pathogenesis of nonalcoholic fatty liver in patients with normal body weight. Korean J Intern Med.
1998;13:12-4.
Banerji MA, Faridi N, Atluri R, Chaiken RL, Lebovitz HE. Body composition, visceral fat, leptin, and insulin
resistance in Asian Indian men. J Clin Endocrinol Metab. 1999;84:137-44.6. Younossi ZM, Stepanova M,
Negro F, Hallaji S, Younossi Y, Lam B, et al. Nonalcoholic fatty liver disease in lean individuals in the United
States. Medicine. 2012;91(6):319-27.
Assy N, Nasser G, Kamayse I, Nseir W, Beniashvili Z, Djibre A, et al. Soft drink consumption linked with fatty
liver in the absence of traditional risk factors. Can J Gastroenterol. 2008;22(10):811-8. Musso G, Gambino
R, De Michieli F, Cassader M, Rizzetto M, Durazzo M, et al. Dietary habits and their relations to insulin
resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003;37(4):909-16.
Yasutake K, Nakamuta M, Shima Y, Ohyama A, Masuda K, Haruta N, et al. Nutritional investigation of
non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol. Scandinavian
journal of gastroenterology. 2009;44(4):471-7.
10. Scorletti E, Bhatia L, McCormick KG, Clough GF, Nash K, Hodson L, et al. Effects of purified
eicosapentaenoic and docosahexaenoic acids in non-alcoholic fatty liver disease: Results from the *WELCOME
study. Hepatology. 2014.
11. Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M. No significant effects of ethyleicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology.
2014;147(2):377-84 e1.
12. Argo CK, Patrie JT, Lackner C, Henry TD, de Lange EE, Weltman AL, et al. Effects of n-3 fish oil on
metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. Journal
of hepatology. 2015;62(1):190-7.
13. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio
of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled
trials. The American journal of clinical nutrition. 2003;77(5):1146-55.
14. Garg A. High-monounsaturated-fat diets for patients with diabetes mellitus: a meta-analysis. The American
journal of clinical nutrition. 1998;67(3 Suppl):577S-82S.
15. Trovato FM, Catalano D, Martines GF, Pace P, Trovato GM. Mediterranean diet and non-alcoholic fatty liver
disease.: The need of extended and comprehensive interventions. Clin Nutr. 2014.
16. Bozzetto L, Prinster A, Annuzzi G, Costagliola L, Mangione A, Vitelli A, et al. Liver fat is reduced by
an isoenergetic MUFA diet in a controlled randomized study in type 2 diabetic patients. Diabetes care.
2012;35(7):1429-35.
17. Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, et al. The Mediterranean Diet Improves
Hepatic Steatosis and Insulin Sensitivity in Individuals with Nonalcoholic Fatty Liver Disease. Journal of
hepatology. 2013.
18. Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, Webb M, Blendis L, Halpern Z, et al. Long term nutritional
intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. Journal of
hepatology. 2007;47(5):711-7.
19. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, et al. Fructose consumption as a risk factor
for non-alcoholic fatty liver disease. Journal of hepatology. 2008;48(6):993-9.
20. Abid A, Taha O, Nseir W, Farah R, Grosovski M, Assy N. Soft drink consumption is associated with fatty liver
disease independent of metabolic syndrome. Journal of hepatology. 2009;51(5):918-24.
21. Ma J, Fox CS, Jacques PF, Speliotes EK, Hoffmann U, Smith CE, et al. Sugar-sweetened beverage, diet soda,
and fatty liver disease in the Framingham Heart Study cohorts. Journal of hepatology. 2015;63(2):462-9.
22. Gaby AR. Adverse effects of dietary fructose. Alternative medicine review : a journal of clinical therapeutic.
2005;10(4):294-306.
23. Koschinsky T, He CJ, Mitsuhashi T, Bucala R, Liu C, Buenting C, et al. Orally absorbed reactive glycation
products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proceedings of the National
Academy of Sciences of the United States of America. 1997;94(12):6474-9.
24. Maersk M, Belza A, Stodkilde-Jorgensen H, Ringgaard S, Chabanova E, Thomsen H, et al. Sucrose-sweetened
beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study.
The American journal of clinical nutrition. 2012;95(2):283-9.
25. Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, et al. Increased fructose
consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease.
Hepatology.51(6):1961-71.
26. Choi JW, Ford ES, Gao X, Choi HK. Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level:
the Third National Health and Nutrition Examination Survey. Arthritis and rheumatism. 2008;59(1):109-16.
27. Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, Harrison SA. Association of coffee and caffeine
consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology.
2012;55(2):429-36.
28. Zelber-Sagi S, Salomone F, Webb M, Lotan R, Yeshua H, Halpern Z, et al. Coffee consumption and
nonalcoholic fatty liver onset: a prospective study in the general population. Translational research : the journal
of laboratory and clinical medicine. 2015;165(3):428-36.
29. Anty R, Marjoux S, Iannelli A, Patouraux S, Schneck AS, Bonnafous S, et al. Regular coffee but not espresso
drinking is protective against fibrosis in a cohort mainly composed of morbidly obese European women with
NAFLD undergoing bariatric surgery. Journal of hepatology. 2012;57(5):1090-6.
65
9.
30. Bambha K, Wilson LA, Unalp A, Loomba R, Neuschwander-Tetri BA, Brunt EM, et al. Coffee consumption in
NAFLD patients with lower insulin resistance is associated with lower risk of severe fibrosis. Liver international
: official journal of the International Association for the Study of the Liver. 2014;34(8):1250-8.
31. Setiawan VW, Wilkens LR, Lu SC, Hernandez BY, Le Marchand L, Henderson BE. Association of coffee intake
with reduced incidence of liver cancer and death from chronic liver disease in the US multiethnic cohort.
Gastroenterology. 2015;148(1):118-25; quiz e15.
32. Catalano D, Martines GF, Tonzuso A, Pirri C, Trovato FM, Trovato GM. Protective role of coffee in nonalcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2010;55(11):3200-6.
33. Birerdinc A, Stepanova M, Pawloski L, Younossi ZM. Caffeine is protective in patients with non-alcoholic fatty
liver disease. Aliment Pharmacol Ther. 2012;35(1):76-82.
34. Vitaglione P, Morisco F, Mazzone G, Amoruso DC, Ribecco MT, Romano A, et al. Coffee reduces liver
damage in a rat model of steatohepatitis: the underlying mechanisms and the role of polyphenols and
melanoidins. Hepatology. 2010;52(5):1652-61.
35. Salomone F, Li Volti G, Vitaglione P, Morisco F, Fogliano V, Zappala A, et al. Coffee enhances the
expression of chaperones and antioxidant proteins in rats with nonalcoholic fatty liver disease. Translational
research : the journal of laboratory and clinical medicine. 2013.
36. Lirussi F, Azzalini L, Orando S, Orlando R, Angelico F. Antioxidant supplements for non-alcoholic fatty liver
disease and/or steatohepatitis. Cochrane Database Syst Rev. 2007(1):CD004996.
37. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or
placebo for nonalcoholic steatohepatitis. The New England journal of medicine. 2010;362(18):1675-85.
38. Guerrerio AL, Colvin RM, Schwartz AK, Molleston JP, Murray KF, Diehl A, et al. Choline intake in a
large cohort of patients with nonalcoholic fatty liver disease. The American journal of clinical nutrition.
2012;95(4):892-900.
39. Eliades M, Spyrou E, Agrawal N, Lazo M, Brancati FL, Potter JJ, et al. Meta-analysis: vitamin D and nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2013;38(3):246-54.
40. Bril F, Maximos M, Portillo-Sanchez P, Biernacki D, Lomonaco R, Subbarayan S, et al. Relationship of
vitamin D with insulin resistance and disease severity in non-alcoholic steatohepatitis. Journal of hepatology.
2015;62(2):405-11.
66
NASH AND WEIGHT LOSS: MANAGEMENT AND
BENEFICIAL ASPECTS
Eduardo Vilar-Gomez* 1
Unit for the Clinical Management of Digestive Disease,Virgen del Rocio andVirgen de Macarena
University Hospitals, Seville, Spain
1
Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic
syndrome, has emerged as a leading cause of chronic liver disease worldwide and has
been associated with an increased risk of diabetes and ischemic heart disease. Its overall
incidence is growing rapidly associated with the parallel epidemics of obesity and type 2
diabetes. NAFLD encompasses a clinicopathologic spectrum ranging from simple steatosis
to steatohepatitis (NASH), the more aggressive form of NAFLD which may progress to
cirrhosis and its associated complications. Thus, an effective treatment of NASH is needed
to halt disease progression. Whereas several drugs have been evaluated in clinical trials,
there are currently no approved therapies for NASH. Thus, lifestyle changes focusing on
weight loss remain the cornerstone of NASH treatment. Several studies have reported that
degree of weight reduction appears to be positively correlated to histological improvements,
and most of them concluded that at least 7-10% of WL is required to induce improvement
in NAFLD activity score (NAS) and their components (steatosis, lobular inflammation
and ballooning), however, weight losses ≥ 10% are required to induce highest rates of
steatohepatitis resolution and 1-point of fibrosis reversal. Unfortunately, less than 50%
of patients achieve the necessary weight loss goal of more than 7-10% in the trial setting,
and many have questioned the sustainability of this kind of intervention. Regarding to
specific macronutrient distribution for dietary interventions, benefits of low-fat vs. lowcarb diets in overweight/obese patients suffering NASH are lacking, and only losing weight
is a priority, reaffirming the importance of calories from any source. Adherence is likely
the most important determinant of body weight reduction. More research is needed
to inform future guidelines about dietary interventions for weight loss in patients with
NAFLD. Thus, in the real world, an intensive lifestyle counseling must be offered to all
NASH patients, however, the applicability of these interventions depends largely on their
availability and real world adherence to these programs.
67
Corresponding author’s email: eduardovilar2000@yahoo.com
CURRENT INSULIN SENSITISING AGENTS IN NASH
Philip N. Newsome* 1
1
University of Birmingham, Birmingham, United Kingdom
Corresponding author’s email: p.n.newsome@bham.ac.uk
Insulin resistance is a major component in the pathogenesis of NASH, and indeed
many patients with NASH have concomitant type 2 diabetes mellitus. This has driven
the development of therapies targeting insulin resistance as well as the use of approved
diabetic therapies for patients with NASH. This talk will examine the evolution of insulin
sensitising therapies in patients with NASH and speculate on their future position in the
management of NASH.
Disclosure of Interest: P. N. Newsome: Grant/Research Support: Conflict with:
Pharmaxis, Consultant/ Advisor: Conflict with: Boehringer Ingelheim, Pfizer, Dignity
Sciences, Intercept, Johnson&Johnson, Novo Nordisk and Shire
68
NOVEL PHARMACOLOGICAL THERAPIES FOR NAFLD
Vlad Ratziu* 1
Hopital Pitié Salpétrière, Paris, France
1
Despite the burden of disease associated with NASH, the treatment of NASH remains a
significant unmet need. While simple to recommend, diet and lifestyle measures as a firstline therapy for non-alcoholic steatohepatitis (NASH) are hardly a model of successful
therapy, as most clinicians can testify. They can be complex to implement, hard to
sustain and of limited efficacy in advanced stages of the disease. The need for specific
pharmacotherapy is now acknowledged by practitioners, the pharmaceutical industry
and regulators and is largely expected by patients. The result is a clear move away from
products developed second-hand for NASH (such as pioglitazone or metformin) or from
generic, non-specific hepatoprotectors (such as pentoxifillin, ursodeoxycholic acid or
antioxidants) towards molecules developed and tested specifically for NASH that aim to
correct one or several of the pathways of liver injury in this disease.
The complex pathogenesis of NASH, however, presents multiple potential therapeutic
targets for which compounds are progressing in clinical development. Several compounds
have already received either breakthrough status (obeticholic acid) or fast-track status
(aramchol, cenicriviroc, elafibranor, GR-MD-02) from the FDA. The two most advanced
molecules, obeticholic acid and elafibranor, have shown encouraging data on improving
hepatic histology. Both compounds appear to clear NASH, with obeticholic acid improving
liver fibrosis and elafibranor improving the glycemic and lipid profile. Much larger trials,
currently ongoing, will need to confirm these preliminary data and better characterize
the safety and tolerability profile. Meanwhile, other compounds are being tested, a few
in phase 2b studies (cenicriviroc, aramchol for NASH, simtuzumab for NASH fibrosis)
and many more in earlier, smaller trials. Most of these drug candidates target different
pathways, which speaks to the diversity and dynamism of the NASH pipeline.
Obeticholic acid, a farnesoid X receptor (FXR) agonist, has completed phase IIb
testing. Results from the FLINT trial, demonstrated histologic improvement in patients
with NASH compared with placebo: the drug improved steatosis, liver-cell injury and
inflammation resulting in a significant reversal of steatohepatitis. Morevover there was
also an improvement of fibrosis regardless of the baseline fibrosis stage. Findings from
a subgroup analysis showed histologic improvement even in a subset of high-risk NASH
patients. Adverse effects were mild to moderate and similar to those observed in the
placebo group, with the exception of pruritus, which was more common and more intense
compared with placebo and an increase in LDL. Recently published data with elafibranor,
a dual PPAR alpha/delta agonist also have shown its ability to reverse NASH without
69
Corresponding author’s email: vratziu@teaser.fr
fibrosis worsening, particularly in a subpopulation of patients with moderate/advanced
disease. This compound also improved the glycemic and lipid profile.
Aramchol, a fatty acid and bile acid modifier, also has published phase II data. Patients
who received aramchol 300 mg for 3 months showed a significant reduction in liver fat
content compared with patients who received placebo. There was no difference in safety
profiles between the treatment and control groups, and no adverse effects were attributed
to therapy.
A number of other compounds are currently in phase IIb testing, with no data yet
available. Simtuzumab is an anti-LOXL2 monoclonal antibody with two 240-week, phase
IIb trials under way in patients with NASH, with and without cirrhosis. A 2-year, placebocontrolled, phase IIb trial of cenicriviroc, a dual inhibitor of CCR2 and CCR5, is ongoing
in noncirrhotic patients with NASH.
Substantial progress has been made in recent years in the care of patients with NASH,
including recognition of medical need, acceptance of NASH as an indication of therapy,
agreement on an operational definition of NASH, and an improved understanding of
targeted compounds and the path of clinical development. As additional phase IIb and
phase III data accrue, and as clinicians are educated about the opportunities for reduced
disease burden with targeted therapies, progress toward meeting the unmet needs of
NASH is expected to move forward in strides.
Suggested Readings
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for
non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet.
2015;385:956-965.
Armstrong MG, Gaunt P, Aithal GP et al. Liraglutide safety and efficacy in patients with non-alcoholic
steatohepatitis (LEAN) a multicentre double-blind randomized, placebo-controlled phase 2 study. Lancet
2016;387:679-690.
Ratziu V, Harrison S, Francque S et al. Elafibranor an agonist of the PPAR alpha and delta induces resolution of
NASH without fibrosis worsening. Gastroenterology 2016 in press.
Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the
development of a pathologic microenvironment. Nat Med. 2010;16:1009-1017.
Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014;147:577-594.
Sanyal A . use of FXR agonists to treat non alcoholic fatty liver disease. Dig Dis 2015;33:426-32
Safadi R, Konikoff FM, Mahamid M, et al. The fatty acid-bile acid conjugate aramchol reduces liver fat content in
patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12:2085-2091.
Ratziu V. Novel pharmacological options for NASH. Dig Dis Sci 2016 in press
70
ePOSTER
ABSTRACTS
Thursday 12 May 2016
ePoster Session 1: 13:30 – 14:00
Screen 1: MR-146
DYSMETABOLIC IRON OVERLOAD SYNDROME IN
NON-ALCOHOLIC FATTY LIVER DISEASE PATIENTS
ePOSTER ABSTRACTS
Paula Fabrega1, Claudia P. Oliveira* 2, Hilton M. Leão-Filho3, Jose Tadeu Stefano2,
Cintia Cercato1
1
ENDOCRINOLOGY, 2GASTROENTEROLOGY, 3RADIOLOGY, University of São Paulo
School of Medicine, SAO PAULO, Brazil
Corresponding author’s email: cpm@usp.br
Introduction: Dysmetabolic iron overload syndrome (DIOS) is characterized by
hyperferritinemia with normal transferrin saturation, metabolic disorders and mild liver
iron overload. DIOS occurs in non-alcoholic fatty liver disease (NAFLD) mainly in
steatohepatitis (NASH).
Aims: This study aimed at assessing the DIOS characteristics of our NAFLD patients.
Material and Methods: We conducted a retrospective analysis of 202 patients that
underwent liver biopsy due to NAFLD histologic evaluation. The period of analysis was
January 2007 to December 2014. Patients were discriminate by gender, age, ferritin serum
levels, liver transaminases levels, presence of comorbidities (hypertension, diabetes and
dyslipidemia) and histological features of liver biopsy (inflammation, ballooning, fibrosis
and steatosis).
Results: The prevalence of DIOS in our NAFLD sample was 7.7% (IC 95% 4.3 – 12.6%).
The median ferritin in patients with liver iron overload was 444 ug/L (290 – 536) and in
patients without was 152 ug/L (74 – 269). The difference between ferritin level in patients
with and without liver iron overload was statistically significant. The cut off level of ferritin
to identify liver iron overload was 329.9 ug/L (ROC curve – IC 95% = 0.72 – 0.92),
sensibility of 75% and specificity of 82%. The comparison of ferritin levels and biopsy
characteristic showed that higher ferritin levels is related with a more severe ballooning
degree, the others features were not statistically significant.
72
Conclusions: The ferritin serum level is an important evaluation tool for NAFLD
patients, level above 329.9 ug/L may suggest liver iron overload and higher ferritin is
related to a worst histological features (ballooning).
ePOSTER ABSTRACTS
73
Screen 2: MR-185
NAFLD IN CHRONIC HEPATITIS B: A COMMON
FINDING WITHOUT IMPACT ON THE LIVER DISEASE
PROGRESSION
Leila Mouelhi* 1, Moufida Mahmoudi1, Shema ayadi1, Fatma Houissa1, Kaouther
Jery1, Yosra Said1, Radhouene Debbech1, Taoufik Najjar1
1
Gastroenterology, Charles Nicolle Hospital, Tunis, Tunisia
ePOSTER ABSTRACTS
Corresponding author’s email: leilamouelhi@yahoo.fr
Introduction: Nonalcoholic fatty liver disease (NAFLD) and chronic infection with
hepatitis B virus (CHB) are two common causes of chronic liver disease in Tunisia.
Approximately one third of patients with CHB have been reported to have NAFLD.
Recent studies suggested that NAFLD is associated with antiviral therapy failure; others
report suppression of viral replication in NAFLD.
Aims: We aimed to investigate the prevalence of histological evidence of hepatic steatosis,
a common hepatocyte change in NAFLD, in a group of patients with chronic HBV
infection undergoing liver biopsy and compared clinical data, laboratory features, severity
of hepatic fibrosis, viral kinetics and virologic response to entecavir treatment, between
patients both with and without steatosis.
Material and Methods: This study was designed as a retrospective monocenter cohort
study. All patients with CHB, who underwent liver biopsy for diagnostic purposes over a
5-year period were enrolled in this study. Clinical, biological, and histological factors were
evaluated. The impact of hepatic steatosis on pre-treatment serum HBV DNA levels and
also on the virologic response to entecavir at 6 and 12 months of therapy was investigated.
Results: A total of 127 cases were involved in the study [median age 43 (19–68) years,
79 (62.2%) males, 26 received an entecavir therapy for at least 48 weeks. Steatosis was
present in 28 (19.3%) of the patients.
Our data showed that LS is not associated with age, sex, body mass index, HBeAg status,
viral load, severity of fibrosis, amount of activity, aspartate aminotransferase, alanine
aminotransferase, γ-glutamyl transpeptidase and alkaline phosphatase.
However, patients with liver steatosis had higher serum triglyceride, fasting blood glucose,
and serum cholesterol level (p=0.04 and 0.01 respectively).
74
Liver steatosis had no effect on virologic response to entecavir at 6 and 12 months of
treatment.
Conclusions: Steatosis is a relatively common finding in CHB associated with metabolic
host factors. NAFLD had no impact on either the disease progression or the virologic
response to entecavir treatment.
ePOSTER ABSTRACTS
75
Screen 3: MR-163
PNPLA3 AND TNF-α G238A GENETIC POLYMORPHISMS
IN EGYPTIAN PATIENTS WITH DIFFERENT GRADES OF
SEVERITY OF NAFLD
Mona A.-E. Hegazy* 1, Ahmed Ezzat1, Laila Rashed2, Abeer Mostafa3
Internal Medicine, 2Medical Biochemistry, Faculty of Medicine. Cairo University, 3Pathology,
National Cancer Institute. Cairo University, Cairo, Egypt
1
ePOSTER ABSTRACTS
Corresponding author’s email: monahegazy@hotmail.com
Introduction: Background: There is growing evidence that genetic as well as
environmental factors play an important role in the development and progression of
NAFLD. In recent years, the genetic determinants of steatosis are being identified using
genome-wide association studies. We investigated the association of the SNP rs738409
in the PNPLA3 gene and the TNF-α G238A polymorphism with the development and
severity of NAFLD in an overweight and obese Egyptian population.
Methods: 100 overweight and obese patients with NAFLD and 30 age- and sex- matched
controls attending the Gastroenterology and Hepatology outpatient clinic of Kasr Al Ainy
Hospital, Cairo University were enrolled in the study. All patients with NAFLD underwent
a confirmatory biopsy after a written consent. Fasting plasma glucose, kidney and liver
function tests, ALT, AST, GGT, lipid profile, HCV antibodies and HBsAg were measured
in all subjects. Abdominal ultrasound was performed and all subjects were genotyped for
(rs738409) PNPLA3 and (rs361525) TNF-α gene polymorphisms using PCR-RFLP.
Results: As regard the PNPLA3 gene SNP, the homozygous GG genotype was most
frequent among patients with NASH (26%) when compared to those with borderline
NASH (20.5%) and simple steatosis (20%). Higher serum levels of ALT and AST were
observed in NAFLD patients and control subjects who were carriers of the G allele of
rs738409, but this did not reach statistical significance. As regards the TNF-α G238A
SNP; the frequency of the A allele was higher in NAFLD patients (20%) compared to the
controls (5%) with p value=0.006. The highest TNF G allele frequency was observed in
the NASH group (88%) and this was statistically significant with a p value=0.009.
Conclusion: Our study confirmed the association of the PNPLA3 (rs738409) and
TNF-α promoter region G238A polymorphisms with susceptibility to NAFLD and its
progression.
76
Screen 4: YI-MR-117
THE CONTROLLED ATTENUATION PARAMETER (CAP) IN
NAFLD AND OTHER NON-ALCOHOLIC CHRONIC LIVER
DISEASES: SHOULD IT BE CONSIDERED A DIAGNOSTIC
CRITERIA FOR METABOLIC SYNDROME?
Corresponding author’s email: rosacoelhoabrantes@hotmail.com
Introduction: The prevalence of metabolic syndrome (MS) has been increasing
around the world and nonalcoholic fatty liver disease (NAFLD) seems to be its liver
manifestation. Fibroscan® is considered a validated alternative to liver biopsy for assessing
liver stiffness. It allows the simultaneous measurement of hepatic steatosis through the
controlled attenuation parameter (CAP).
Aims: The aims of this study were: i) to evaluate the CAP’s utility in chronic liver
diseases (CLD), specifically in NAFLD patients, and its association with demographic,
anthropometric and biochemical parameters classically evaluated in clinical practice; and
ii) to establish the association between the CAP value and the MS parameters.
Material and Methods: This prospective cohort study included 94 patients with CLD:
chronic hepatitis B (CHB) and C (HCV), NAFLD and autoimmune hepatitis (AIH).
Anthropometric measurements, Fibroscan® values, cardiovascular risk factors, alcohol
intake, medications and biochemical data were obtained.
Results: In our study, 53% of the patients were male and the mean age was 56.3±12.5
years. Disease etiology was evenly distributed: 25 patients had NAFLD (27%), 25 CHB
(27%), 25 CHC (27%) and 19 AIH (20%). Considering cardiovascular risk factors, 16%
of patients had type 2 diabetes and 32% hypertension. Obesity (body mass index (BMI)
>30 kg/m2) was present in 16% of the patients and 23% of the patients fulfilled the MS
criteria. Patients with NAFLD had higher BMI and a higher proportion of hypertension.
NAFLD patients presented the highest values for γ-GT (p<0.001) and ferritin (p=0.0017).
Median CAP value was higher in NAFLD patients than AIH (p=0.002) and HCV patients
77
ePOSTER ABSTRACTS
Rosa Coelho* 1, Gonçalo Marinho2, Luís Ferreira-Pinto 3, Ana Maria Horta-Vale1,
Guilherme Macedo1
1
Gastrenterology Department, Centro Hospitalar São João, 2Faculty of Medicine,
University of Porto, Porto, Portugal, 3Department of Health and Decision Sciences –
CIDES, Faculty of Medicine, University of Porto, Porto, Portugal
(p=0.004). In NAFLD patients, median CAP value was correlated to HbA1c (p=0.019),
AST (p=0.036) and γ-GT (p=0.040); it was also strongly correlated to the number of
MS variables (correlation coeficient ρ=0.669, p=0.001). Considering individually the
variables that define the MS, only hypertension showed a significantly higher median CAP
value (p=0.038).
Conclusions: CAP is a simple, operator-independent and non-invasive tool for hepatic
steatosis detection, strongly correlated to the number of MS parameters in NAFLD
patients. In the future it could be added to the MS diagnostic criteria.
ePOSTER ABSTRACTS
78
Screen 5: YI-MR-124
REFRACTORY SUBACUTE STEATOHEPATITIS AFTER
BILIOPANCREATIC DIVERSION: A CASE REPORT
Sander Lefere* 1, Xavier Verhelst2, Sarah Raevens1, Roberto Troisi3, Hans Van
Vlierberghe1, Anja Geerts1
1
Department of Gastroenterology and Hepatology, Ghent University Hospital, 2Department
of Gastroenterology and Hepatology, hent University Hospital, 3Department of General,
Hepatobiliary and Liver Transplantation Surgery, Ghent University Hospital, Ghent, Belgium
Introduction: As the prevalence of obesity has risen dramatically over the last decades,
non-alcoholic steatohepatitis (NASH) has become a major cause of chronic liver disease.
Bariatric surgery is an important therapeutic option in NASH if more conservative
options fail. Nevertheless, hepatic complications following bariatric surgery, especially
jejunoileal bypass surgery, occur in some patients. Severe steatohepatitis necessitating
liver transplantation has also been reported following biliopancreatic diversion (BPD, or
Scopinaro operation). The pathogenesis of NASH progression after bariatric surgery is
poorly understood, yet small intestinal bacterial overgrowth in the surgical blind loop is a
known risk factor.
Material and Methods: We present the case of a female patient who underwent BPD
surgery at 19 years of age and presented with decompensated NASH cirrhosis five years
later.
Results: Her condition deteriorated rapidly and she was listed for transplantation. Partial
dismantling of the intestinal bypass, to prevent relapse of liver failure, was postponed until
eight weeks after transplantation due to her bad general condition. Bacterial overgrowth
was persistently present despite adequate antibiotic treatment. Liver biopsy at the time of
dismantling already showed signs of recurrent severe steatohepatitis with hepatocellular
necrosis. Because of progression to cirrhosis and clinical decompensation, she underwent
retransplantation and a full restoration of intestinal anatomy. Unfortunately, refractory
bacterial overgrowth remained present and the patient again developed cirrhosis. After
three failed transplantations, we decided in deliberation with the patient not to pursue
further therapy. The patient died shortly after.
79
ePOSTER ABSTRACTS
Corresponding author’s email: sander.lefere@ugent.be
Conclusions: BPD surgery may result in severe NASH. Therapy consists of liver
transplantation and timely dismantling of BPD, yet these measures were unsuccessful in
our patient. Although the pathogenesis of NASH development post-bariatric surgery is
complex and poorly understood, our case highlights bacterial overgrowth as a major risk
factor in disease progression.
ePOSTER ABSTRACTS
Disclosure of Interest: S. Lefere: Grant: Conflict with: Fund for Scientific Research
(FWO Flanders, FWO15/ASP/146)), X. Verhelst: Grant: Conflict with: Fund for
Scientific Research (FWO Flanders,1700214N), S. Raevens: Grant: Conflict with: Fund
for Scientific Research (FWO Flanders, 11W5715N), R. Troisi: : None Declared, H. Van
Vlierberghe: : None Declared, A. Geerts: : None Declared
80
Screen 6: MR-106
CONTROLLED ATTENUATION PARAMETER AND LIVER
STIFFNESS MEASUREMENTS BY FIBROSCAN FOR THE
DETECTION OF NON-ALCOHOLIC FATTY LIVER DISEASE
IN PATIENTS WITH TYPE 2 DIABETES: RESULTS FROM A
PILOT STUDY
Department of
3
Corresponding author’s email: dryusufyilmaz@gmail.com
Introduction: Type 2 diabetes mellitus (T2DM) is a paramount risk factor for nonalcoholic fatty liver disease (NAFLD). However, the optimal diagnostic modality for the
detection of NAFLD in patients with T2DM remains controversial. In addition, current
guidelines do not recommend screening for NAFLD in diabetic patients. Successful
FibroScan measurements were obtained in 52 (96.2%) study patients. Hepatic steatosis,
moderate fibrosis (≥F2), severe fibrosis (≥F3), and cirrhosis (F4) were detected in 90.3%,
36.6%, 19.2%, and 11.5% of the participants. Surprisingly, normal values of alanine
aminotransferase (ALT) and platelet count were observed in 74.0% and 98.1% of the
cirrhotic patients, respectively.
Aims: Here, we investigated the potential usefulness of FibroScan for the detection of
NAFLD and severe liver fibrosis in patients with T2DM.
Material and Methods: A total of 54 patients were prospectively enrolled from the
Internal Medicine Clinic of the Marmara University Medical School. Hepatic steatosis
ratios were obtained with the Controlled Attenuation Parameter (CAP), whereas the
fibrosis stage was investigated using Liver Stiffness Measurment (LSM) values. At least 10
valid measurements with ≤ 30% interquartile range/median (IQR/M) ratios were required
to consider the tests reliable. The LSM score was calculated as the median of 10 valid
measurements. In line with previous studies, the following cut-offs were used: ≥222dB/m
for hepatic steatosis, ≥7.0 kPa for ≥F2 fibrosis, ≥9.6 kPa for ≥F3 fibrosis, and ≥11.5 kPa
for F4 fibrosis.
81
ePOSTER ABSTRACTS
Meryem Durgay1, 2, Oguzhan Deyneli1, Yusuf Yilmaz* 3
Department of Endocrinology, 2Department of Internal Medicine,
Gastroenterology, Marmara University, School of Medicine, Istanbul, Turkey
1
Results: Successful FibroScan measurements were obtained in 52 (96.2%) study patients.
Hepatic steatosis, moderate fibrosis (≥F2), severe fibrosis (≥F3), and cirrhosis (F4) were
detected in 90.3%, 36.6%, 19.2%, and 11.5% of the participants. Surprisingly, normal
values of alanine aminotransferase (ALT) and platelet count were observed in 74.0% and
98.1% of the cirrhotic patients, respectively.
Conclusions: Patients with T2DM have a high prevalence of NAFLD and severe fibrosis
that can be efficiently detected with FibroScan. Further studies on the potential clinical
usefulness of this screening methodology are warranted.
ePOSTER ABSTRACTS
82
Screen 1: MR-103
Lívia M. C. Linhares1, Claudia P. Oliveira* 1, Mario R. Alvares-da-Silva2, Jose
Tadeu Stefano1, Debora R. B. Terrabuio1, Edson Abdala1, Flair Jose Carrilho1,
Alberto Q. Farias1, Luiz Augusto C. D ‘ Albuquerque1
1
Gastroenterology (LIM 07/ 37), University of São Paulo School of Medicine, SAO PAULO,
2
Gastroenterology, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do
Sul, Porto Alegre, Brazil
Introduction: Cardiovascular (CV) disease is a common complication following
orthotopic liver transplantation (OLT). Coronary artery calcium score (CACS) is
considered a robust tool to assess cardiovascular risk (CVR). We hypothesized that liver
transplantation aggravates MS and CVR along time.
Aims: The aim of the present study is to register the prevalence of MS and related diseases
among OLT recipients and to know how that impacts on their CVR stratification, using
FRS and CACS. Also, we want to determine whether CACS has additive value to FRS in
CVR classification.
Material and Methods: Forty consecutive adult patients who underwent OLT were
evaluated during outpatient clinic visits in the following four years. Anthropometric and
clinical data, Framingham score (FS) and blood biomarkers of atherosclerosis after one
and four years of OLT were analysed. CACS was performed at the end of the follow-up.
Results: There were 25 (62.5%) male patients, mean age of 53.8 years and mean body
mass index (BMI) of 26.9 kg/m2 at the final evaluation. Prevalence of hypertension,
dyslipidemia and metabolic syndrome (MS) significantly increased over time, from 37.5%
to 65%, 30% to 60% and 22.5% to 47.5%, respectively. The median FS increased from
83
ePOSTER ABSTRACTS
CORONARY ARTERY CALCIUM SCORE (CACS)
AND FRAMINGHAM SCORE (FS) IN EVALUATION
OF CARDIOVASCULAR RISK AFTER LIVER
TRANSPLANTATION
7.5% to 21% (p=0.0354), demonstrating that the 10-year CVR changed from low to high.
According to CACS, 27.5% of patients had moderate/severe calcification. Five patients
(12.5%) presented at least one CV event after OLT. Patients with previous CV event had
higher values of CACS when compared with patients who did not have a history of CV
morbidity (median 140.0 x 0; P = 0.001). A significant correlation between CACS and
FS, age, alcohol, glucose, glycosylated hemoglobin and triglycerides was found. Levels of
blood biomarkers of atherosclerosis did not correlated with MS, FS or CACS.
Conclusions: We concluded that the prevalence of MS and the CVR have a great increase
four years after OLT, which is known to impact on late survival. CACS is a useful tool in
evaluating liver transplant recipients, and probably can enhance CVR stratification and
help prevent CV events in the future.
ePOSTER ABSTRACTS
84
Screen 2: MR-133
PREVALENCE AND CHARACTERISTICS OF PATIENTS
WITH OBESE VERSUS NON-OBESE NON-ALCOHOLIC
FATTY LIVER DISEASE (NAFLD) IN THAILAND
Chalermrat Bunchorntavakul1, Thanaya Techasirioangkun1, Tawesak Tanwandee* 2
1
Internal Medicine, Rajavithi Hospital, 2Faculty of Medicine Siriraj Hospital, Mahidol University,
Bangkok, Thailand
Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic
liver disease worldwide that is highly associated with obesity and metabolic syndrome.
The occurrence of NAFLD in non-obese population has been increasingly seen, especially
in Asia. However, the characteristics and long-term prognosis of this group of NAFLD
remain unclear.
Aims: To evaluate the prevalence and clinical characteristics of non-obese NAFLD.
Material and Methods: Data of > 200 consecutive patients underwent controlled
attenuation parameter (CAP) and transient elastography (TE) between October 2015 and
December 2015 at a tertiary center in Bangkok were analyzed. NAFLD was defined as
CAP >250 without history of alcohol consumption >14 drinks per week. Obesity and
overweight was defined as body mass index (BMI) ≥25 kg/m2 and ≥23 kg/m2, respectively.
Metabolic comorbidities, including diabetes, dyslipidemia and hypertension, were recored.
Results: Overall, 81 patients have NAFLD: 58% were men, median age 50 (20-74) years,
BMI 26.9 (18.1-40.5) kg/m2, ALT 44 (8-314) U/L and 25% have metabolic comorbidities.
Among patients with NAFLD, 68% (55/81) were obese and 16% (13/81) were overweight.
Transient elastography (TE) results were <7.5 kPa in 53% (43/81), 7.5-8.9 kPa in 5%
(4/81), 9-11.9 kPa in 16% (13/81) and ≥12 kPa in 26% (21/81) of patients. There was no
significant difference in demographic data, aminotransferase levels, degree of liver fibrosis,
and comorbidities between patients with non-obese and obese NAFLD. Though, there
was a trend in higher rates of advanced fibrosis among obese patients, compared to nonobese patients with NAFLD. After an exclusion of patients with HCV positive (n=31), the
prevalence of non-obese NAFLD remained unchanged (32% of all NAFLD), and still
there was no significant difference in clinical characteristics between patients with nonobese and obese NAFLD.
85
ePOSTER ABSTRACTS
Corresponding author’s email: dr_chalermrat@yahoo.com
Conclusions: Non-obese NAFLD is common in Thailand, with an overall prevalence
of 32% among all patients with NAFLD. There was significant difference in clinical
characteristics between patients with non-obese and obese NAFLD.
ePOSTER ABSTRACTS
Figure:
86
Screen 3: YI-MR-160
María Teresa Arias Loste* 1, Esther Nistal2, Carmen Alonso-Martin1, María
Ballesteros Pomar3, Paula Iruzubieta1, Marta Aparicio Cabezudo4, Marcos
Jimenez4, Patricia Ruiz1, Monica Molina-Edesa5, Emilio Fábrega1, Juan María
García-Lobo6, Jose Luis Olcoz2, Javier Crespo1
1
Hepatology Unit, Digestive Service, Hospital Universitario Marqués de Valdecilla, Research
Institute Valdecilla (IDIVAL), Santander, 2Department of Gastroenterology, University
Hospital of León, Institute of Biomedicine (IBIOMED) University of León,, 3Department of
Endocrinology and Nutrition, University Hospital of León, 4Department of Gastroenterology,
University Hospital of León, Leon, 5Department of Applied Mathematics and Computer Science.,
University of Cantabria. Institute of Biomedicine and Biotechnology of Cantabria (IBBITEC),
6
Department of Molecular Biology., Faculty of Medicine. University of Cantabria. Institute of
Biomedicine and Biotechnology of Cantabria (IBBITEC), Santander, Spain
Corresponding author’s email: ariasloste@gmail.com
Introduction: Several studies suggest a role for the gut microbiota in the development
of obesity, metabolic syndrome and NAFLD in patients and experimental models. In
addition, microbial profiling techniques developed in the past few years enabled major
advances in our understanding of the role of gut bacteria and raised possible new
therapeutic approximations based on the modification of the intestinal microbioma.
Aims: The aim of this study was to characterize the composition of the gut microbiota in
obesity-related to NAFLD.
Material and Methods: Gut bacterial communities were identified by pyrosequencing of
the 16S rDNA extracted from faecal samples of 53 obese patients and 20 healthy controls.
According to clinical, analytical and ultrasonographic data, patients were classified as
NAFLD or non- NAFLD.
Results: Statistical analysis showed that the number of reads of the phylum Proteobacteria
was higher in obese patients than in healthy controls (p<0.05). There were also significant
changes in the phylum Firmicutes (p<0.05). Obese patients with NAFLD had a higher
87
ePOSTER ABSTRACTS
CHANGES OF THE GUT MICROBIOTA IN PATIENTS WITH
OBESITY, METABOLIC SYNDROME AND NONALCOHOLIC
FATTY LIVER DISEASE (NAFLD) VERSUS HEALTHY
CONTROLS
ePOSTER ABSTRACTS
number of reads of this phylum than obese patients without NAFLD. In total, 617
different genera were identified. Most of the sequences were classified within six genera:
Bacteroides, Prevotella, Blautia,Faecalibacterium, Clostridium and Oscillospira. The
number of Blautia, Oscillospira, Flavobacterium, Alkaliphilus and Eubacterium sequences
was lower in obese patients than in controls. The Mann-Whitney U-test indicated that
these differences were significant (p<0.05) according to the diagnosis. While, the number
of Prevotella, Megasphaera, Lactobacillus, Megamonas and Acidaminococcus sequences
revealed an increase in obese patients. These changes were also significant (p<0.05). Obese
patients with NAFLD showed similar changes in the same genera in comparison with
healthy controls. However, there were not significant differences associated to metabolic
syndrome.
Conclusions: Besides differences in phylum, we have observed differences in the
proportion of bacterial genera within gut microbiota of obesity-related NAFLD. Obese
patients display a higher bacterial richness, and these differences are distinct between
NAFLD and non-NAFLD patients. Taken together, our data support the role of dysbiosis
in NAFLD development, pointing to the potential role of microbiota modification as a
target in obesity-related NAFLD management.Supported by BFU2013-48141-R and
BIO/LE02/15. CIBERehd funded by ISCIII.
88
Screen 4: YI-MR-161
INTERVENTION WITH THE CCR2 INHIBITOR
PROPAGERMANIUM ATTENUATES INSULIN
RESISTANCE, ADIPOSE TISSUE INFLAMMATION AND
DEVELOPMENT OF NASH
Petra Mulder* 1, Anita M. van den Hoek1, Robert Kleemann1
1
Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO),
Leiden, Netherlands
Introduction: Obese patients with insulin resistance (IR) and chronic inflammation in
white adipose tissue (WAT) have a high risk of developing non-alcoholic steatohepatitis
(NASH). The C-C chemokine receptor-2 (CCR2) has a crucial role in the recruitment
of immune cells to WAT and liver thereby promoting the inflammatory component of the
disease.
Aims: Herein, we examined whether intervention with propagermanium, an inhibitor
of CCR2, would attenuate tissue inflammation and NASH development. To mimic the
situation in patients, mice with established obesity, IR and WAT inflammation were
subjected to treatment.
Material and Methods: Male C57BL/6J mice received a high-fat diet (HFD) for
0,6,12 and 24 weeks to characterize IR development and WAT inflammation (by
hyperinsulinemic-euglycemic clamp and histology, respectively) and to define the optimal
time point for intervention. In a separate study, mice were pretreated with HFD and then
treated with propagermanium (0.05% w/w) after 6 weeks (early intervention) or 12 weeks
(late intervention). NASH was analyzed after a total of 24 weeks.
Results: IR developed in WAT after 6 weeks of HFD, which was paralleled by modest
WAT inflammation. IR and inflammation in WAT intensified after 12 weeks of HFD,
and preceded the development of NASH (24 weeks). The subsequent CCR2 intervention
experiment showed that early, but not late, propagermanium treatment attenuated IR.
Only the early treatment significantly decreased Mcp-1 and Cd11c gene expression in WAT
indicating reduced WAT inflammation. Histopathological analysis of liver demonstrated
that propagermanium treatment decreased macrovesicular steatosis and tended to
reduce lobular inflammation, with more pronounced effects in the early intervention
89
ePOSTER ABSTRACTS
Corresponding author’s email: petra.mulder@tno.nl
group. Propagermanium improved the ratio between pro-inflammatory (M1) and antiinflammatory (M2) macrophages, quantified by Cd11c and Arginase-1 gene expression in
both intervention groups.
Conclusions: Early therapeutic intervention with the CCR2 inhibitor propagermanium
improves IR, reduces WAT inflammation and attenuates NASH development.
ePOSTER ABSTRACTS
90
Screen 5: YI-MR-164
NorUDCA IMPROVES LIVER INJURY AND GLUCOSE
SENSITIVITY IN MOUSE MODELS OF OBESITY AND
STEATOSIS
Daniel Steinacher* 1, Thierry Claudel1, Tatjana Stojakovic2, Elisa Einwallner3,
Michael Trauner1 and Prof. Dr. Michael Trauner
1
Internal Medicine 3, Medical University of Vienna, Vienna, 2Clinical Institute of Medical and
Chemical Laboratory Diagnostics, Medical University of Graz, Graz, 3Clinical Institute of
Medical and Chemical Laboratory Diagnostics, Medical University of Vienna,Vienna, Austria
Introduction: Bile acids (BA) have signaling functions and regulate a variety of
metabolic and inflammatory pathways. Ursodeoxycholic acid (UDCA) is the only BA
used as therapeutic in humans, but showed only limited efficacy in NASH. NorUDCA is
a side-chained shortened derivative of UDCA improving liver injury in mouse models of
cholestatic liver and bile duct injury.
Aims: We aim to explore whether NorUDCA improves hepatic steatosis and insulin
resistance in mouse models of obesity and steatosis.
Material and Methods: ob/ob mice received either a diet supplemented with 0.5%
NorUDCA(n=7) or chow diet(n=7) for 6weeks. Intraperitoneal glucose and insulin
tolerance tests (IPGTT,IPITT) were performed at week 5&6. wt/wt mice received either
high-fat-diet (HFD 61% fat) supplemented with 0.5% NorUDCA (n=6) as prevention
arm for 28 weeks or HFD alone for 28 weeks (n=7) or HFD for 22weeks following 6
weeks of HFD supplemented with 0.5% NorUDCA (n=6) as treatment arm. Metabolic
characterizations was done by metabolic cages, IPGTT and IPITT. Food and water intake
as well as bodyweight were recorded weekly. Serum biochemistry, liver histology, mRNA
and protein expression of key markers of inflammation, ER-stress, lipid and glucose
metabolism were analyzed.
Results: ob/ob mice treated with NorUDCA showed a reduction in serum AST, ALT
and AP levels. mRNA expression of inflammatory markers (F4/80, MCP1 and tnfalpha)
were reduced in liver and F4/80 was reduced in white adipose tissue. Furthermore, ER
stress markers GRP78, CHOP, sXPB1, ErDj4 were lowered in liver. WAT/bodyweight
ratio was increased 1.4 times in NorUDCA group, non-esterified fatty acids decreased
91
ePOSTER ABSTRACTS
Corresponding author’s email: daniel.steinacher@meduniwien.ac.at
as well as markers for improved lipid storage function PPARG2, MPGES1 and FABP4
were induced. IPGTT uncovered a significantly faster glucose clearance at 60&90min.
TG content in liver did not differ, but TG in serum was increased. The prevention arm
with NorUDCA in DIO setting shows a clear reduction in body weight (37% less). The
treatment arm shows already within 4 weeks a weight reduction of 13% despite pair
feeding to its control group. The analysis of this experimental arm is still ongoing and will
be available at the time of the meeting.
ePOSTER ABSTRACTS
Conclusions: NorUDCA treatment improves liver cell injury via reducing NASH features
such as inflammation and ER stress. We observed similar beneficial effects on WAT,
resulting in an overall improved metabolic situation. NorUDCA may open a new avenue
of pharmacological treatment for fatty liver disease and clinical studies are warranted.
Disclosure of Interest: D. Steinacher: : None Declared, T. Claudel: : None Declared, T.
Stojakovic: : None Declared, E. Einwallner: : None Declared, M. Trauner: Grant: Conflict
with: Albireo, Falk, Intercept, MSD, Consultant: Conflict with: Phenex, Albireo, Falk,
Genfit, Gilead, Intercept, MSD, Novatis, Other: Conflict with: norUDCA Co-Inventor
Patent Held
92
Screen 6: YI-MR-178
ASSOCIATION BETWEEN LEFT VENTRICULAR MASS
AND HEPATIC FAT CONTENT IN PATIENTS WITH
Daniele Pastori* 1, Roberto Cangemi1, Licia Polimeni1, Francesco Baratta1,
Francesco Violi1, Maria Del Ben1, Francesco Angelico2
1
Internal Medicine and Medical Specialties, 2Public Health and Infectious Diseases, Sapienza
University of Rome, Rome, Italy
Introduction: Cardiac abnormalities have been described in patients with non-alcoholic
fatty liver disease (NAFLD) compared to those without. Transthoracic echocardiography
(TTE) is a simple and accurate method to evaluate cardiac function and structure. The
relationship between cardiac structure and hepatic fat content is still undefined.
Aims: To investigate the association between cardiac structure and function, and non
invasive markers of fatty liver.
Material and Methods: NAFLD was diagnosed by ultrasonography in 247 subjects, and
classified according to Hamaguchi criteria. Fatty liver index (FLI) and Lipid Accumulation
Product (LAP) were used as markers of hepatic fat content. CK-18 M30 (mIU/ml) was
measured. Resting TTE was performed (GE Vivid S6). Left ventricular mass (LVM, g)
was calculated by the Devereux formula. Diastolic function was assessed by pulse-wave
Doppler of the mitral inflow, for peak velocity of early (E) and late (A) diastolic filling, and
its ratio (E/A). The TDI of the diastolic velocities was obtained from the apical 4-chamber
view at septal corner of mitral annulus for early (E’). The ratio of E/E’ was also calculated.
Systolic left ventricular function was assessed by ejection fraction (EF, %).
Results: Mean age was 58.3±11.0 years; 36.8% were female and 31.2% were diabetic
patients. Mean LAP was 89.9±59.8: mean FLI was 73.1±23.3. Mean CK18 was
152.7±46.0 mIU/ml. In women, LVM was correlated to FLI (r=0.388, p<0.001), LAP
(r=0.317, p=0.002), CK18 (r=0.276, p=0.019) and BMI (r=0.338, p=0.001). LVM
was correlated with FLI (r=0.198, p=0.019), BMI (r=0.361, p<0.001) and HOMA-IR
(r=0.265, p=0.002) in men. Diastolic function and EF were not correlated with hepatic
indexes. A multivariable linear regression analysis, showed that LAP (B: 0.227, p=0.048)
was independently associated with LVM in women but not in men. Similar results were
93
ePOSTER ABSTRACTS
Corresponding author’s email: daniele.pastori@uniroma1.it
obtained in a second model, in which FLI was associated with LVM in women but not in
men (B: 0.375, p=0.033).
Conclusions: We found that LVM, assessed by TTE is associated with fat liver content
in women but not in men. Mechanisms underlying this gender difference deserve more
investigation.
ePOSTER ABSTRACTS
94
Screen 1: MR-102
Fernando G. Costa1, Jose Tadeu Stefano1, Caio S. Levy1, Mariana M. Torres1,
Camila Maria L. Machado2, Camila G. Carneiro2, Daniele P. Faria2, Carlos
Alberto Buchpiguel2, Bruno Cogliati3, Flair Jose Carrilho1, Claudia P. Oliveira* 1
1
Gastroenterology (LIM-07), 2Radiology and Oncology (LIM-24), University of São Paulo
School of Medicine, 3Pathology, School of Veterinary Medicine and Animal Science, University of
São Paulo, SAO PAULO, Brazil
Introduction: Our group have been showed a mixed rodent model that develops NASH,
cirrhosis and hepatocellular carcinoma (HCC). Positron emission tomography (PET)/
computed tomography (CT) with 18F-FDG (18-fluoro-2-deoxyglucose) may be applied
to evaluate HCC development, quantify the tumor load, identify metastatic spread and
quantify the treatment response to a testing drug.
Aims: Our aim is to evaluate advanced HCC using 18-FDG PET/CT on experimental
mixed rodent model of HCC NASH-related.
Material and Methods: Male Sprague-Dawley rats with 8 weeks were used and NASHrelated HCC was induced by hyperlipidic choline-deficient diet and diethylnitrosamine
(100 mg/L) in the drinking water during 19 weeks. After this period, the animals were
anesthetized using isoflurane (5% for induction, 2.0%–3.0% for maintenance) in 100%
oxygen, injected intravenously with 37 MBq of 18F-FDG and submitted to 18FDG
microPET/CT. CT images were acquired immediately before PET imaging for helping
anatomical information for fusion with PET images. The PET image is acquired using
1536 ring detectors, detectors LYSO and LGSO. PET and CT) were fused using PMOD™
software. On the day after the last PET/CT, they were anesthetized and sacrificed. Liver
samples were collected for histological analysis.
95
ePOSTER ABSTRACTS
EVALUATION OF HEPATOCELLULAR CARCINOMA (HCC)
BY 18 FDG MICROPET-CT ON EXPERIMENTAL MIXED
RODENT MODEL OF NONALCOHOLIC STEATOHEPATITIS
(NASH)-RELATED HCC
ePOSTER ABSTRACTS
Results: We studied by PET scan nine animals that survived until 19 weeks. The mortality
of all the animals was 22% in this animal model. CT showed low-attenuation lesions
with early contrast enhancement. Besides, PET scan analyses, some of these lesions have
increased 18FDG uptake, suggesting a high glycolytic metabolic rate according grade of
differentiation. The mean number of nodules was 5.12 ± 6.36. Of these nodules, 53.7%
were HCC in PET scan, 14.6% and 31.7% high grade and low grade dysplastic lesion
respectively. Using Edmondson & Steiner classification for HCC lesion we had: 22.7%
grade 1, 22.7% grade 2, 36.4% grade 3 and 18.2% grade 4. 18-FDG PET/CT had
62.5% of sensitivity and 100% specificity for diagnosing HCC. Also, PET/CT identified
metastases in this model.
Conclusions: 1) Our mixed rodent model is suitable to study early and advanced NASHrelated HCC, as well high and low grade dysplasia; 2) PET-CT scan can be used in this
HCC rodent model for diagnosis, however primarily, evaluates the aggressive behavior of
HCC demonstrated by high glycolytic metabolic rate according grade of differentiation.
This approach can have utility to follow new therapeutic drugs, and identify metastatic
spread.
96
Screen 2: YI-MR-162
HIGH INCIDENCE OF NON-ALCOHOLIC FATTY
LIVER DISEASE IN FIRST EPISODE SCHIZOPHRENIA
SPECTRUM PATIENTS: A 3 YEARS PROSPECTIVE STUDY
Introduction: Patients with schizophrenia spectrum disorders have increased morbidity
and mortalitylargely due to cardiovascular (CV) disease, which is associated with weight
gain and metabolic side effects from antipsychotic medications. In this scenario, it
is reasonable to expect an increase in the incidence of nonalcoholic fatty liver disease
(NAFLD).
Aims: Therefore, the aim of our study is to investigate the development of NAFLD during
the first 3 years of antipsychotic treatment in drug-naïve patients with first episode nonaffective psychosis.
Material and Methods: Subjects included in this study were drawn from a prospective,
randomized, open-label clinical trial. 205 subjects were included in the analysis. The
NAFLD fibrosis score, FIB-4 score and the Fatty Liver Index (FLI), were calculated at
baseline, 3 months, and then yearly for 3 years.
Results: Based on the FLI, 14 patients (6.83%; 14/205) had a basal score that predicted
hepatic steatosis (HS) and, therefore, were excluded. Thus, 191 subjects were included
in the final analysis and showed either an indeterminate score (34/191; 17.8%) or were
ruled out for HS (157/191; 82.2%). At the end of the follow-up, 25.1% (48/191) of
the individuals showed a FLI score ≥60, which is a predictor of HS. Of the individuals
considered indeterminate at baseline, 64.7% developed HS, most within the first 2 years.
In contrast, only 16.6% of the individuals who had a FLI score <30 at baseline, developed
HS during the follow-up. HS development was significantly associated with an increase
97
ePOSTER ABSTRACTS
María Teresa Arias Loste* 1, María José Morlan-Coarasa2, Carmen AlonsoMartin1, Paula Iruzubieta1, Silvia Alvarez1, Obdulia Martínez-García2, Angel
Estebanez1, Victor Ortiz-García de la Foz2, Emilio Fábrega1, Benedicto CrespoFacorro2, Javier Crespo1
1
Institute Valdecilla (IDIVAL), 2Psychiatric Unit, Hospital Universitario Marqués de Valdecilla,
Research Institute Valdecilla (IDIVAL) , Santander, Spain, Santander, Spain
>7% of the BMI (HS 91.7%; non-HS 55.9%; p<0.001), an increase in the triglyceride
levels >150 mg/dl (HS 54.2%; non-HS 5.6%; p< 0.001), a decrease in the HDL levels
<40 mg/dl in men and 50 mg/dl in women (HS 41.7%; non-HS 17.5%; p=0.001),
hypertension (HS 19.5 %; non-HS 4.5%; p=0.002) and a waistcircumference >102 cm
in men and >88 cm in women (HS 68.8 %; non-HS 14.0%; p<0.001) at the end of the
follow up. None of the patients showed significant liver fibrosis according to the NAFLD
fibrosis or FIB-4 scores.
ePOSTER ABSTRACTS
Conclusions: A significant proportion of patients develop NAFLD in a short period of
time after the first episode of their illness. Although further studies, including imaging
techniques, liver stiffness and/or biopsy, are needed to confirm our data, our results
support the importance of monitoring NAFLD development in these patients. The early
detection of features of NAFLD may lead to a more careful and accurate cardiovascular
surveillance and management in this subset of patients.
98
Screen 3: YI-MR-167
OBETICHOLIC ACID ATTENUATES FIBROSIS
DEVELOPMENT IN A HIGH-FAT DIET INDUCED NASH
MODEL (LDLR-/-.LEIDEN MICE)
Martine C. Morrison1, Petra Mulder* 1, Roeland Hanemaaijer1, Reinout Stoop1,
Claire Emson2, Kelvin Li2, Martin Decaris2, Scott Turner2, Robert Kleemann1,
Peter Y. Wielinga1
1
Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO),
Leiden, Netherlands, 2KineMed Inc., Emeryville, CA, United States
Introduction: The LDLr-/-.Leiden mouse is a translational, diet-inducible model for
non-alcoholic steatohepatitis (NASH) with associated fibrosis, displaying many clinically
relevant features of NASH.
Aims: Here, we aimed to study whether the progression of fibrosis in this model can be
retarded or reverted by dietary or pharmaceutical intervention.
Material and Methods: LDLr-/-.Leiden mice were fed a high-fat diet (HFD) for 24w,
after which mice were randomized into 4 groups: one group was sacrificed, one continued
on HFD, one was switched to chow (dietary intervention) and one received HFD + 10
mg/kg obeticholic acid (OCA) for the remainder of the study (up to 34w). Development
of NASH and hepatic fibrosis was assessed blindly by a pathologist, as well as by direct
measuring collagen synthesis rates (assessed as the incorporation of deuterium from
heavy water into the stable C-H bonds of hydroxyproline (OHP) in the newly synthesized
protein).
Results: Both, dietary and OCA intervention improved hepatic steatosis and inflammation,
which were manifest after 24w and continued to progress in the 34w HFD group. After
24 weeks of HFD feeding, mice displayed mild fibrosis (5.6±1.4% of perisinusoidal area)
which progressed to 25.3±4.9% after 34w of HFD. Mice that were switched to chow diet
or treated with OCA showed reduced fibrosis development (9.8±2.8% and 14.5±3.4% at
t=34w resp., both p<0.05 vs HFD at t=34w). In line with this, analysis of de novo collagen
synthesis showed that both the dietary and the OCA intervention reduced the rate of
fibrogenesis relative to HFD control (10.8±1.0% new OHP in 14 days in HFD; 7.5±1.0%
in chow and 8.3±0.6% in OCA; both p<0.05 vs HFD).
99
ePOSTER ABSTRACTS
Corresponding author’s email: petra.mulder@tno.nl
Conclusions: These data show that LDLr-/-.Leiden mice develop NASH with progressive
fibrosis when fed a HFD, which is modifiable by dietary and pharmaceutical interventions.
ePOSTER ABSTRACTS
Disclosure of Interest: M. Morrison: : None Declared, P. Mulder: : None Declared,
R. Hanemaaijer: : None Declared, R. Stoop: : None Declared, C. Emson: Employee:
Conflict with: KineMed Inc., K. Li: Employee: Conflict with: KineMed Inc., M. Decaris:
Employee: Conflict with: KineMed Inc., S. Turner: Employee: Conflict with: KineMed
Inc., R. Kleemann: : None Declared, P. Wielinga: : None Declared
100
Screen 4: YI-MR-105
EXERCISE THERAPY IN PATIENTS CONSUMING
MODERATE ALCOHOL: A RANDOMISED CONTROL TRIAL
Corresponding author’s email: david.houghton@ncl.ac.uk
Introduction: Lifestyle change remains the cornerstone of non-alcoholic fatty liver
disease (NAFLD) management. Given the interaction between alcohol consumption and
obesity-related liver injury, it is important to determine the impact of increased exercise in
people that drink moderate amounts of alcohol.
Aims: This study aimed to define the effect of a 12-week exercise intervention on liver
steatosis and its mediators in patients with metabolic syndrome associated fatty liver
disease that also consume moderate amounts of alcohol.
Material and Methods: 27 patients (mean age 54 ± 11 years, BMI 31 ± 4kg/m2) who
were drinking moderate amounts of alcohol (mean 221 ± 75 g/week) were randomised
to either 12-weeks exercise (n = 14) or continued standard care (n = 13). Patients were
instructed to maintain baseline weight and alcohol consumption. Hepatic triglyceride
content (HTGC), subcutaneous and visceral adiposity, body composition, metabolic
control, and non-invasive scores for fibrosis were measured at baseline and 12-weeks.
Results: 12-weeks of exercise produced beneficial effects on subcutaneous fat (-23 ± 28
vs. 12 ±19 cm2, P<0.01), whole body fat (-2.1 ± 1.1 vs. 0.2 ± 2.1 kg, P<0.01) and lean
body mass (+1.9 ± 1.4 vs. +0.7 ± 1.5 kg, P<0.01) without any change in body weight.
There was a significant exercise-induced reduction in cytokeratin-18 (CK-18) (-49 ± 82
vs. 17 ± 38 U/L, P<0.05). No change in HTGC (-0.2 ± 1.2 vs. +0.5 ± 2.1%, P>0.05),
HOMA IR (-0.1 ± 0.5 vs. +0.1 ± 0.7, P>0.05), ALT (-6.8 ± 21.3 vs. +3.8 ± 40.0, P>0.05)
or NAFLD fibrosis score were observed.
101
ePOSTER ABSTRACTS
David Houghton* 1, Kate Hallsworth2, Christian Thoma3, Sophie Cassidy3,
Timothy Hardy3, Kieren G. Hollingsworth4, Roy Taylor4, Christopher P. Day3,
Steve Masson3, Stuart McPherson3, Quentin M. Anstee3, Micahel I. Trenell3 and
MoveLab, Newcastle University
1
Institute of Cellular Medicine, Newcastle University, Newcastle UpinTyne, 2Institute of Cellular
Medicine, Newcastle University, Newcastle Upon Tyne, 3Institute of Cellular Medicine, 4Newcastle
Magnetic Resonance Centre, MoveLab, Newcastle University, Newcastle UpinTyne, United
Kingdom
Conclusions: This is the first randomised controlled trial reporting the effects of exercise
on liver steatosis and its mediators in patients consuming moderate amounts of alcohol.
Exercise significantly improved body composition and markers of hepatocyte apoptosis
(CK-18) but, in contrast to reports in strictly defined NAFLD, there was no benefit on
HTGC or metabolic control. This suggests that exercise on its own, without a concomitant
reduction in alcohol intake may be insufficient to alter steatosis. However, may still
ameliorate steatohepatitic liver injury in ‘real-world’ alcohol consuming dual-aetiology fatty
liver patients. These pilot data warrant further investigation with histological endpoints.
ePOSTER ABSTRACTS
102
Screen 5: MR-130
Diego Caroli* 1, Andrea Nogara1, Erik Rosa Rizzotto2, Gianni Ballarin1, Angelo
Boscolo Bariga1, Silvia Zanoni1, Stefano De Boni1, Giorgio Cavallarin1, Cinzia
Marafin1, Margherita Inglese1, Mario Della Loggia1, Marina Bortolotti1, Roberto
Valle1, Laura Peraro2, Salvatore Lobello2, Franca De Lazzari2 and A.Nogara1,
E.Rosa-Rizzotto2, G.Ballarin1, A.Boscolo Bariga1, S.Zanoni1, S.De Boni1,
G.Cavallarin1, C.Marafin1, M.Inglese1, M.Della Loggia1, M.Bortolotti3, R.Valle3,
L.Peraro2, S.Lobello2, F. De Lazzari2
1
Hospital, Chioggia-Venice, 2Gastroenterology, Hospital, Sant Antonio Padova, Italy
Corresponding author’s email: d.caroli@libero.it
Introduction: NAFLD is an increasingly cause of liver damage in western countries and
it is characterized by increased serum triglyceride and LDL,reduction of HDL,insulin
resistance,glucose intolerance;all of those are crucial risk factors for the development of
atherogenesis. The United Kingdom Prospective Diabetes Study(UKPDS risk engine v
2.0) and Fatty liver index(FLI) are validated prognostic scores for cardiovascular (CV)
risk in diabetics patients and NAFLD respectively.
Aims: to compare FLI and UKPDS scores to predict CV risk in a cohort of diabetic type
2 patients regularly followed up and undergone to cardiological screening according to a
high risk value of UKPDS.
Material and Methods: We retrospectively analyzed 1902 patients regularly followed in
our Diabetes Ambulatory in 2012-2013. Data concerning UKPDS risk engine,FLI and
the successive CV screening were collected for each patient. 99/1902(19.2%) patients
resulted at high CV risk after UKPDS evaluation and undergone to CV screening
(ergometric/ecostress test (EET), coronarography (CORO)). Statistical analysis Two
tailed t-test,Person’s Chi square test and Analysis of variance(ANOVA) were used.
103
ePOSTER ABSTRACTS
FATTY LIVER INDEX (FLI) AS A MULTIDISCIPLINARY
SCORE NOT ONLY FOR A CORRECT DIAGNOSIS OF
NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) BUT
ALSO TO IMPROVE ACCURACY IN CARDIOVASCULAR
DISEASE IN DIABETIC TYPE 2 PATIENTS
ePOSTER ABSTRACTS
Results: 66(59 M,mean age 68.1y,mean duration disease 16.1 y, HbA1c>7 prevalent) pts
presented UKPDS positive/FLI >60, 8/66 CORO+ (5 PTCA,3 CABG,1PTA AAII) and
5 (4M,mean age 68.6y, mean duration disease 18.4 y,HbA1c >7 prevalent) pts presented
UKPDS positive/FLI<20,1/5 CORO+ (1 PTCA;1 CABG;0 PTA AII). We were able to
assess a FLI cutoff to better identify,compared to UKPDS, patients that will be positive
at CORO(FLI > 52 detected 9/14 pts positive at CORO with p<0.05). 99 pts UKPDS
positive(EET negative 69.6%>69/99) (100%>14/14 CORO+) vs 81 pts FLI >52 (EET
negative 92.5%>75/81) (64.2%>9/14 CORO+). As expected we found a significative
association between CORO+ and FLI+ patients for microalbuminuria (p<0.048);
Cholesterol (p<0.020); triglyceride (p<0.001); LDL (p<0.005). The only drug associated
to CV risk was the cardioaspirn(p< 0.003).
Conclusions: . FLI could be used to attribute the correct CV risk in patient with FLI>52
in these way we can reduce the number of patients that undergo to CV screening with low
percentage of positivity.An early and aggressive program of follow up and treatment could
be established in diabetic type 2 patients with FLI>52 and with reasonable suspicion of
NAFLD because this population has higher risk to develop CVevents in comparison to
FLI<20.
104
Screen 6: MR-109
TM6SF2 KO AND PNPLA3 I148M KNOCKIN MICE AS
NAFLD ANIMAL MODELS: SIMILAR BUT NOT THE SAME
Eriks Smagris* 1 on behalf of Helen Hobbs /Jonathan Cohen Lab and Helen Hobbs
/ Jonathan Cohen Lab
1
Molecular Genetics, The University of Texas Southwestern Medical Center at Dallas, Dallas,
United States
Introduction: Uncertainty regarding the molecular basis of nonalcoholic fatty liver disease
(NAFLD) has been a significant obstacle toward development of effective therapies.
To overcome this problem in recent years our lab generated several animal models for
nonalcoholic fatty liver disease using 2 most common mutation (PNPLA3 I148M and
TM6SF2 E167K) associated with human fatty liver diseases.
Aims: To compare two mice NAFLD models – Pnpla3 I148M knock in and Tm6sf2
knock out mice, trying to understand pathophysiological differences between them.
Material and Methods: Homozygous Pnpla3 I148M KI and Tm6sf2 E167K KO mice
were generated by homologous recombination, heterozygous mice breeding and were
compared with wild type littermates, to see differences in response on different diets
(chow, high sucrose diet and high fat diet), changes in liver and plasma, changes in glucose
homeostasis.
Results: For Pnpla3 I148M KI only feeding with high sucrose diet (HSD) cause excess
fat accumulation in liver, without any evidence of dyslipidemia, liver inflammation
or disturbances in glucose metabolism. Instead Tm6sf2 KO mice shows fatty liver
accumulation on any of tried diets, accumulates in liver not only triglycerides but also
cholesterol esters, have lover levels of plasma cholesterol, shows mild transaminitis and
impairment of fat absorption from small intestine. Similar to Pnpla3 I148M KI, Tm6sf2
KO mice shows no changes in glucose homeostasis and no hepatic inflammation. For
Pnpla3 I148M KI mice shows 40 X accumulation of mutant protein on lipid droplets, but
absence of Tm6sf2 cause also reduced expression of hepatic Pnpla3.
Conclusions: Even Pnpla3 I148M KI and Tm6sf2 E167K KO mice have histologically
similar NAFLD, mechanism of fat accumulation in liver is quite different. In case of
105
ePOSTER ABSTRACTS
Corresponding author’s email: eriks.smagris@inbox.lv
Pnpla3 mutation, Pnpla3 protein accumulates on lipid droplets disrupting normal lipid
droplet architecture. Instead absence of Tm6sf2 impairs lipidation of interahepatic and
small intestine lipoproteins. In both cases NAFLD don’t change glucose homeostasis.
ePOSTER ABSTRACTS
106
Screen 1: MR-108
Rosamar E. Rezende 1, Sebastião M. Duarte 1, Jose Tadeu Stefano1, Hamilton
Roschel2, Bruno Gualano2, Ana Lucia Sa-Pinto2, Denise C. Vezozzo1, Flair Jose
Carrilho1, Claudia P. Oliveira* 1
1
GASTROENTEROLOGY – LIM 07, 2DIVISION OF RHEUMATOLOGY, UNIVERSITY
OF SAO PAULO SCHOOL OF MEDICINE, SAO PAULO, Brazil
Introduction: Nonalcoholic fatty liver disease (NAFLD) is common in postmenopausal
women and it is associated with an increased prevalence of cardiovascular disease.
Aims: We evaluated the effectiveness of aerobic physical activity in reducing hepatic
steatosis, metabolic and cardiovascular risks in postmenopausal women with NAFLD.
Material and Methods: Forty sedentary postmenopausal women (mean age 55.3 ±
8.0 years), biopsy-proven NAFLD were randomly divided into two parallel groups: an
exercising group (19 patients) and a control group (non-exercising, 21 patients). The
exercise group underwent a supervised aerobic physical activity program of 120min/
week for 24 weeks. The anthropometric parameters, body composition, hepatic, lipid,
and glycemic profiles, homeostasis model assessment-insulin resistance index, cytokines,
transient elastography – FibroScan [liver stiffness/controlled attenuation parameter
(CAP)], cardiopulmonary exercise test were evaluated at baseline and after 24 weeks of
protocol.
Results: At baseline there were no significant differences in anthropometric, metabolic,
inflammatory parameters; stiffness and liver fat content by FibroScan between the groups.
After 24 weeks, we observed a decrease of waist circumference (WC), an increase of highdensity lipoprotein cholesterol (HDL) levels (p<0.05) and improved cardiopulmonary
functional capacity in the exercise group. Besides, the CAP analysis showed no significant
107
ePOSTER ABSTRACTS
IMPACT OF AEROBIC EXERCISE IN POSTMENOPAUSAL
WOMEN WITH NONALCOHOLIC FATTY LIVER DISEASE:
A 24 – WEEK RANDOMIZED CLINICAL TRIAL
decrease of hepatic steatosis in the exercise group. However, in regards the systemic
inflammation there were no significant differences in the cytokines between the groups.
Conclusions: An aerobic physical activity program of 24 weeks in NAFLD
postmenopausal women showed improvement in some variables such as WC, HDL,
cardiopulmonary performance that may be beneficial in improving cardiovascular risk
factors in this population.
ePOSTER ABSTRACTS
108
Screen 2: YI-MR-168
María Teresa Arias Loste* 1, Rocío Gallego-Durán2, Carmen Alonso-Martin1,
Paula Iruzubieta1, Susana Llerena1, Javier Ampuero2, Antonio Gil-Gómez2,
Javier Abad3, Jose Luis Calleja3, Raúl Jesús Andrade4, Carmelo García-Monzón5,
Manuel Romero-Gómez2, Javier Crespo1
1
InstituteValdecilla (IDIVAL), Santander, 2Inter-Centre Unit of Digestive Diseases & CIBERehd,
Virgen Macarena – Virgen del Rocío University Hospitals, University of Sevilla. Instituto de
Biomedicina de Sevilla (IBiS), Sevilla, 3Gastroenterology Department, Hospital Puerta de Hierro,
Madrid, Madrid, 4Inter-Centre Unit of Digestive Diseases & CIBERehd.,Virgen de la Victoria
University Hospital. Instituto de Investigación Biomédica de Málaga (IBIMA), Malaga, 5Liver
Research Unit, University Hospital Santa Cristina and CIBERehd. Instituto de Investigación
Sanitaria Princesa, Madrid, Spain
Introduction: It has been recently described the role of FTO rs1421085 T>C
polymorphism in the downregulation of adipocyte thermogenesis and its association with
obesity development
Aims: The aim of our study was to evaluate the role of FTO rs1421085 variant in NAFLD
severity in a cohort of Spanish patients
Material and Methods: Cross-sectional multicentre study including a cohort of
consecutive NAFLD patients. Patients from a single centre as well as a subset of healthy
controls composed estimation cohort. Diagnosis of NAFLD was established according
to clinical, ultrasonography, and transient elastometry criteria, and also histological
evaluation when available. FTO rs1421085 SNP was determined by allelic discrimination
using Taqman probe. A set of biopsy-proven multicentre NAFLD patients was used as
validation cohort.
Results: 393 subjects were genotyped: 185 NAFLD patients and 208 healthy volunteers.
Genotype frequency was similar between both groups. Rs1421085 genotype distribution in
NAFLD patients was: CC 22.2% (41/185), CT 49.2% (91/185) and TT 28.6% (53/185).
109
ePOSTER ABSTRACTS
THE FTO rs1421085 T>C POLYMORPHISM IS
ASSOCIATED WITH THE SEVERITY OF NON-ALCOHOLIC
FATTY LIVER
ePOSTER ABSTRACTS
In 88/185 cases (47.6%) liver biopsy was performed. Of them, 60% (53/88) of patients
confirmed NASH diagnosis according to Brunt´s classification. Additionally, in absence of
histological data, the diagnosis of NASH was established in 5/97(5.2%) cirrhotic patients
according to transient elastometry, biochemistry and clinical criteria. A statistically
significant higher proportion of CC genotype was found among NASH compared to
steatosis simple patients (32.8% (19/58) vs 17.3%(22/127); [O.R. 2.33 [95%CI 1.144.76]; p = 0.03). In the subset of patients with BMI<40 kg/m2 40.54%(75/185), these
differences were remarkable ( 40%(10/25) vs 14%(7/50); [O.R. 4.10 [95%CI 1.3212.69]; p =0.02). In the validation set, 216 patients were included. Fibrosis distribution
was F0: 58.8% (127/216), F1: 19.0%(41/216), F2: 11.6% (25/216), F3: 9.7%(21/216)
and cirrhosis 1% (2/216). 12% (26/216) of patients showed a NAS score higher than
5. Rs1421085 genotype distribution was: CC 14.4% (31/216), CT 43.5% (94/216) and
TT 42.1% (91/216). Genotype CC was found associated with NAS Score >5 [O.R. 2.55
(95% CI 0.97-6.69); p=0.05] and lobular inflammation [O.R. 2.32 (95%CI 1.03-5.19);
p=0.04].
Conclusions: To our knowledge, this is the first study showing an association between
FTO rs1421085 and NAFLD severity. The reduction in adipocyte mitochondrial
thermogenesis of this polymorphism could be associated, with the severity of liver injury
in non-morbid obese NAFLD
110
Screen 3: MR-192
SILIBININ EXERTS BENEFICIAL EFFECTS ON GUT-LIVER
AXIS IN MURINE AND HUMAN NON-ALCOHOLIC FATTY
LIVER DISEASE
Corresponding author’s email: federicosalomone@rocketmail.com
Introduction: Clinical and experimental studies have highlighted the importance of
gut-liver axis in the onset and progression of non-alcoholic fatty liver disease (NAFLD).
Silibinin, a natural phenolic antioxidant, has been demonstrated to improve liver injury in
human and experimental NAFLD, although it is unknown whether its hepato-protective
effects may depend on modulation of gut-liver crosstalk.
Aims: In this study we aimed to identify whether silibinin may favorably impact on gutliver axis in murine and human NAFLD.
Material and Methods: We examined the effects of silibinin in mice fed a high fat and
high fructose (HFF) diet for 3 months. Expression of occludin and ZO-1 was assessed
by real time PCR and western blot on jejunum samples. Portal LPS was assessed by
ELISA. Liver TLR4 expression was determined by real time PCR. In a pilot study of thirty
patients with NAFLD, we assessed intestinal permeability by the lactulose-mannitol test
at baseline and after three months of treatment with Realsil, a nutraceutical containing
silibinin.
Results: Treatment of mice with silibinin improved liver steatosis and inflammation. HFF
diet was associated with reduced intestinal expression of occludin and ZO-1, indicating
disruption of gut epithelial barrier. As a consequence, mice fed HFF diet displayed
increased levels of portal LPS and increased liver TLR4 expression. In silibinin-treated
animals, intestinal expression of occludin and ZO-1 was restored to control levels;
similarly, silibinin administration reduced portal LPS and liver TLR4 levels. Interestingly,
in patients with NAFLD a three month-treatment with Realsil not only decreased liver
111
ePOSTER ABSTRACTS
Federico Salomone* 1, Justyna Godos2, Maurizio Catania3, Giovanni Magrì1, Fabio
Galvano2
1
Division of Gastroenterology, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania,
2
Department of Biomedical Sciences and Biotechnologies, University of Catania, 3Division of
Laboratory Medicine, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania,
Italy
enzymes and insulin resistance but also preserved intestinal permeability as showed by
values of the lactulose-mannitol ratio.
Conclusions: In this study, we demonstrated for the first time that silibinin exerts
beneficial effects on gut-liver axis both in murine and human NAFLD.
ePOSTER ABSTRACTS
112
Screen 4: YI-MR-188
SELECTIVE TARGETING OF FXR ISOFORMS α1-4 BY
NOVEL BILE ACID DERIVATIVES AND INHIBITION OF
LIPOTOXICITY IN HEPG2 CELLS
Hugo Brito* 1, Salete Batista2, Jorge A. Salvador2, Rui E. Castro1, Cecília M.
Rodrigues1
1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa,
Lisbon, 2Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
Introduction: Farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear receptor,
plays a critical role in maintaining lipid, glucose and BA homeostasis. FXR expression is
significantly decreased in livers of non-alcoholic fatty liver disease (NAFLD) patients and
genetic ablation leads to hepatic steatosis and hyperlipidaemia. The FXR gene expresses
four biologically active variants (FXRα1-4), regulating hepatic and lipid metabolism in an
isoform-dependent manner. Activation of FXR variants α1 and α2 significantly reduces
hepatic lipid accumulation.
Aims: Our aim was to screen potential BA-derived FXR agonists for their ability to
selectively activate different FXR isoforms and protect HepG2 cells against palmitate
toxicity.
Material and Methods: Twenty novel BA derivatives, synthesized based on the cholic
(CA), deoxycholic (DCA), chenodeoxycholic (CDCA) and ursodeoxycolic (UDCA)
acid scaffolds were incubated in HepG2 cells transfected with a dual-luciferase reporter
construct and overexpression vector plasmids for FXRα1-4 isoforms. In parallel, BAderivatives were co-incubated in HepG2 cells treated with 250-500 μM palmitate-BSA,
for cell viability assays.
Results: As a result of the different structural modifications, BA derivatives showed
differential activation of the FXRα1-4 isoforms, when compared to their precursor BAs.
From the precursor BAs, only CDCA, a natural FXR ligand, significantly activated FXRα1
and α2 isoforms, with CA and UDCA displaying a modest activation of FXRα1 isoform
only. Interestingly, 2 novel CA-, 1 DCA- and 4 UDCA-derivatives were stronger activators
of both FXRα1 and α2, comparing with their corresponding precursors. Further, 3 novel
CA-, 2 DCA-, 3 CDCA- and 4 UDCA-derivatives specifically and significantly activated
113
ePOSTER ABSTRACTS
Corresponding author’s email: ruieduardocastro@ff.ul.pt
FXRα3 and α4. Finally, incubation of HepG2 cells with palmitate-BSA led to up to 35%
reduction in cell viability. Co-incubation of cells with BA-derivatives targeting the FXRα1
and α2 isoforms reverted most of the palmitate-BSA-induced lipotoxicity.
Conclusions: In conclusion, herein we provide a novel strategy to screen for selective
agonists of FXRα1-4 isoforms and have identified new selective BA-derived FXRα1
through 4 agonists. In addition, specific derivatives appear to afford cytoprotection against
lipotoxicity. The differential functional effect of these new molecules will undoubtedly
contribute for a better understanding of pharmacological targeting and therapeutic
efficacy of FXR agonists in liver diseases such as NAFLD.
ePOSTER ABSTRACTS
114
Screen 5: YI-MR-134
SMOKING IS ASSOCIATED WITH FIBROSIS BUT NOT
WITH NAFLD ACTIVITY
Isabelle Munsterman* 1, Mark Smits2, Rene Andriessen3, Karin van Nieuwkerk2,
Elisabeth Bloemena4, Chris Mulder2, Eric Tjwa3, Erwin van Geenen3
1
Gastroenterology and Hepatology, Radboud university medical center, Nijmegen,
2
Gastroenterology & hepatology, Vu university medical center, Amsterdam, 3Gastroenterology &
Hepatology , Radboud university medical center, Nijmegen , 4Pathology, Vu university medical
center, Amsterdam, Netherlands
Introduction: Smoking is considered to be a modifying factor in the progression from
non-alcoholic fatty liver disease (NAFLD) to steatohepatitis. Smoking is also associated
with the onset of fibrosis in various diseases, such as NAFLD. The link with NAFLD
disease activity is still unclear.
Aims: We aim to investigate the associations between smoking and NAFLD activity and
fibrosis.
Material and Methods: Patients with liver biopsies performed between 2008 and 2013
in two Dutch tertiary referral university centres were identified. Characteristics such as
smoking status, number of pack-years, alcohol use, diabetes and BMI were collected. A
pathologist, blinded for clinical information, revised biopsies and determined the BRUNT
and NAFLD activity score (NAS, ranging 0-8). Patients with a high NAS (≥ 5) were
compared to patients with a low NAS (<5) and with advanced fibrosis (stage 3-4) to
patients with early fibrosis (stage 0-2). We used Spearman’s Rho to assess correlation and
multivariate logistic regression to identify predictors for severity of NAFLD activity and
fibrosis.
Results: Sixty-five patients were included (mean age 49 ± 14.3, mean BMI of 30.3 ± 5.9,
32% female and 39% with a history of smoking).
The number of pack-years was significantly higher in patients with advanced compared to
early fibrosis (p = 0.011). Patients with advanced fibrosis were also older (p<0.001). For
all characteristics see table 1. Additionally, there was a significant correlation between the
severity of fibrosis and number of pack-years (Spearman’s rho=0.376, p=0.010).
Patients with a high NAS had a median number of pack-years of 10,3 (IQR 0-24) and
115
ePOSTER ABSTRACTS
Corresponding author’s email: Isabelle.Munsterman@radboudumc.nl
patients with a low NAS a median of 0 (IQR 0-9). This was not significantly different
between groups (p=0,127). No correlation was detected between smoking and NAS
(Spearman’s Rho=0,224, p=0,097). Furthermore other patient characteristics such as
age, diabetes, BMI or alcohol-use were similar between NAS groups. In multivariate
analysis the number of pack-years was independently of diabetes associated with severity
of fibrosis (OR 1,080, 95% CI 1,0180-1,146, p=0,011).
Conclusions: Smoking is associated with advanced fibrosis, but not with severity
of disease activity in this cohort of patients with NAFLD. A moderate correlation was
identified between the number of pack-years and increasing severity of fibrosis. These
results support the advice to cease smoking in NAFLD patients.
ePOSTER ABSTRACTS
Figure:
116
Screen 6: MR-143
CIRCULATING MICRORNAS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE IN TAIWAN
Jee-Fu Huang* 1, Ming-Lung Yu1, Chi-Ming Tai2, Chia-Yen Dai1, Wan-Long
Chuang1
1
Hepatobiliary Division, Department of Internal Medicine, KAOHSIUNG MEDICAL
UNIVERSITY HOSPITAL, 2Institute of Clinical Medicine, College of Medicine, KAOHSIUNG
MEDICAL UNIVERSITY, Kaohsiung City, Taiwan
Introduction: Nonalcoholic steatohepatitis (NASH) is the extreme form of non-alcoholic
fatty liver disease (NAFLD) and may progress to advanced liver disease and liver cancer.
Aims: This study aimed to assess the difference of serum miRNAs levels between patients
with simple steatosis and those with NASH in Taiwanese patients.
Material and Methods: We prospectively recruited 25 NAFLD patients with elevated
alanine aminotransferase (ALT) levels (>1.5 upper limit of normal) after at least 3 months
of life style modification. Liver biopsy was performed to evaluate the presence of NASH.
The serum miRNAs was extracted using the Complete DNA and RNA Purification Kit
(Epicentre, Illumina Corp, USA). MiRNA arrays were performed to obtain miRNA
profiles using the TaqMan Array Human MicroRNA Panel v3.0 (Applied Biosystems,
Foster City, USA). Each array includes Cards A and B, together containing 768 TaqMan
MicroRNA Assays enabling a simultaneous quantification of 754 human miRNAs and 3
endogenous controls. The experiments were performed on an Applied Biosystems 7900
Real-time PCR System (Applied Biosystems). The data were collected and processed
using SDS 2.3 (Applied Biosystems) and analyzed using RealTime StatMiner software
(Integromics, Armilla, Spain).
Results: A total of 10 NASH patients (5 males, age= 38.9 ± 13.6 years) and other 15
simple steatosis patients (6 males, age= 41.3 ± 16.4 years) were enrolled. The body mass
index (BMI) were 29.0 ± 5.1 kg/m2 of NASH group, and 31.8 ± 6.8 kg/m2 of simple
steatosis group, respectively. There were significantly increases of mi-423-5p, mi-637 and
mi-211 with the fold changes of 2.53 (P= 0.005), 2.33 (P= 0.006), and 2.23 (P= 0.007),
respectively. Other metabolic and demographic profiles were comparable between groups.
117
ePOSTER ABSTRACTS
Corresponding author’s email: jfliver@kmu.edu.tw
Conclusions: The serum expressions of microRNAs were different between Taiwanese
patients with simple steatosis and NASH. Further validation of tissue expression for
potential biomarker exploration will be warranted.
ePOSTER ABSTRACTS
118
Friday 13 May 2016
Screen 1: MR-110
Daniel F. C. Mazo1, Rejane Mattar1, Jose Tadeu Stefano1, Joyce M. K. Silva-Etto1,
Márcio A. Diniz1, Sebastião M. B. Duarte1, Fabíola Rabelo1, Rodrigo V. C. Lima1,
Priscila B. Campos1, Flair Jose Carrilho1, Claudia P. Oliveira* 1
1
Gastroenterology (LIM-07), University of São Paulo School of Medicine, SAO PAULO, Brazil
Introduction: Nonalcoholic fatty liver disease (NAFLD) has a close relationship with
metabolic syndrome. The association of LCT-13910CT and LCT-13910TT genotypes
with metabolic syndrome components is controversial.
Aims: We assessed hypolactasia (LCT-13910CC) and lactase persistence genotypes in
Brazilian NAFLD patients compared to healthy controls and analyzed in nonalcoholic
steatohepatitis (NASH) patients its association with biochemical tests, metabolic syndrome
and severity of liver histology.
Material and Methods: LCT-13910C>T polymorphism was performed by PCRrestriction fragment length polymorphism in 102 biopsy-proven NAFLD patients
(steatosis in 9 and NASH in 93) and compared to that of 501 unrelated healthy volunteers.
Anthropometric, clinical, biochemical and liver histology data were analyzed.
Results: No difference in LCT-13910 genotypes profile was noted between NAFLD
patients and healthy controls (p=0.941) and also between steatosis and NASH. There
were no associations between LCT genotypes with diabetes (p=0.651), dyslipidemia
(p=0.328), hypertension (p=0.507) or liver histology in NASH patients. In NASH,
hypolactasia was an independent risk factor of insulin resistance, even after adjusting for
gender and age (OR=5.0 [95%CI=1.35-20; p=0.017]).
Conclusions: LCT-13910 genotypes distribution in NAFLD patients was the same of
general population, but hypolactasia was an independent risk factor of insulin resistance
in NASH patients. Further studies including alimentary report are needed.
119
ePOSTER ABSTRACTS
HYPOLACTASIA (LCT-13910CC GENOTYPE) IS ASSOCIATED
WITH INSULIN RESISTANCE IN BRAZILIAN PATIENTS WITH
NONALCOHOLIC STEATOHEPATITIS (NASH)
Screen 2: YI-MR-126
POSSIBILITY OF GHRELIN AS NON-INVASIVE MARKER
FOR NAFLD/NASH DIAGNOSIS
Nazarii Kobyliak* 1, Tetyana Falalyeyeva2, Galyna Mykhalchyshyn1, Petro Bodnar1
1
Endocrinology, Bogomolets National Medical University, 2Taras Shevchenko
National University of Kyiv, Kyiv, Ukraine
ePOSTER ABSTRACTS
Corresponding author’s email: nazariikobyliak@gmail.com
Introduction: Ghrelin is a hormone produced mainly by the cells lining the fundus of the
stomach, which is involved in regulation of lipid and glucose metabolism. Two major forms
of ghrelin can be found in circulation: an acylated form, and non-acylated form. Serum
acyl-ghrelin (AG) concentration is significantly increased in patients with visceral obesity
and insulin resistance.
Aims: This study was conducted to evaluate changes in serum AG levels, its diagnostic
accuracy and association with NAFLD in patients with type two diabetes (T2D).
Material and Methods: In this cross-sectional study, 91 T2D patients, age of 40–80
years, were included. All patients were divided into 3 groups. The control group included
28 T2D patients without NAFLD. The main group included 63 T2D patients with
NAFLD, which was divided in 2 subgroups depending on transaminase levels: normal (n
= 37) and elevated (n = 26) transaminases group. To assess the diagnostic accuracy of AG
for NAFLD we used ROC-analysis
Results: We observed 1.5 (p = 0.016) and 2.5 (p < 0.001) fold increasing of serum AG
levels in patients with NAFLD and normal or elevated transaminases compared to control
groups. In multivariate logistic regression analysis high AG level was an independent,
from transaminases activity, triglycerides (OR 1.791; 95%CI 1.162-2.759; p = 0.008) and
degree of IR (OR 1.599; 95%CI 1.019-2.508; p = 0.044) predictor that associated with
NAFLD. When serum AG used as non-invasive marker for NAFLD detection AUROC
was 0.835 (95 % CI 0.752-0.918, p < 0.001). The cut-off value was >0.52 ng/ ml, with
sensitivity, specificity, PPV and NPV – 60.3 %, 92.8 %, 95.0 %, 50.9 % respectively.
For distinguishing patients with NAFLD and elevated transaminases from patients with
NAFLD and normal values AG was less effective. The cut-off value was >0.84 ng/ml.
Sensitivity, specificity, PPV and NPV were 50.0 %, 91.8 %, 81.2 %, 72.3 % respectively.
120
Conclusions: Our study has demonstrated that elevated AG level were associated with
NAFLD. Patients with elevated transaminases had significantly higher AG levels. An
increase of AG over 0.52 ng/ml can be used as a diagnostic marker for NAFLD detection
in patients with T2D.
ePOSTER ABSTRACTS
121
Screen 3: YI-MR-129
SECRETOME PROFILES OF HUMAN MESENCHYMAL
STEM CELLS BEFORE AND AFTER HEPATOCYTIC
DIFFERENTIATION – IDENTIFICATION OF PATHWAYS
IMPACTING ON POTENTIAL TREATMENT OF NASH
Sandra Winkler* 1, Madlen Hempel1, Sandra Brückner2, Bruno Christ1
Applied Molecular Hepatology Lab, Department of Visceral, Transplantation, Thoracic and
Vascular Surgery, 2’Applied Molecular Hepatology Lab, Department of Visceral, Transplantation,
Thoracic and Vascular Surgery, UNIVERSITY OF LEIPZIG, Leipzig, Germany
1
ePOSTER ABSTRACTS
Corresponding author’s email: sandra.pelz@medizin.uni-leipzig.de
Introduction: Cell therapy is a very promising option to treat acute and chronic liver
diseases like e.g. after liver resection or NASH. Because of their known pleiotropic mode
of action, mesenchymal stem cells (MSC) seem to be appropriate candidates. Yet, so far,
the underlying molecular mechanisms are poorly understood.
Aims: This work aimed to identify and highlight potential factors, mechanisms of action
and differences between undifferentiated and hepatocytic differentiated MSC derived
from human adipose tissue and bone marrow
Material and Methods: Human MSC were isolated from subcutaneous adipose tissue
and bone marrow. Both were differentiated into hepatocyte-like cells for 16 days. The
Proteome Profiler Antibody Array (R&D Systems) was applied to identify cytokine profiles
of native and hepatocytic differentiated MSC. The data analyses were done using String,
David and Pathcards databases.
Results: As markers of hepatocytic differentiation, cell surface antigens CD54 increased
and CD166 decreased. Cytokine profiles differed between between MSC from the different
tissue sources and changed after differentiation. Using David, cytokine-cytokine receptor
interactions, chemokine signaling pathways, the complement and coagulation cascades
as well as the JAK-STAT and NOD-like receptor signaling pathways were identified
as relevant networks and associated pathways in KEGG. A new online tool, Pathcards,
allowed identifying even more relationships like the involvement of the TGF-beta pathway.
Also HIF1-alpha signaling pathway might be important.
122
Conclusions: In summary, MSC from various tissues secrete a basic protein profile,
which differs depending on the cell source and the degree of differentiation. Factors
involved mainly address inflammatory and growth factor pathways as well as chemoattraction and innate immunity. Since these are relevant in the pathogenesis of most liver
diseases, the elucidation of the molecular mode of actions of MSC might facilitate their
clinical translation.
ePOSTER ABSTRACTS
123
Screen 4: YI-MR-181
MELANIN PRODUCED BY YEAST NADSONIELLA NIGRA
AS NOVEL THERAPEUTICS AGENTS IN NAFLD/NASH
MANAGEMENT
Savytska Maryana* 1, Nazarii Kobyliak2, Tetyana Falalyeyeva3, Petro Bodnar2,
Tetyana Beregova3, Lyudmyla Ostapchenko3
1
Danylo Halytsky Lviv National Medical University, Lviv, 2Endocrinology, Bogomolets National
Medical University, 3Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
ePOSTER ABSTRACTS
Introduction: One of the pathogenic mechanisms of the progression NAFLD to NASH
is the accumulation of reactive oxygen species. So, antioxidant therapy is necessary for
successful treatment of the liver injury. We have paid attention to melanin produced by
yeast Nadsoniella nigra strain X-1 as novel antioxidant and anti-inﬂammatory agents with
low toxicity.
Aims: In current study we aimed to investigate the preventive effect of melanin on the
monosodium glutamate (MSG) induced NAFLD model in rats.
Material and Methods: The study was carried out on 45 Wistar rats, that were divided
into 3 groups: intact, MSG- and MSG+melanin groups (n=15 in each group). Newborn
rats of MSG- and MSG+melanin groups were administered with MSG (4 mg/g, 8 µl/g,
subcutaneously) at 2nd -10th days of life. Since the age of 1 month, rats of MSG-group
were treated with water (0.25 ml/100 g), rats of MSG+melanin groups with melanin (1 mg/
kg) dissolved in water (0.25 ml/100 g). Introduction had been performed intermittently
(two-week courses alternated with two-week breaks) for 3 months. In 4-month rats
anthropometrical parameters and VAT mass were estimated. To assess morphological
changes in liver we used NAS (NAFLD activity score). Lipid extraction from liver was
performed according to Folch. The content of proinflammatory cytokines (IL-1β, IL12Bp40, INF-γ) and anti-inflammatory cytokines (IL-4, IL-10, TGF-β) were measured
by ELISA.
Results: We found significantly lower total score (1.0±0.19 vs 3.33±0.36, p<0.001), degree
of steatosis (0.73±0.18 vs 1.80±0.17, p<0.001) and manifestation of lobular inflammation
(0.27±0.11 vs 1.20±0.17, p<0.001) due to NAFLD activity score in MSG+melanin
group compared to MSG-obesity. NASH we confirmed only in 33.3 % of rats with MSG-
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obesity that was significantly higher than after melanin (6.7 %) administration (p=0.033).
Melanin administration reduce total lipids and triglycerids content in liver approximately
by 22-25% (p<0.001) and amount of visceral fat on 40% (p<0.001) as compared to
MSG-obesity group. Melanin reduced the content of IL-1β in rat serum and restored the
level of anti-inflammatory cytokines (IL-10, TGF-β) to the control values.
Conclusions: Thus, the administration of melanin can prevent development of NAFLD/
NASH in rats with MSG-induced obesity and can be considered as possible novel
therapeutic agents but further studies to confirm its action needed.
ePOSTER ABSTRACTS
125
Screen 5: MR-195
THE BERLIN QUESTIONNAIRE SCREENS AND EPWORTH
SLEEPINESS SCALE FOR OBSTRUCTIVE SLEEP APNEA
IN NON-ALCOHOLIC FATTY LIVER DISEASE
Haifa Romdhane1, Bochra Bouchabou* 1, Hend Ayadi1, Myriem Cheikh1, Najet
Belhadj1
1
Department of gastroenterology, Mongi Slim Universitary Hospital, Tunis, Tunisia
ePOSTER ABSTRACTS
Corresponding author’s email: ayadi.hbm@gmail.com
Introduction: Obstructive sleep apnea (OSA) is associated with non-alcoholic fatty liver
disease (NAFLD), a disorder most commonly occurring in patients with obesity and/or
metabolic syndrome. Because polysomnography, the standard test for diagnosing OSA, is
expensive and time consuming, questionnaires have been developed to identify persons
with OSA. The Berlin questionnaire (BQ) reliably and Epworth Sleepiness Scale (ESS)
identify middle-aged and older persons in the community who are at high-risk for OSA.
Aims: We aimed to validate the BQ and ESS as a screening tool for OSA in NAFLD
patients.
Material and Methods: Patients with ultrasound-diagnosed NAFLD completed the BQ
and ESS. Then, we underwent diagnostic polysomnography. The BQ and ESS were scored
as high or low risk for OSA, and the diagnosis of OSA was based on polysomnography
findings. OSA was defined as an apnea-hypopnea index of ≥ 5 on polysomnography.
Results: Thirty eight patients were evaluated. There were 11 men and 27 women with a
mean age of 50 years old [19-79]. Body mass index was on average of 32, 4 kg/m2 [21,443]. Twenty three patients (60.5%) had a high-risk BQ score and six patients (15, 7%) had
a high-risk ESS. Fifteen of 23 (65, 2%) with a high-risk BQ score had OSA, while 3 of 15
(20%) with a low-risk score had OSA (Fisher test, P = 0.025). Five of 6 (83, 33%) patients
with high-risk ESS had OSA, while 4 of 32 (12,5%) with a low-risk score had OSA (Fisher
test, P = 0,04). The sensitivity and specificity of the BQ for OSA in NAFLD patients were
82% and 57%, respectively while the sensitivity and specificity of the ESS for OSA were
74% and 43%.
Conclusions: A low-risk BQ score and ESS identify NAFLD patients who are unlikely to
have OSA. Polysomnography should be considered in those with a high-risk score.
126
Screen 6: YI-MR-149
AN OPEN LABEL RANDOMIZED CONTROLLED TRIAL
OF VITAMIN D VS PENTOXIFYLLINE IN NON-DIABETIC
PATIENTS OF NAFLD
Sanchit Budhiraja* 1, Ashok K. Jain1, Vinod K. Dixit1, Sunit K. Shukla1, Ravika
Budhiraja2, Ashutosh Jain3
1
Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi,
2
Dermatology, SGRDIMSR, Amritsar, 3Internal Medicine, Institute of Medical Sciences,
Banaras Hindu University,Varanasi, India
Introduction: Nonalcoholic fatty liver disease (NAFLD) encompasses a histological
spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Diet and
lifestyle changes are a rational first-line therapy in NAFLD. Pharmacologic therapy is
important when lifestyle measures fail.
Aims: The aim of this study was to compare the response to two different treatments
i.e. Vitamin E and Pentoxifylline (PTX) in non-diabetic patients of NAFLD in terms of
clinical and biochemical outcomes.
Material and Methods: In this open label study, in addition to lifestyle modification
advice, non-diabetic patients with biopsy proven NAFLD were randomized to receive
either Vitamin E (800 mg in 2 divided doses) or PTX (1200 mg in 3 divided doses).
Results: A total of 48 patients (26 in Vitamin E group and 22 in the PTX group) with a
mean follow up of 166.8 days completed the study. At follow up, FBS was less in Vitamin
E group (94.69±6.72 mg/dl vs 100.45±9.82 mg/dl; p 0.020). The level of VLDL was lower
(p 0.015) in the PTX group (33.15±7.51mg/dl). There was no difference in any other
parameter between the two groups.
In the Vitamin E group, there was a decrease in systolic blood pressure (SBP) and diastolic
blood pressure (p <0.0001), weight (67.96±8.2 kg vs 67.00±7.28 kg; p 0.003), BMI (from
24.14±2.93 kg/m2 to 23.75±2.66 kg/m2; p 0.008), waist and hip circumference. There
was a decrease in ALT to 55.38±29.90 at follow up from 67.54±34.50 U/L at baseline (p
0.016). Median triglyceride level decreased from 251.5 mg/dl to 194.5 mg/dl (p 0.002) and
HDL increased from 38.08 at baseline to 41.15 at follow up (p 0.0001). FBS decreased
127
ePOSTER ABSTRACTS
Corresponding author’s email: reachthestars123@yahoo.com
from 97.88mg/dl at baseline to 94.69 mg/dl at follow up (p 0.018). There was a decrease
in the CK18-F level from 348.95 U/L to 319.79 U/L (p 0.0001).
In the PTX group, there was a decrease in weight (70.77±7.32 kg to 70.00±6.91 kg;
p 0.009) and waist circumference (92.14±11.88 cm to 91.27±11.91cm; p 0.007). ALT
decreased from 83.55±38.96 U/L to 64.51±26.54 U/L (p 0.008) and HDL increased
from 37.64 mg/dl to 40.5 mg/dl (p 0.0001). There was also a decrease in CK18-F from
344.01 U/L to 303.78 U/L (p 0.022).
Conclusions: Vitamin E therapy was effective in reducing weight, BMI, systolic blood
pressure and ALT, improving dyslipidemia as well as blood sugars and CK18-F. PTX
therapy improved weight, ALT, HDL and CK18-F. Overall, even though both the
treatments decreased ALT and CK18-F, Vitamin E appears to offer distinct advantage
over PTX in terms of improvement in dyslipidemia and blood sugars.
ePOSTER ABSTRACTS
Figure:
128
Friday 13 May 2016
Screen 1: MR-115
Claudia P. Oliveira* 1, Sebastião M. Duarte 1, Jose Tadeu Stefano1, Marcela Souza2,
Livia Rodrigues1, Priscila B. Campos1, Fernando G. Costa1, Daniel F. Mazo1,
Flair Jose Carrilho1, Ester C. Sabino2
1
GASTROENTEROLOGY (LIM-07), 2Infectious Disease and Institute of Tropical Medicine,
University of São Paulo School of Medicine, SAO PAULO, Brazil
Introduction: Evidence for the role of the gut microbiota in energy storage and the
development of NAFLD (Non-alcoholic fatty liver disease) has provided new insight to the
pathophysiology of this disease and may help explain the observed phenotypic differences.
Aims: The aim of the study was to compare the gut microbiome from Brazilian obese
patients with or without NASH versus Brazilian healthy controls.
Material and Methods: We performed a cross sectional study comprising patients
biopsied-proven NASH obese (NO; n=11]; obese without NASH (OWN; n=4) and
lean healthy controls (HC; n=6). Stool samples were prospectively collected, mixed
with RNAlater and stored at -20°C. DNA was extracted from stool samples and PCR
amplification was performed using primers for the V4 region of the 16S rRNA gene. The
amplicons were sequenced using Ion PGM Torrent platform and data analyzed using
QIIME software.
Results: NO or OWN patients had higher percentages of Firmicutes compared to HC
(p<0.04) according Phylum. Furthermore, according Class obese in both groups with
(NO) or without NASH (OWN) had a tendency a greater percentage of Clostridia than
HC (p=0.062). As regards the Family obese patients with or without NASH had higher
percentages of Enterobacteriaceae than HC (p<0.037). Curiously, NO patients had some
interesting microbioma aspects that are different from obese OWN and HC. There was a
129
ePOSTER ABSTRACTS
MOLECULAR CHARACTERIZATION OF THE FECAL
MICROBIOME IN BRAZILIAN NASH OBESE AND OBESE
WITHOUT NASH PATIENTS COMPARED TO LEAN
HEALTHY CONTROLS
tendency to have higher percentage of Tenericutes compared to OWN and HC (p=0.063)
according Phylum. Analyzing the Class, NO patients had higher percentages of Mollicutes
that OWN and HC (p<0.039) and in the other hand, there is a tendency that NO patients
have a greater percentage of some types of bacteria Rikenellaceae families, Odoribacteraceae
and Mogibacteriaceae that OWN and HC. Finally, according Genero, NO patients had
higher percentages of Anaerostipes compared to OWN and HC (p<0.046).These aspects
suggest that NASH obese patients could have different microbioma than obese without
NASH and healthy controls.
ePOSTER ABSTRACTS
Conclusions: Our data suggest that Brazilian NASH obese and obese without NASH
patients have fecal dysbiosis compared with Brazilian lean healthy controls. In the other
hand, NASH obese patients in Brazil also have a different microbioma than obese without
NASH and healthy controls. Further studies are required to investigate the mechanism
underlying the interaction between gut microbes and NASH in obese and lean subjects
across the world.
130
Screen 2: YI-MR-171
SYNERGISTIC EFFECT OF ALIVE PROBIOTIC AND
ABSORBENT SMECTITE GEL FOR NAFLD/NASH
PREVENTION: EXPERIMENTAL STUDY
Nazarii Kobyliak* 1, Tetyana Falalyeyeva2, Galyna Mykhalchyshyn1, Tetyana
Beregova2, Petro Bodnar1
1
Endocrinology, Bogomolets National Medical University, 2Taras Shevchenko National University
of Kyiv, Kyiv, Ukraine
Introduction: Today probiotics have been suggested as a treatment for the prevention of
NAFLD. Smectite is a natural silicate that binds to digestive mucous and has the ability
to bind endo- and exotoxins, increased water and electrolyte absorption and restored the
barrier properties of human intestinal cell monolayers.
Aims: The present study was designed to determine whether probiotics plus smectite
is superior to probiotic alone on the monosodium glutamate (MSG) induced NAFLD
model in rats.
Material and Methods: We included 60 rats divided into 4 groups 15 animals in each.
Rats of group I were intact. Newborns rats of groups II-IV were injected with MSG (4.0
mg/g body weight) subcutaneously at postnatal days 2, 4, 6, 8 and 10. The III (Symbiter)
group received 2.5 ml/kg of multiprobiotic “Symbiter” containing concentrated biomass of
14 probiotic bacteria genera Bifidobacterium, Lactobacillus, Lactococcus, Propionibacterium.
The III (Symbiter+Smectite) groups received “Symbiter Forte” combination of probiotic
biomass with smectite gel (250 mg). Administration was started at 4 weeks after birth and
continued intermittently two-week course in 2 weeks intervals. To assess morphological
changes in liver we used NAS (NAFLD activity score). Lipid extraction from liver was
performed according to Folch. The content of proinflammatory cytokines (IL)-1β, IL12Bp40, INF-γ) and anti-inflammatory cytokines (IL-4, IL-10, TGF-β) were measured
by ELISA.
Results: In both interventional groups reduction of total NAS score as compared to
MSG-obesity was observed. However only for Symbiter+Smectite group we don’t find
significant changes as compared to intact rats (1.0±0.21 vs 0.20±0.13, p=0.223). Indeed
similar values of steatosis score (0.93±0.22 vs 0.87±0.16) in both treatment groups,
131
ePOSTER ABSTRACTS
we observed that lower total score for Symbiter+Smectite are associated with more
pronounced reduction of lobular inflammation (0.13±0.09 vs 0.33±0.15) as compared
to administration of probiotic alone. This data accompanied with significant reduction of
IL-1β and restoration of IL-10 between these 2 groups.
Conclusions: Additional to alive probiotic administration of smectite gel due to his
absorbent activity and stabilization mucus layer properties can impact on synergistic
enhancement of single effect which manifested with reduction of lobular inflammation
and at list partly NASH prevention.
ePOSTER ABSTRACTS
132
Screen 3: YI-MR-184
LIVER AND SYSTEMIC IRON LOADING CHARACTERISE
INITIAL DISEASE PROGRESSION IN NAFLD
John D. Ryan* 1, Andrew Armitage2, Jeremy F. Cobbold1, Rajarshi Banerjee3,
Stefan Neubauer3, Lai Mun Wang1, Sant-Rayn Pasricha2, Jane Collier1, Alexander
Drakesmith2, Eleanor Barnes1, Michael Pavlides3
1
Translational Gastroenterology Unit, 2MRC Human Immunology Unit, Weatherall
Institute of Molecular Medicine, 3Oxford Centre for Clinical Magnetic Resonance
Research, University of Oxford, Oxford, United Kingdom
Introduction: Non-alcoholic fatty liver disease (NAFLD) often presents with raised
serum ferritin levels. Both raised ferritin and hepatic iron levels have been associated with
more advanced NAFLD, although ferritin levels may relate to inflammation rather than
iron. Excess iron causes oxidative stress, and may worsen insulin resistance (IR) through
the modulation of adipokines such as adiponectin.
Aims: As both oxidative stress and IR are key features of the pathogenesis and progression
of NAFLD, deciphering the role of iron in this process is important.
Material and Methods: In this study we examined the iron status of individuals across
the clinical spectrum of NAFLD (n=51), using blood, tissue and magnetic resonance
(MR) imaging markers. We compared them with chronic viral hepatitis patients (n=30)
and healthy controls (n=20).
Results: NAFLD patients were significantly heavier, with significantly higher liver fat
and iron measured by MR (proton spectroscopy and T2* respectively), higher insulin and
CRP, and lower total adiponectin than viral hepatitis or controls (all p<0.005). Examining
NAFLD subgroups by Brunt fibrosis stage revealed a progressive increase in liver fat and
iron from early (F0-1, n=17) to moderate fibrosis (F2, n=16) which declined in advanced
disease (F3-4, n=18), (p=0.002 for iron). This was mirrored by elevated serum ferritin
and hepcidin during the progression from F0-1 to F2, followed by a significant decline in
advanced fibrosis (p=0.002 and p=0.0004, respectively). Furthermore, serum ferritin or
hepcidin were significant independent predictors of progression from F0-1 to F2 stage by
multiple logistic regression. Serum ferritin correlated closely with serum hepcidin, MR
liver fat and iron in NAFLD (r=0.73, r=0.56 and r=-0.76 respectively, all p<0.0001)
133
ePOSTER ABSTRACTS
Corresponding author’s email: john.ryan@ndm.ox.ac.uk
but not with CRP or inflammation on biopsy. Total adiponectin correlated inversely with
serum ferritin, hepcidin and liver iron levels (r=-0.27, p=0.05; r=-0.28, p=0.049 and
r=0.38, p=0.005, respectively), and declined significantly from F0-1 to F2 (p=0.02).
Conclusions: Raised serum ferritin in NAFLD patients reflects increased hepcidin and
liver iron, which is associated with insulin resistance markers. Moreover, an increase in
iron appears to mark the progression through early fibrosis stages, supporting a causal
relationship with the metabolic changes that drive the pathogenesis and progression of
the disease, warranting further interventional studies to exploit this important therapeutic
target.
ePOSTER ABSTRACTS
134
Screen 4: YI-MR-174
DIAGNOSTIC ACCURACY OF SHEAR WAVE
ELASTOGRAPHY FOR THE ASSESSMENT OF LIVER
STIFFNESS IN CHILDREN WITH FATTY LIVER DISEASE
Corresponding author’s email: matteogarcovich@yahoo.it
Introduction: Non-invasive assessment of liver fibrosis by ultrasound elastography
techniques has received increasing attention as a means to evaluate disease progression in
chronic liver disease patients.
Aims: In this study, we assessed the value of shear wave elastography with Supersonic
Shear Imaging (SSI) for the prediction of fibrosis stage in a cohort of pediatric patients
with nonalcoholic steatohepatitis.
Material and Methods: Consecutive patients scheduled for liver biopsy were studied
by using SSI ultrasound system, a non-invasive method of assessing tissue stiffness.
The correlations between laboratory findings, liver stiffness and the fibrosis score were
analyzed using logistic regression and receiver operating characteristic curve analyses were
performed to calculate area under the receiver operating characteristics curves for the
presence of “any” (F≥1) or significant (F≥2) fibrosis.
Results: SSI was performed in 69 consecutive biopsy-proven nonalcoholic steatohepatitis
patients (38 males, 31 females, age 12.7±2.65 years). In univariate analysis, SSI showed
a very high correlation with liver fibrosis (P< 10-5), a high correlation for degree of portal
inflammation (P=0.001), lobular inflammation (P=0.001) and a moderate correlation for
degree of histologic steatosis (P=0.032) and histological hepatocyte ballooning (P=0.025).
SSI values showed a moderate correlation with ALT and AST, but no correlation was
found with other variables. Multivariate analysis confirmed the strong correlation of SSI
with fibrosis stage (P< 10-5). Overall, SSI correctly classified 57 of 69 patients (83%).
In particular, the ROC curve drawn to differentiate “any” fibrosis (F≥1) from absence
135
ePOSTER ABSTRACTS
Matteo Garcovich* 1, Silvio Veraldi2, Enrico Di Stasio3, Maria A. Zocco1, Lidia
Monti4, Paolo Tomà4, Maurizio Pompili1, Antonio Gasbarrini1, Valerio Nobili2
1
Internal Medicine, Gastroenterology and Liver Diseases Unit, CATHOLIC UNIVERSITY
OF SACRED HEARTH, 2Hepatometabolic Unit, Bambino Gesù Children’s Hospital, 3Institute
of Biochemistry and Clinical Biochemistry, CATHOLIC UNIVERSITY OF SACRED
HEARTH, 4Radiology Unit, Bambino Gesù Children’s Hospital, Rome, Italy
of fibrosis (F0) yielded an AUROC of 0.92 (95% CI:0.86-0.98), with an optimal cutoff of 5.1 kPa (sensitivity 84%; specificity 95%). The AUROC values for differentiating
significant fibrosis (F ≥2) from fibrosis degree of less than F2 was 0.97 (95% CI:0.950.99), with an optimal cut-off value of 6.7 kPa.
Conclusions: To date this is the largest case series evaluating the accuracy of SSI in
children with fatty liver disease. SSI is an accurate and reproducible non invasive technique
detecting efficiently the presence of any degree of fibrosis or significant fibrosis in this
population. Larger clinical prospective studies are warranted to confirm SSI accuracy and
establish threshold values for fibrosis grading in comparison or in combination with other
non-invasive methodologies.
ePOSTER ABSTRACTS
136
Screen 5: YI-MR-150
Milena Marietti* 1, Chiara Rosso1, Konstantin Kazankov2, Melania Gaggini3,
Holger Jon Moller4, Chiara Saponaro3, Gian Paolo Caviglia1, Emma Buzzigoli3,
Rami I. K. Jouness1, Maria Lorena Abate1, Antonina Smedile1, Giorgio Maria
Saracco5, Hendrik Vilstrup2, Jacob George6, Amalia Gastaldelli3, Henning
Gronbaek2, Elisabetta Bugianesi1
1
Medical Sciences, UNIVERSITY OF TURIN, Torino, Italy, 2Department of Hepatology and
Gastroenterology, Aarhus University Hospital, Aarhus, Denmark, 3Cardiometabolic Risk Unit,
CNR-Institute of Clinical Physiology, Pisa, Italy, 4Department of Clinical Biochemistry, Aarhus
University Hospital, Aarhus, Denmark, 5Department of Oncology, UNIVERSITY OF TURIN,
Torino, Italy, 6The Storr Liver Centre, University of Sydney and Westmead Hospital, Westmead,
Australia
Corresponding author’s email: crosso3@cittadellasalute.to.it
Introduction: Non-alcoholic fatty liver disease (NAFLD) has a bidirectional relationship
with insulin resistance (IR): the liver is the target of an increased flux of Free Fatty
Acids (FFAs) and adipokines stemming from a dysfunctional adipose tissue (AT) but
a fatty liver actively contributes to the dyslipidemic profile and to the chronic low grade
inflammation. Soluble CD163 (sCD163), a marker of hepatic macrophages activation,
has been associated with fibrosis in NAFLD.
Aims: Our aim is to elucidate the link between IR in the liver and in the AT, hepatic
macrophages activation and liver damage in 40 non-diabetic patients with NAFLD.
Material and Methods: All study subjects underwent tracers studies with [2H5]glycerol
and [2H2]glucose in fasting conditions. AT-IR was calculated as FFAs x insulin (AT-IR1)
and as Glycerol Ra x insulin (AT-IR2). Hepatic-IR was derived from endogenous glucose
production x insulin. sCD163 levels were measured by an enzyme-linked immunosorbent
assay. Hepatic fat was assessed by liver biopsy while visceral fat (VF) and subcutaneous
fat (SF) were measured with standard magnetic resonance imaging (MRI). Histology was
scored according to Kleiner.
137
ePOSTER ABSTRACTS
ADIPOSE TISSUE INSULIN RESISTANCE IS ASSOCIATED
WITH MACROPHAGE ACTIVATION IN NON-DIABETIC
PATIENTS WITH NON ALCOHOLIC FATTY LIVER DISEASE
Results: AT-IR showed a significant association with hepatic fat (AT-IR1: r=0.50,
p=0.001; AT-IR2: r=0.44, p=0.004), with NAS score (p=0.006 and 0.05 respectively) and
with fibrosis (p=0.001 for both) at liver biopsy. Plasma levels of sCD163 were significantly
associated with fasting plasma levels of FFAs and with lipolysis (r=0.35, p=0.026; r =0.35,
p=0.028, respectively). sCD163 levels were also directly related to AT-IR (AT-IR1 r=0.38,
p=0.016 and AT-IR2 r=0.31, p=0.005) and with liver fat (r=0.53; p=0.005), while no
correlation was found with Hepatic-IR (r=0.22, p=0.170), VF (r=0.15, p=0.407) or
SF (r=0.08, p=0.655). Among histological features, sCD163 plasma levels increased in
proportion to the NAS score (r=0.54; p=0.003) and to the degree of fibrosis (p<0.001).
At logistic regression analysis, sCD163 plasma levels better predicted moderate/severe
(≥F2) fibrosis than AT-IR (OR 5.2, CI:1.1-24.6).
ePOSTER ABSTRACTS
Conclusions: We hypothesize that in NAFLD AT-IR can stimulate hepatic macrophage
activation via an increased flux of FFAs thus concurring to liver damage.
Funded by FP7/2007-2013under grant agreement no.HEALTH-F2-2009-241762 for the
project FLIP;PRIN2009ARYX4T. Horizon2020 under grant agreement no.634413 for the
project EPoS
138
Screen 6: MR-152
PATATIN-LIKE PHOSPHOLIPASE DOMAIN-CONTAINING
PROTEIN 3 POLYMORPHISM AND THE RISK OF
HEPATOCELLULAR CARCINOMA DEVELOPMENT IN
RELATION TO UNDERLYING LIVER DISEASES
Pisit Tangkijvanich* 1, Maneerat Raksayot1 on behalf of Research Unit of Viral
Hepatitis and Liver Cancer, Apichaya Khlaiphuengsin1 and Research Unit of
Hepatitis and Liver Cancer
1
Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Introduction: A single nucleotide polymorphism (SNP) of patatin-like phospholipase
domain containing protein 3 (PNPLA3) (rs738409, C>G) has been associated with
disease progression in fatty liver diseases. However, the role of the SNP in patients with
hepatocellular carcinoma (HCC) in relation to underlying chronic liver diseases is less clear.
Aims: This study was aimed at evaluating the association between rs738409 and the
development of HCC in Thai patients.
Material and Methods: PNPLA3 rs738409 genotypes was determined by allelic
discrimination in blood samples of 200 heathy controls and 574 HCC cases [303 with
viral hepatitis B, 154 with viral hepatitis C, 46 with alcoholic steatohepatitis (ASH) and 71
with non-alcoholic steatohepatitis (NASH)].
Results: The prevalence of rs738409 genotypes CC, CG and GG in controls was 91
(45.5%), 88 (44.0%), and 21 (10.5%), respectively, while the corresponding figures in
all patients with HCC was 243 (42.34%), 259 (45.12%), and 72 (12.54%). The GG
genotype had significantly higher distribution in patients with ASH/NASH-related HCC
compared with controls (OR=2.09, 95% CI=1.10- 3.96, P=0.025), and viral-related HCC
(OR=2.04, 95% CI=1.18- 3.51, P= 0.010). However, the frequency of the GG genotype
was similar between controls and patients with viral-related HCC.
Conclusions: These data suggested an association of the PNPLA3 polymorphism with
HCC development in patients with ASH/NASH but not among those with chronic viral
hepatitis.
139
ePOSTER ABSTRACTS
Corresponding author’s email: pisittkvn@yahoo.com
Friday 13 May 2016
Screen 1: MR-172
COMPARATIVE ANALYSIS OF ONLINE PATIENT
EDUCATION RESOURCES PERTAINING TO NASH OR
NAFLD
ePOSTER ABSTRACTS
Rishabh Gulati* 1, Mohammad Nawaz2, Nikolaos Pyrsopoulos1
1
Rutgers NJMS, Newark, 2Rutgers NJMS, Bloomfield, United States
Corresponding author’s email: rishabhgulati@hotmail.com
Introduction: Role of the Internet is ever increasing in the present era as the first source
of medical information. Imprecise, partial comprehension of textual information limits its
efficacy in communicating the disease process to the patient. Here, we report a comparative
analysis of readability of patient-centered text pertaining to Non-Alcoholic Fatty Liver
Disease (NAFLD) and/or Non-alcoholic Steatohepatitis (NASH) available online.
Aims: To determine the readability of online patient centered health information
pertaining to NASH or NAFLD
Material and Methods: From September to November 2015, patient-centered
information from websites of American College of Gastroenterology (ACG), Mayo
Clinic, Medicinenet.com, National Institutes of Health (NIH), Patient.info, Uptodate &
WebMD were downloaded & processed in Microsoft Word. All data were formatted &
categorized into subsections. Copyright, propriety information & certain medical terms
were omitted to limit bias. Text was then analyzed for their specific level of readability
using 6 quantitative scales: Flesch–Kincaid level, Gunning fog index, SMOG, ColemanLiau, FRY & New Dale–Chall.
Results: Modified documents had a mean grade level that was 1 less than their original
counterparts. ACG had the highest mean grade level of readability of it’s content
(14±0.56), with the lowest being for WebMD (7.1±0.61). When compared with all
subsets, the treatment subsection had the highest mean grade level (11.9±0.61). ANOVA
analysis showed that there were significant differences in the grade level depending on
the source website (p < 0.05), and subsection when compared with all readability tests.
140
Forest plot analysis depicts significant higher readability grade level of various subsections
and websites. The treatment section was usually the most difficult section written when
compared with other subsections (p < 0.05).
Conclusions: Patient material is above the recommended 6th grade level across all
websites. Treatment section is often the most difficult section to comprehend. Greater
emphasis on clear & simple language is warranted to increase quality & comprehension of
online patient education resources.
ePOSTER ABSTRACTS
Figure:
141
Screen 2: YI-MR-159
ePOSTER ABSTRACTS
IMPACT OF GWAS-IDENTIFIED COMMON VARIANTS ON
HISTOPATHOLOGICAL FEATURES OF NAFLD PATIENTS
Rocío Gallego-Durán* 1, 2, Javier Ampuero2, 3, Jose Antonio Del Campo2, 4, Helena
Pastor-Ramírez2, 3, Eduardo Vilar-Gómez2, 3, Antonio Gil-Gómez2, 3, María
Teresa Arias-Loste5, 6, María Jesús Pareja-Megía7, Javier Abad8, María Carmen
Rico2, 3, Marta García-Valdecasas2, 3, Inmaculada Moreno9, 10, Jose Luis Calleja11,
Raúl Jesús Andrade9, 10, Javier Crespo5, 12, Carmelo García-Monzón13, 14, Manuel
Romero-Gómez2, 3
1
Inter-Centre Unit of Digestive Diseases & CIBERehd, Virgen Macarena – Virgen del Rocío
University Hospitals, University of Sevilla, 2Instituto de Biomedicina de Sevilla (IBiS), 3InterCentre Unit of Digestive Diseases & CIBERehd,Virgen Macarena – Virgen del Rocío University
Hospitals, University of Sevilla, 4Digestive Diseases Unit, Valme University Hospital, Sevilla,
5
Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital,
6
Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla
(IDIVAL), Santander, 7Pathology Unit, Valme University Hospital, Sevilla, 8Gastroenterology
Department, Hospital Puerta de Hierro, Madrid, 9Inter-Centre Unit of Digestive Diseases &
CIBERehd, Virgen de la Victoria University Hospital, 10Instituto de Investigación Biomédica de
Málaga (IBIMA), Málaga, 11Gastroenterology and Hepatology Department, Hospital Puerta
de Hierro, Madrid, 12Research Institute Marqués de Valdecilla (IDIVAL), Santander, 13Liver
Research Unit and CIBERehd , University Hospital Santa Cristina , 14Instituto de Investigación
Sanitaria Princesa, Madrid, Spain
Corresponding author’s email: rociogallegoduran@gmail.com
Introduction: Due to considerable interindividual variation in NAFLD development and
progression, in recent years several GWAS studies have been performed to determine
genetic influence on this disease.
Aims: The main aim of this study was to evaluate the impact of certain single nucleotide
polymorphisms (SNPs) on histopathological features in a cohort of Spanish patients.
Material and Methods: Cross-sectional and multicentre study including 225 biopsydiagnosed NAFLD patients. After literature search, four SNPs from candidate genes were
selected from GWAS (rs738409 from PNPLA3, rs58542926 from TM6SF2, rs2645424
from FDFT1 and rs838145 from IZUMO1) with potential clinical relevance on NAFLD.
Clinical, epidemiological and analytical data were recorded. These SNPs were genotyped
142
Results: It was performed univariate analyses by NASH and significant fibrosis (F2F4) presence. Independent variables with significance p ≤ 0.05 were introduced in the
multivariate analysis (backward Wald logistic regression analysis), in order to avoid
potential confounding factors, to identify features related to NASH and significant liver
fibrosis. Independent predictor variables for NASH were male gender [OR 3.02 (CI95%
1.02-6.79); p=0.006]; diabetes mellitus [OR 5.70 (CI95% 2.14-15.21); p=0.001] and
bear GG genotype from IZUMO1 gene [OR 2.62 (CI95% 1.02-6.76; p=0.046] and GG
genotype from PNPLA3 gene [OR 4.16 (CI95% 1.68-10.28); p=0.002]. Area under
receiver operating curve (AUROC) obtained for NASH prediction was 0.79 [CI95%
0.71-0.86].
Likewise, age at liver biopsy [OR 1.07 (CI95% 1.03-1.11); p=0.001], ALT [OR 1.02
(CI95% 1.01-1.03); p=0.006], insulin levels [OR 1.10 (CI95% 1.04-1.17); p=0.001]
and being carrier of GG genotype from IZUMO1 gene [OR 3.10 (CI95% 1.07-8.94);
p=0.037] were found independently associated to significant fibrosis development.
AUROC achieved for significant fibrosis prediction was 0.88 [CI95% 0.83-0.94].
Conclusions: Influence of both genetic variants, located on IZUMO1 and PNPLA3
genes, were closely related to NAFLD severity, and could be useful as an effective tool for
screening and detection of patients suffering from advanced disease stages.
143
ePOSTER ABSTRACTS
by allelic discrimination using Taqman probe (Applied Byosistems, Spain). Histological
assessment was performed using Kleiner score, calculating lobular inflammation,
ballooning and steatosis degree. Statistical analysis was performed using SPSS 22.0
software.
Screen 3: MR-182
NASH: AN UNDERECOGNIZED CAUSE OF CRYPTOGENIC
CIRRHOSIS
Rym Ennaifer* 1, Hend Ayadi1, Myriam Cheikh1, Hayfa Romdhane1, Najet
BelHadj1
1
Mongi Slim Universitary Hospital, Tunis, Tunisia
ePOSTER ABSTRACTS
Corresponding author’s email: rym.ennaifer@yahoo.fr
Introduction: Nonalcoholic steatohepatitis (NASH) is a major cause of chronic liver
disease and its prevalence is rapidly increasing worldwide. At end-stage, steatosis and livercell injury can disappear and the cirrhosis can be wrongly classified as cryptogenic.
According to the European guidelines, the diagnosis of NASH at stage of cirrhosis can be
made when an overweight or diabetes are present together with hypertension, dyslipidemia,
or atheromatosis without histological proof.
Aims: The aim of our study was to evaluate the prevalence of risk factor of metabolic
syndrome over a cohort of patients followed for cryptogenic cirrhosis and to determine
how much can be attributed to burned-out NASH according to the criteria established by
the European guidelines.
Material and Methods: Retrospective study including patients followed in our
department for cryptogenic cirrhosis between January 2011 and December 2015.
Results: Among 142 cirrhotic patients, 21 patients were considered as having cryptogenic
cirrhosis. They were 11 men and 10 women with a mean age of 61.5 years [49-77].
Alcoholic, viral, autoimmune, vascular and other metabolic causes of chronic liver diseases
were excluded. 61.9% of patients (n=13) were overweighted with a mean BMI equal to
28.8 kg/m2 [20-39]. A type 2 diabetes mellitus was diagnosed in 57 % of cases (n=12) and a
dyslipidemia in 23.8% of cases (n=5). 28.5% of patients had hypertension. One patient had
a history of ischemic stroke. A metabolic syndrome was present in 33.3% of cases (n=7).
Abdominal ultrasound revealed hepatic increased echogenicity in 2 cases. According to
the European guidelines, the diagnosis of NASH was attributed to 52.3% of patients
(n=11): 7 patients had 2 criteria, 2 had 3 criteria and 2 had 4 criteria.
Conclusions: In this Tunisian cohort, 52.5% of cryptogenic cirrhosis could be related to
burned out NASH.
End-stage NASH should be mentioned as a frequent cause of cryptogenic cirrhosis not
only in Western countries.
144
Screen 4: YI-MR-136
HIGH RISK POPULATIONS: ATTITUDES TO NAFLD
AMONG DIABETOLOGISTS
Thomas Marjot* 1, Emilia Sbardella2, Jonathan Hazlehurst3, Ahmad Moolla3,
Jeremy Cobbold4, Jeremy Tomlinson3
1
Oxford Centre for Diabetes, Endocrinology and Metabolism, 2Oxford Centre for Diabetes,
Endocrinology and Metabolism, Churchill Hospital, 3Oxford Centre for Diabetes, Endocrinology
and Metabolism, University of Oxford, 4Department of Gastroenterology and Hepatology, Oxford
University Hospitals NHS Foundation Trust, Oxford, United Kingdom
Introduction: Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM)
are common conditions that regularly coexist and can act synergistically to drive adverse
outcomes. The prevalence of NAFLD in T2DM is 70%, with 16% having evidence of
advanced hepatic fibrosis. There is accumulating evidence for a role of screening for
NAFLD +/- fibrosis in diabetic populations.
Aims: Our study therefore had 3 aims: Firstly, to define the attitudes and current clinical
practice of diabetes specialists towards NAFLD across the UK. Secondly, to implement
an evidenced-based pathway for the assessment of NAFLD in patients attending diabetes
outpatient clinics and finally, to assess the impact of a multidisciplinary approach (with
combined hepatology and diabetes input) to their clinical management.
Material and Methods: An online survey was disseminated to diabetologists across
the UK. Based on findings from this survey, all diabetic patients attending outpatient
clinics at Oxford University Hospitals were screened for advanced fibrosis using a Fib-4
score. Those with elevated scores may then benefit from referral to the multidisciplinary
metabolic hepatology clinic.
Results: 116 diabetes specialists responded to the survey. Only 4.5% of responders
correctly judged the prevalence of NAFLD in diabetic patients to be >50%. Even fewer
(1.5%) correctly judged the prevalence of advanced fibrotic disease to be >15%. Whilst
most diabetologists performed liver function tests, the vast majority (68%) had not used
any non-invasive scoring system to assess risk of advanced disease within the last 12
months. For 20% of responders, a diagnosis of NAFLD did not affect their approach to
management. In light of these findings, a local ‘think NAFLD’ campaign was launched
145
ePOSTER ABSTRACTS
Corresponding author’s email: thomas.marjot@ouh.nhs.uk
to educate diabetologists on the assessment, risk and impact of NAFLD in patients with
diabetes. In the subsequent 3 months 188 patients attending diabetic clinics were screened
for advanced fibrosis using Fib-4. 16% of those screened had an elevated Fib-4. Data has
been analyzed from >90 patients attending the multidisciplinary clinic. After 6 months
follow up weight reduced by 3% (p=0.0003), ALT by 29% (p=0.0008) and HbA1c by
6.5mmol/mol (p=0.0006).
Conclusions: Amongst diabetologists, there remains limited awareness of the prevalence
and severity of NAFLD in the patients they treat. Fib-4 score can easily be used in clinical
practice to identify patients at risk of advanced fibrosis who are likely to benefit from a
dedicated multidisciplinary approach to their management.
ePOSTER ABSTRACTS
Figure:
146
Screen 5: YI-MR-154
Tim Hendrikx* 1, 2, 3, Martin L. Watzenböck2, 3, Sofie M. Walenbergh1, Shahzada
Amir2, 3, Sabrina Gruber2, 3, Heike I. Grabsch4, Ger Koek5, Marieke Pierik6, Daisy
Jonkers6, Satish Kalhan7, Marten Hofker8, Christoph J. Binder2, 3, Ronit ShiriSverdlov1
1
Molecular Genetics, MAASTRICHT UNIVERSITY, Maastricht, Netherlands, 2Laboratory
Medicine, Medical University of Vienna, 3CeMM,Vienna, Austria, 4Patholgy, MAASTRICHT
UNIVERSITY, 5Division of gastroenterology and hepatology, MUMC, 6Internal Medicine,
MAASTRICHT UNIVERSITY, Maastricht, Netherlands, 7Pathobiology, Lerner Research
Institute, Cleveland, United States, 8Pathology and Laboratory Medicine, UMC, Groningen,
Netherlands
Corresponding author’s email: t.hendrikx@maastrichtuniversity.nl
Introduction: Lipid oxidation of membrane phospholipids is accompanied by the
formation of oxidation-specific epitopes (OSE). These epitopes are recognized by specific
antibodies and represent danger-associated molecular patterns that are generated during
chronic inflammatory processes. In a murine model for hepatic inflammation during nonalcoholic fatty liver disease (NAFLD), increased antibody levels targeting OSE were found
to be protective.
Aims: Here, our aim was to determine an association between OSE-specific antibody
titers and NAFLD in humans.
Material and Methods: IgM and IgG levels with specificity for various OSE were assessed
in plasma of NAFLD patients (n = 71) and healthy controls (n = 68). Antibody titers were
comprehensively analyzed in NAFLD patients after classification by histological evaluation
of liver biopsies. Statistical analysis was performed to determine significant correlations
and odds ratios. To study the specificity for lipid-induced inflammation, plasma antibody
titers were measured in inflammatory bowel disease (IBD) patients (n = 62).
Results: IgM titers against OSE are lower in NAFLD patients compared to controls.
Further biopsy-based classification of NAFLD patients did not show any difference in
IgM levels. Importantly, low IgM titers towards the P1 mimotope demonstrated a high
147
ePOSTER ABSTRACTS
THE RECOGNITION OF OXIDIZED LIPIDS BY IgM
ANTIBODIES IS AN EARLY EVENT IN THE PATHOGENESIS
OF HUMAN NON-ALCOHOLIC FATTY LIVER DISEASE
predictive value for the presence of NASH, even after adjusting for total IgM level. In
contrast, increased disease activity during IBD was not associated with reduced IgM titers.
Conclusions: Our data highlight the importance of immune recognition of oxidationspecific epitopes by IgM antibodies and support a protective role for specific IgM in the
pathophysiology of non-alcoholic fatty liver disease.
ePOSTER ABSTRACTS
148
Screen 6: YI-MR-104
ASSOCIATION OF Pro12Ala POLYMORPHISM OF PPAR-γ
GENE WITH BIOCHEMICAL MARKERS OF LIVER INJURY
IN NONALCOHOLIC FATTY LIVER DISEASE PATIENTS
Vasyl Prysyazhnyuk* 1
Depatment of Propaedeutics of Internal Medicine, Bukovinian State Medical University,
Chernivtsi, Ukraine
1
Introduction: One of the most important genes that regulate adypo- and fibrogenesis are
genes which code the synthesis of peroxisome proliferation activator receptors (PPAR).
The physiological expression of PPAR-γ in adipocytes provides balanced adipocytokines
(adiponectin and leptin) secretion and thus prevents the development of nonalcoholic
fatty liver disease (NAFLD).
Aims: The aim of the study was to investigate a possible association of Pro12Ala
polymorphism of PPAR-γ gene with biochemical markers of liver injury in NAFLD
patients.
Material and Methods: Pro12Ala polymorphism of PPAR-γ gene was studied in 64
NAFLD patients and 20 healthy individuals (control group). All patients and healthy
volunteers gave written informed agreement to participate in research. Biochemical blood
parameters were investigated at the biochemical analyzer “Accent-200” (“Cormay SA”,
Poland) using standard reagents and techniques. To determine the polymorphic variants
of genes PPARγ (Pro12Ala) rs 1801282 modified protocols with oligonucleotide primers
were used.
Results: Among patients with NAFLD Ala/Ala genotype was diagnosed in 1 person
(1,6%), Pro/Ala – 12 (18,7%), Pro/Pro – 51 (79 7%); Ala allele of PPAR-γ gene was
observed in 14 cases (10,9%) among 128 selected alleles, Pro-allele – in 114 cases (89,1%)
respectively. In the group of healthy volunteers homozygous carriers of Ala-allele were
not found, 3 persons (15,0%) from this group were heterozygotes, 85,0% – homozygous
carriers of Pro-allele, which did not differ significantly from the genotypes distribution
among NAFLD patients.
Aspartataminotransferase activity in NAFLD patients Ala-allele carriers was
significantly higher at 55,5% (p = 0,007) than in patients with Pro/Pro-genotype.
149
ePOSTER ABSTRACTS
Corresponding author’s email: prysyaznyuk_v@ukr.net
Alaninaminotransferase activity in Ala-allele cariers was significantly higher by 80,0% (p
= 0,03) compared with patients with Pro/Pro genotype. Patients with minor Ala-allele
diagnosed higher γ-glutamiltransferase activity, which in 2,1 times (p = 0,04) prevailed
appropriate indicator in patients with Pro/Pro-genotype.
Conclusions: Frequency of minor Ala-allele of PPAR-γ gene in patients with nonalcoholic
fatty liver disease was not significantly different from that in healthy individuals. The Alaallele of PPAR-γ gene in patients with nonalcoholic fatty liver disease was associated with
significantly higher activity of biochemical markers of cytolytic and cholestatic syndromes
compared with those in Pro/Pro-genotype carriers.
ePOSTER ABSTRACTS
150
Friday 13 May 2016
Screen 1: MR-210
ELAFIBRANOR, A LIVER TARGETED PPARα/δ AGONIST
FOR GLOBAL MANAGEMENT OF NASH
Dean Hum* 1, Arun Sanyal2, Stephen A. Harrison3, Sophie Megnien1, Pierre
Bedossa4, Alice Roudot1, Robert Walczak1, Remy Hanf1, Bart Staels5, 6, Vlad Ratziu7,
8
Genfit SA, Loos, France, 2Virginia Commonwealth University, Richmond, 3Department of
Medicine, Gastroenterology & Hepatology Service, Brooke Army Medical Center, Fort Sam
Houston, Texas, United States, 4Department of Pathology, Hôpital Beaujon, University ParisDenis Diderot, Paris, 5Université Lille 2, 6INSERM U1011, European Genomic Institute for
Diabetes (EGID), Institute Pasteur de Lille, Lille, 7Université Pierre et Marie Curie, Hopital
Pitié Salpétrière, 8Insititute of Cardiometabolism and Nutrition (ICAN), INSERM, UMRS
938, Paris, France
Corresponding author’s email: Dean.Hum@Genfit.com
Introduction: Elafibranor (Ela) is in late stage clinical development for NASH. Through
its liver targeting and dual activation of PPARα and PPARδ in parenchymal and nonparenchymal cells, Ela has demonstrated preventive and curative effects in animal models
of NASH and fibrosis (Staels et al). Consistent with these preclinical studies, a randomized,
placebo controlled trial (GOLDEN-505) has shown efficacy of a 1-year treatment with Ela
at 120 mg/d on the primary outcome of resolution of NASH without worsening of fibrosis
in non-diabetic and diabetic patients with NAS≥4 at inclusion (Raziu et al). This effect
was seen mainly on improvement in hepatocyte ballooning and lobular inflammation, two
histopathologic lesions associated with fibrosis evolution in NASH. Accordingly, most
patients who resolved NASH under Ela treatment also had a significant reduction of liver
fibrosis. Histological improvement was associated with improvement in hepatic markers
(ALT, AST, GGT and ALP) and non-invasive scores of NASH and fibrosis. Confirming
previous results in patients with metabolic disorders (Cariou et al), GOLDEN505 showed
an improvement of the cardiometabolic risk profile with concomitant improvement of
plasma lipids (reduction of triglycerides, total-C, LDL-C and increased HDL-C), insulinsensitivity and glucose homeostasis (notably further decrease in HbA1c in diabetics), and
inflammation/fibrosis markers. Post-hoc analyses suggest that a more marked improvement
151
ePOSTER ABSTRACTS
1
in insulin resistance and glucose homeostasis is associated with the histological efficacy in
patients with moderate to high NASH severity at baseline (NAS≥6), whereas there was
no apparent relationship between changes in plasma lipids, baseline NASH severity and
histological changes. In all clinical trials, Ela was safe and well tolerated without causing
serious adverse effects. Overall, Ela has an ideal efficacy:safety profile to improve liver
histology and outcomes while also providing a benefit on cardiovascular risk. Ela is being
assessed in a phase 3 trial, RESOLVE-IT, which will recruit approximately 2000 patients
with NASH and fibrosis (NAS≥4 and F2-F3). An interim analysis on the first ~1000
patients after 72 weeks will support approval based on efficacy on a histological primary
end-point.
ePOSTER ABSTRACTS
V.
B.
B.
B.
Ratziu et al. Gastroenterology (2016), doi: 10.1053/j.gastro.2016.01.038
Staels et al. Hepatology (2013) 58:1941-52
Cariou et al. Diab. Care (2011) 34:2008-14
Cariou et al. Diab. Care (2013) 36:2923-30
152
Screen 2: YI-MR-169
Rocío Gallego-Durán* 1, 2, Rocío Aller3, Helena Pastor-Ramírez1, 2, Carmelo
García-Monzón4, Jesús Bañales5, María Teresa Arias-Loste6, Eduardo VilarGómez1, 2, Víctor Aguilar-Urbano7, María Luisa García-Torres8, Jose Luis
Calleja9, Jose Luis Olcoz10, Javier Salmerón11, Salvador Benlloch12, Javier GarcíaSamaniego13, Moisés Diago14, María Jesús Pareja-Megía15, Javier Ampuero1, 2,
Miguel Fernández-Bermejo16, Judith Gómez-Camarero17, Raúl Jesús Andrade18,
Pamela Estévez19, Conrado Fernández-Rodríguez20, Lourdes Grande21, Jose
María Moreno-Planas22, Marta Maraver23, Agustín Albillos24, Manuel RomeroGómez1, 2 on behalf of HEPAmet Registry
1
Inter-Centre Unit of Digestive Diseases & CIBERehd, Virgen Macarena – Virgen del Rocío
University Hospitals, 2Instituto de Biomedicina de Sevilla (IBiS), Sevilla, 3Gastroenterology and
Hepatology Department, Clínico de Valladolid University Hospital, Valladolid, 4Liver Research
Unit and CIBERehd, University Hospital Santa Cristina , Madrid, 5Biodonostia Research
Institute, San Sebastián, 6Gastroenterology and Hepatology Department,, Marqués de Valdecilla
University Hospital & IDIVAL, Santander, 7Gastroenterology and Hepatology Department,
Costa del Sol Hospital, Málaga, 8Gastroenterology and Hepatology Department, Clínico de
Valencia University Hospital, Valencia, 9Gastroenterology and Hepatology Department, Puerta
de Hierro Hospital, Madrid, 10Gastroenterology and Hepatology Department, León University
Hospital, León, 11Gastroenterology and Hepatology Department, San Cecilio University
Hospital, Granada, 12Gastroenterology and Hepatology Department , La Fe University Hospital,
Valencia, 13Gastroenterology and Hepatology Department , La Paz University Hospital, Madrid,
14
Gastroenterology and Hepatology Department , General de Valencia University Hospital,
Valencia, 15Pathology Unit,Valme University Hospital, Sevilla, 16Gastroenterology and Hepatology
Department , San Pedro de Alcántara Hospital, Cáceres, 17Gastroenterology and Hepatology
Department , Burgos University Hospital, Burgos, 18Inter-Centre Unit of Digestive Diseases &
CIBERehd ,Virgen de laVictoria University Hospital, Málaga, 19Gastroenterology and Hepatology
Department, Meixoeiro Hospital,Vigo, 20Gastroenterology and Hepatology Department, Fundación
Alcorcón University Hospital, Madrid, 21Gastroenterology and Hepatology Department, Valme
University Hospital, Sevilla, 22Gastroenterology and Hepatology Department, Albacete University
Hospital, Albacete, 23Gastroenterology and Hepatology Department, , Juan Ramón Jiménez
University Hospital, Huelva, 24Gastroenterology and Hepatology Department, Ramón y Cajal
University Hospital, Madrid, Spain
Corresponding author’s email: rociogallegoduran@gmail.com
153
ePOSTER ABSTRACTS
VALIDATION OF NON-INVASIVE METHODS FOR
ADVANCED FIBROSIS DETECTION IN NAFLD PATIENTS
Aims: The main aim of this study was to compare the usefulness of NAFLD fibrosis score
(NFS) and FIB-4 methods in predicting advanced fibrosis in a cohort of NAFLD patients.
ePOSTER ABSTRACTS
Material and Methods: HEPAmet Registry, endorsed by Spanish Association for the
Study of the Liver (AEEH), is a multicentric monitored patient database, including
Spanish biopsy-proven NAFLD patients that fulfilled at least 2/4 inclusion criteria
(steatosis defined by ultrasound (US); ALT or AST above upper limits of normality (ULN);
HOMA-IR > 4 or Metabolic syndrome (MetS) defined by ATPIII criteria). Demographic,
anthropometric, concomitant diseases and medication, US, transient elastography,
analytical and anatomopathological data were recorded. Area under receiver operating
curve (AUROC) and predictive values of these non-invasive scores were determined for
advanced fibrosis (F3-F4) detection according to Kleiner Score. Statistical analysis was
performed using SPSS 22.0 software.
Results: This interim analysis included 693 biopsy-diagnosed NAFLD patients, 42.6%
(295/693) men, mean age 47.4+12 years. Of them, 53% displayed metabolic syndrome,
71.6% overweight (defined as BMI>25 kg/m2) and 27.2% suffered from type 2 diabetes
mellitus. NASH was identified on 54.8% (380/693) of patients, and 11.5% (80/693)
showed advanced fibrosis. Correlation coefficient between NFS and FIB4 scores respect
to advanced fibrosis was 0.33 (p<0.01) and 0.29 (p<0.01) respectively. Likewise, it
was obtained a correlation rate between them of 0.55 (p<0.01). 34.1% (236/693) and
15%(104/693) of patients were classified as indeterminate for NFS and FIB4 respectively.
Both methods reached a similar AUROC for advanced fibrosis prediction, NFS: 0.75
[CI95% 0.69-0.81] and FIB-4: 0.74 [CI95% 0.67-0.81]. NPV for FIB4 cut-off ≤1.45
was 93.7% (536/572) and for NFS threshold ≤-1.45 was 95% (363/382). Nevertheless,
using highest cutt-offs for both methods (FIB4 ≥ 3.25 and NFS≥ 0.67), PPV were 58.8%
(10/80) and 34.6% (27/100) respectively.
Conclusions: Both models showed similar diagnostic efficacies for advanced fibrosis
prediction, however NFS classified a higher proportion as indeterminate. PPVs were lower
due in part to a low prevalence of advanced fibrosis in our cohort.
154
Screen 3: YI-MR-144
ARE FEMALES REALLY MORE PROTECTED THAN MALES
IN THE PROGRESSION FROM NAFLD TO NASH?
Veronica Marin* 1, Silvia Gazzin1, Matteo Dal Ben1, Alan Raseni2, Claudio
Tiribelli1, 3, Natalia Rosso1
1
ITALIAN LIVER FOUNDATION, 2S.C. Laboratorio Analisi Cliniche, IRCCS Burlo
Garofalo, 3Department of medical sciences, University of Trieste, Trieste, Italy
Corresponding author’s email: veronica.marin@csf.units.it
Aims: The aim of this study is to assess if females are really more protected than males in
the pathogenesis of NAFLD and in the progression to NASH.
Material and Methods: Males and females C57BL/6 mice, immediately after weaning
were fed ad-libitum with control (CTRL) or High-Fat High-Carbohydrate diet (HFHCD)
for 16 weeks. Body-weight, glycaemia, insulinemia, triglycerides, total cholesterol, HDL-C,
LDL-C, ALT and liver histology were screened every 4 weeks. Gene expression analysis
and oxidative stress (MDA, GSH/GSSG) were also assessed.
Results: Soon after the 1st week, HFHCD induced a significant bodyweight gain in both
genders. Males, after 4 weeks presented hyperplasia of epididymal fat-pads and after week
12th, a significant hepatomegaly, with alteration of glycaemia, insulinemia, lipid profile
and ALT. Interestingly, comparable body/blood changes were observed in females only
at the 16th week. Despite these differences, liver histology showed in both sexes a mixed
macro-microvesicular steatosis increasing steadily after 8 weeks. DGAT2 gene expression
was enhanced in both genders. Inflammatory foci were observed only in males, confirmed
also by an increase in MCP-1 and TNF-α gene expression. Conversely, females had no
signs of inflammation but rather presented an enhanced lipid peroxidation (MDA) and
a reduction of GSH/GSSG ratio, confirming an oxidative stress (absent in males). Of
notice, both sexes developed progressive fibrosis from week 8th, which rose steadily over
the time (confirmed by the up-regulation of Col1A1 and αSMA mRNA expression, and
the enhanced extracellular collagen deposition -Sirius Red staining).
Conclusions: Our data highlight a strong gender difference in the onset of liver damage
in NAFLD/NASH. Even if the outcome (fibrosis) is similar in both sexes, from blood
155
ePOSTER ABSTRACTS
Introduction: It is well accepted that NASH is more common in men than in women.
parameters analysis females show no evident signs of injury until a late stage. Translating in
clinical practice the lack of alteration in liver tests observed in females might be worrisome,
increasing the number of potential undiagnosed NASH cases in women. This finding
opens a relevant dilemma: are females really less predisposed to develop steatohepatitis
during their life or is just a lack of the standard symptoms for the diagnosis?
ePOSTER ABSTRACTS
156
Screen 4: MR-147
REGENERATE: A PHASE 3, DOUBLE-BLIND,
RANDOMIZED, PLACEBO-CONTROLLED MULTICENTER
STUDY OF OBETICHOLIC ACID THERAPY FOR
NONALCOHOLIC STEATOHEPATITIS
Corresponding author’s email: zobair.younossi@inova.org
Introduction: Nonalcoholic Steatohepatitis (NASH) is a slowly progressive chronic liver
disease without approved therapies. Patients with NASH and fibrosis are at high risk of
increased mortality. Obeticholic Acid (OCA) is a selective and potent farnesoid X receptor
(FXR) agonist, that has been shown to improve liver histology, including NAFLD activity
score (NAS) and fibrosis, in a Phase 2 clinical trial (FLINT). Furthermore in FLINT,
OCA treated patients had significant improvements in select liver biochemistries, markers
of inflammation, and select cardiometabolic parameters. The ongoing, randomized, global,
Phase 3 study REGENERATE, will further evaluate the effect of OCA on liver histology
and clinical outcomes in patients with biopsy-confirmed NASH with stage 2-3 fibrosis.
Material and Methods: 2065 patients will be randomized 1:1:1 to 10 mg OCA, 25
mg OCA or placebo (Figure), each added to standard of care. An interim analysis at 18
months will evaluate the effect of OCA on liver histology. Total study duration is driven
by time required to accrue a total of 264 outcome events and is estimated to be ~6 years.
Safety assessments will include adverse events (AEs), adjudicated cardiovascular events,
and hepatic events as well as laboratory assessments. The effect of OCA on NASH and
fibrosis severity will also be assessed by multiple noninvasive methods (FIB-4, APRI,
transient elastography, magnetic resonance elastography, etc.).
Results: The co-primary liver histology endpoints at 18 months include: (I) improvement
in fibrosis by ≥1 stage with no worsening of NASH and (II) resolution of NASH with
no worsening in fibrosis stage. Further, confirmation of clinical benefit of OCA will be
assessed at the end of the study by comparing the time to first occurrence of any of the
157
ePOSTER ABSTRACTS
Vlad Ratziu* 1, Arun J. Sanyal2, Leigh MacConell3, Reshma Shringarpure3, Tonya
Marmon3, David Shapiro3, Zobair M. Younossi4, 5
1
Hepatology, Hopital Pitie Salpetriere, Paris, France, 2Virginia Commonwealth University,
Richmond, 3Intercept Pharmaceuticals, Inc., San Diego, 4Center for Liver Disease, Inova Fairfax
Hospital,, 5Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls
Church, United States
following adjudicated events: histological progression to cirrhosis; uncontrolled ascites;
hospitalization for: variceal bleed, hepatic encephalopathy or spontaneous bacterial
peritonitis; hepatocellular carcinoma; liver transplant or eligibility for liver transplant
(defined by model for end stage liver disease (MELD) score ≥15); and death.
Conclusions: REGENERATE is the first pivotal study in NASH, designed in conjunction
with FDA and meant to support approval of OCA for NASH with fibrosis. This robust
Phase 3 study is designed to evaluate the effect of OCA on liver histology and effects on
progression to cirrhosis, liver-related clinical outcomes and mortality.
ePOSTER ABSTRACTS
Figure:
Disclosure of Interest: V. Ratziu: Consultant: Conflict with: Tobira, Intercept, Exalenz,
Sanofi-Synthelabo, Boehringer-Ingelheim, Other: Conflict with: GalMed, Abbott, Genfit,
Enterome, Gilead, A. Sanyal: Grant: Conflict with: Salix, Genentech, Intercept, Ikaria,
Takeda, GalMed, Novartis, Gilead, Tobira, Consultant: Conflict with: Salix, Immuron,
Exhalenz, Nimbus, Genentech, Echosens, Takeda, Merck, Enanta, Zafgen, JD Pharma,
Islet, Sciences, Other: Conflict with: Bristol Myers, Gilead, Genfit, Abbott, Ikaria,
Exhalenz, UpToDate, Elsevier, L. MacConell: Stockholder: Conflict with: Intercept
Pharmaceuticals, Inc., Employee: Conflict with: Intercept Pharmaceuticals, Inc., R.
Shringarpure: Stockholder: Conflict with: Intercept Pharmaceuticals, Inc., Employee:
Conflict with: Intercept Pharmaceuticals, Inc., T. Marmon: Stockholder: Conflict with:
Intercept Pharmaceuticals, Inc., Employee: Conflict with: Intercept Pharmaceuticals,
Inc., D. Shapiro: Stockholder: Conflict with: Intercept Pharmaceuticals, Inc., Employee:
Conflict with: Intercept Pharmaceuticals, Inc., Z. Younossi: Consultant: Conflict with:
Gilead, Enterome, Coneatus, Other: Conflict with: Salix, Janssen, Vertex
158
Screen 5: MR-180
SARCOPENIA IS AN INDEPENDENT RISK FACTOR FOR
BIOPSY-PROVEN NON-ALCOHOLIC STEATOHEPATITIS
IN A KOREAN POPULATION
Won Kim* 1, Bo Kyung Koo2, Sae Kyung Joo1, Jung Ho Kim3, Dong Hyun Lee1, Yong
Jin Jung1, Donghee Kim4
1
Division of Gastroenterology and Hepatology, 2Division of Endocrinology, 3Department of
Pathology, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea, South,
4
Division of Gastroenterology and Hepatology, Stanford University, Stanford, United States
Introduction: Non-alcoholic fatty liver disease (NAFLD) has been frequently found in
the non-obese as well as the obese. Furthermore, Asians have a relatively higher prevalence
of NAFLD despite lower body mass index (BMI).
Aims: We explored whether sarcopenia, independent of total body fat mass, might affect
the histological severity of NAFLD including non-alcoholic steatohepatitis (NASH) and
significant fibrosis in a histologically confirmed NAFLD registry cohort.
Material and Methods: NAFLD was categorized as non-NASH NAFL and NASH
according to the NASH CRN histologic scoring system. To estimate the appendicular
skeletal muscle mass (ASM) and total fat mass, impedance for each segment, including
the four limbs and trunk, was measured using multi-frequency bioelectrical impedance
analysis. Sarcopenia was defined by either sarcopenic index (SI, ASM/height2) or ASM
divided by body weight (ASM%, ASM/Bwt).
Results: Among 309 subjects (145 men and 164 women), 39.8%, 37.9%, and 22.3%
were classified as NASH, non-NASH NAFL, or non-NAFLD, respectively. Subjects with
sarcopenia had a higher BMI (P<0.001), waist circumference (P<0.001), and homeostasis
model assessment of insulin resistance (HOMA-IR) (P=0.004) and a lower cholesterol
level (P=0.029) and more frequently hypertension (P<0.001) compared to those without
sarcopenia. ASM% was inversely correlated with lobular inflammation (r=-0.134,
P=0.029), ballooning (r=-0.148, P=0.013), and fibrosis stages (r=-0.198, P=0.001), but
not steatosis (r=-0.052, P=0.384). In logistic regression analyses adjusted for age and
gender, sarcopenia was an independent risk factor for NAFLD (odds ratio of SI, 2.60;
95% confidence interval, 1.05–6.43; P=0.039 and OR of ASM%, 3.81; 95% CI, 1.57–
159
ePOSTER ABSTRACTS
Corresponding author’s email: wonshiri@yahoo.com
9.25; P=0.033); however, sarcopenia was no more an independent risk factor for NAFLD
in multivariate analysis. On the contrary, sarcopenia was an independent risk factor for
NASH in multivariate analysis even after adjustment for age, gender, BMI, smoking,
hypertension, diabetes, cholesterol, triglycerides, HDL-cholesterol, and HOMA-IR (OR
of ASM%, 1.97; 95% CI, 1.01–3.87; P=0.048). Moreover, sarcopenia was an independent
risk factor for significant fibrosis in multivariate analysis adjusted for age, gender, BMI,
smoking, hypertension, diabetes, triglycerides, platelet, albumin, and HOMA-IR (OR of
SI, 2.24; 95% CI, 1.06–4.73; P=0.034 and OR of ASM%, 2.05; 95% CI, 1.01–4.16;
P=0.048).
Conclusions: Sarcopenia was significantly associated with the histological severity of
NAFLD in a Korean population. Further studies are warranted to validate these findings
in other ethnic populations with NAFLD.
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160
Screen 6: YI-MR-120
LEAN VERSUS OVERWEIGHT/OBESE NONDIABETIC
NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) –
A CLINICOPATHOLOGICAL COMPARATIVE STUDY
Sanchit Budhiraja* 1, Ashok K. Jain1, Vinod K. Dixit1, Sunit K. Shukla1, Pankaj K.
Asati1, Manish K. Tripathi1
1
Gastroenterology, Institute of Medical Sciences, Banaras Hindu University,Varanasi, India
Introduction: Nonalcoholic fatty liver disease (NAFLD) refers to the accumulation of
fat (mainly triglycerides) in hepatocytes that arises due to insulin resistance. A fraction of
NAFLD patients (especially Asians) do not meet weight criteria of obesity. Most low BMI
NAFLD patients have central obesity and are metabolically obese, which includes findings
of insulin resistance.
Aims: The aim of this study was to compare the clinicopathological and biochemical
profile of lean and overweight/obese NAFLD patients with a special emphasis on insulin
resistance.
Material and Methods: This prospective study was conducted in biopsy proven NAFLD
patients aged 18 to 75 years in a university hospital in India. On the basis of Asia Pacific
criteria, the patients were divided into lean (BMI <22.99 kg/m2) and overweight/obese
(BMI ≥23 kg/m2) NAFLD. Histopathological NASH was defined by NAS (NAFLD
activity score) ≥5. Patients with other liver diseases (hepatitis B, C or autoimmune liver
disease) and diabetes mellitus were excluded.
Results: Among 88 NAFLD patients, 29 (33%) and 59 (67%) were in the lean and
overweight/obese group respectively. The mean age was 33.31 years which was similar in
both the groups. Metabolic syndrome was present in 60 (68.2 %) patients. In the lean and
overweight/obese group, 55.2% and 74.6% patients had metabolic syndrome respectively
(p 0.06). In the lean group, the mean weight (62.76kg, p<0.0001), height (1.71m,
p<0.0001), waist circumference (83cm, p<0.0001), hip circumference (89.14cm, p 0.003),
waist:hip ratio(0.93, p<0.0001) was significantly lower as compared to overweight/obese
group (the respective values being 71.25kg, 1.66m, 92.47cm, 94.90cm,0.97). The median
triglyceride level (190mg/dl vs 147 mg/dl; p 0.018) and mean VLDL level (50.40mg/dl vs
33.99mg/dl; p<0.0001) was significantly higher in the lean NAFLD group. However, the
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median levels of fasting serum insulin (5.57µU/ml vs 10.83µU/ml; p 0.009) and HOMAIR (1.37 vs 2.62; p 0.010) were significantly lower in the lean NAFLD group. NASH was
present in 59 patients (67%). 75.9% of the lean patients and 62.7% of overweight/obese
patients had NASH (p 0.22). There was no difference in the level of ALT, AST: ALT ratio,
HDL or total cholesterol in the two groups.
Conclusions: Lean NAFLD patients had lower mean weight, height, waist:hip ratio.
Dyslipidemia was more common in the lean NAFLD group whereas insulin resistance
was less in lean NAFLD group. Metabolic syndrome and NASH were equally present in
both the groups irrespective of BMI.
ePOSTER ABSTRACTS
Figure:
162
Saturday 14 May 2016
Screen 1: MR-125
Priscila B. Campos1, Claudia P. Oliveira* 1, Luciana Kikuchi1, Jose Tadeu Stefano1,
Aline L. Chagas1, Paulo Herman2, Luiz Augusto C. D’Albuquerque2, Mário R.
Alvares-da-Silva3, Flair Jose Carrilho1, Venâncio A. F. Alves4
1
Gastroenterology (LIM-07), 2Gastroenterology (LIM-37), University of São Paulo School of
Medicine, SAO PAULO, 3Gastroenterology, Hospital de Clinicas de Porto Alegre, Universidade
Federal do Rio Grande do Sul, PORTO ALEGRE, 4Pathology (LIM-14), University of São
Paulo School of Medicine, SAO PAULO, Brazil
Introduction: Hepatocellular carcinoma (HCC) is the most common primary malignancy
of the liver. The raise in incidence has been ascribed to the increase in obesity, diabetes and
non-alcoholic fat liver disease (NAFLD).
Aims: The aim of this study is to evaluate the pathological and clinical aspects in patients
with HCC secondary to NAFLD.
Material and Methods: We evaluated 28 HCC specimens from 18 patients diagnosed
with NAFLD undergoing liver resection (10 patients) or liver transplantation (8 patients)
from 2005 to 2015. We compared histological features, clinical aspects, imaging findings,
demographic and biochemical data, as well as their survival.
Results: We analyzed 11 patients with cirrhosis and 7 patients without cirrhosis, and from
them, 28 HCC nodules, 8 (28%) were developed in patients without cirrhosis (NASH
staging: F2: 5pts, F3=2pts), while 20 (72%) nodules were developed in patients with
cirrhosis (8 F4A x 11 F4B, x 1F4C according Laennec Stage). Ages ranged from 58 to
77 years and 13 patients were male (72%). Thirteen patients (72%) had diabetes mellitus,
13 patients (72%) had arterial hypertension, and 14 patients (77%) had BMI above 25.
Only 6 patients (33%) had dyslipidemia. HCC occurred in 7 patients Child A, 4 Child
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HEPATOCELLULAR CARCINOMA IN NON-ALCOHOLIC
STEATOHEPATITIS (NASH) – HISTOPATHOLOGICAL
ASPECTS
B and in 7 patients without cirrhosis. As the performance status, 16 patients had a good
performance status (PS) with Eastern Cooperative Oncology Group (ECOG) = 0. Alphafetoprotein level was normal in 12 patients. The dimensions of the HCC nodules ranged
from 0.8 cm (single nodule) to 15cm in diameter and the predominant macroscopic
pattern was nodular (93%). The predominant microscopic pattern was trabecular (46%).
Major histological features of HCC are depicted at Table 1. Of all the patients, 11 evolved
to death, 8 cases in patients who underwent resection and 3 cases that underwent liver
transplantation. The causes of death were primary non function, infection, acute rejection
and palliative care caused by the evolution of HCC.
ePOSTER ABSTRACTS
Conclusions: HCC secondary to NAFLD can arise in patients without cirrhosis with
normal level of alpha-fetoprotein. Histological markers of “steato-hepatitic HCC” and
high architectural and nuclear degrees (g.3) were prevalent. The survival rate was low,
especially in patients who underwent resection, despite the good performance status.
Figure:
164
Screen 2: YI-MR-121
LIVER STIFFNESS VALUES MEASURED BY SHEAR WAVE
ELASTOGRAPHY DEPENDING ON TRANSAMINASE
ACTIVITY IN PATIENTS WITH NONALCOHOLIC FATTY
LIVER DISEASE
Nazarii Kobyliak* 1, Oleg Dynnyk 2, Galyna Mykhalchyshyn1, Petro Bodnar1
Endocrinology, Bogomolets National Medical University, 2Bogomolets Institute of physiology of
the Ukrainian National Academy of Sciences, Kyiv, Ukraine
1
Introduction: Shear Wave Elastography (SWE) is one of the most promising non-invasive
methods for diagnosis of chronic diffuse liver disease. Given its widespread introduction
into clinical practice, more attention is paid to the group of scientists from around the
world, to the study of factors that can affect the measurement and its diagnostic accuracy.
Aims: The aim of our study was to estimate changes of liver stiffness measured by SWE
and evaluation of factors that may affect its value depending on transaminase activity in
patients with NAFLD.
Material and Methods: We studies 122 patients with T2D who were diagnosed with
fatty liver by abdominal ultrasonography. All patients divided by us on 3 groups. The
control group (n=27) included 34 patients with TD2 without NAFLD. In the other two
groups we identified patients with NAFLD and normal (n=62) or elevated (n=33) level of
transaminases. We performed 10 valid liver stiffness measurement (LSM) in every patient,
and a median value was calculated, the result being measured in kPa.
Results: LSM were significantly higher on 44.6% in the increased ALT group and on
32.3% in patients with normal ALT as compared with control group (p<0.001). Also
we observed significant higher on 10% LSM in patients with NAFLD and elevated
transaminase activity compared to normal ALT group (p=0.003). In univariate correlation
analysis insulin resistance by HOMA-IR was significantly associated with LSM in all
studies groups. In patients with NAFLD independent from transaminase activity LSM
were significantly correlated with anthropometric parameters. Maximum strength of
correlation in patients of normal ALT group was observed between LSM and BMI (r
= 0.651, p<0.001), therefore in elevated transaminase group for waist circumference (r
=0.634, p<0.001). LSM were significantly correlated with ALT (r=-0.483, p=0.004)
165
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and AST (r=0.499, p=0.003) only in patients with it elevation. Step-wise multiple linear
regression analyses demonstrated that in NAFLD patients independent predictors of
LSM increasing were HOMA-IR, waist circumference, ALT (adjusted R2 0.582) and AST
(adjusted R2 0.541) respectively.
Conclusions: Patients with NAFLD and especially with elevated transaminases have
significantly higher liver stiffness values measured by SWE as compared with control. Use
both univariate correlation and multiple linear regression analysis showed that independent
determinants associated with increasing of LSM were degree of insulin resistance, obesity
and transaminase activity.
ePOSTER ABSTRACTS
166
Screen 3: YI-MR-173
LYSOSOMAL ACID LIPASE ACTIVITY IS ASSOCIATED
WITH AST TO PLATELET RATIO INDEX IN PATIENTS
WITH NON-ALCOHOLIC FATTY LIVER DISEASE
Francesco Baratta* 1, Daniele Pastori1, Licia Polimeni1, Giulia Tozzi2, Francesco
Violi1, Maria Del Ben1, Francesco Angelico1
1
SPAIENZA- UNIVERSITÀ DI ROMA, 2Children’s Hospital and Research Institute
“Bambino Gesù, roma, Italy
Introduction: Lysosomal Acid Lipase (LAL) is a key enzyme in lipid metabolism. Recent
evidence suggested that a reduced LAL activity may be found in patients with nonalcoholic fatty liver disease (NAFLD).
Aims: To investigate the relationship between LAL activity and non invasive markers of
liver fibrosis.
Material and Methods: We included 280 consecutive patients with ultrasonography
(us) evidence of NAFLD. Severity of NAFLD was classified according to Hamaguchi’s
criteria. As marker of liver fibrosis, the AST to platelet ratio index (APRI) was calculated
for each patient. LAL activity was assessed on dried blood spot with Lalistat 2 method.
Results: Mean age was 55,2 ± 12,3 year and 35,6% were women. 24,3% patients had
mild, 41% moderate and 35,7% severe US steatosis. Mean HOMA index was 4,5 ± 3,3.
Mean LAL activity was 0,93 ± 0,42 nmol/spot/h. Mean APRI was 0.26 ± 0.18. APRI
was correlated with LAL activity (r=-0.245, p<0.001), HOMA index (r=0.154, p=0.01),
Hamaguchi score (r=0.213, p<0.001). At multivariable linear regression analysis APRI
was indipendently correlated with LAL activity (B: – 0,199; p=0.001), Hamaguchi score
(B: 0,128; p<0.05), HOMA index (B: 0,164; p=0.01).Mean age was 55,2 ± 12,3 year and
35,6% were women. 24,3% patients had mild, 41% moderate and 35,7% severe steatosis.
Mean HOMA index was 4,5 ± 3,3. Mean LAL activity was 0,93 ± 0,42 nmol/spot/h.
Mean APRI was 0.26 ± 0.18. APRI was correlated with LAL activity (r=-0.245, p<0.001),
HOMA index (r=0.154, p=0.01), Hamaguchi score (r=0.213, p<0.001). At multivariable
linear regression analysis APRI was indipendently correlated with LAL activity (B: -0,199;
p=0.001), Hamaguchi score (B: 0,128; p<0.05), HOMA index (B: 0,164; p=0.01).
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Corresponding author’s email: francesco.baratta@uniroma1.it
Conclusions: We found that in patients with NAFLD, LAL activity was associated with
the severity of liver fibrosis, as assessed by the APRI index. Further study are needed to
confirm the association between reduced LAL activity and histological severity of liver
fibrosis.
ePOSTER ABSTRACTS
168
Screen 4: MR-137
NON-ALCOHOLIC FATTY LIVER DISEASE PATIENT’S
PROFILE IN LATVIA
Jekaterina Kucina* 1, Ieva Tolmane2, Ivars Tolmanis3, Baiba Rozentale1
at Riga East Clinical University hospitals, stationary “Infectology Center of Latvia”, Riga,
Latvia, 2Hepatology, at Riga East Clinical University hospitals, stationary “Infectology Center of
Latvia”, 3Digestive Diseases Centre ‘’GASTRO’’, Riga, Latvia
1
Introduction: Non-alcoholic fatty liver disease is becoming a widespread liver disease in
highly developed countries leading to liver insufficiency, which in turn diminishes patients’
quality of life, as well as enhances the development of physical incapacity.
Aims: To identify the profile of patients with non-alcoholic fatty liver disease in Latvia.
Material and Methods: The study was carried out both retrospectively and prospectively
at Riga East Clinical University hospitals clinic “Infectology Center of Latvia”. The study
included 75 patients with morphologically established non-alcoholic fatty liver disease
(NAFLD) or steatohepatitis (NASH). Patients were interviewed by telephone with a
specially designed questionnaire, which included information about lifestyle, physical
activities and health. Analysis of medical documentation was performed.
Results: Among the 75 patients with NAFLD, 45.3% (n=34) of patients were female and
54.7% (n=41) were male. Average age was 47.6 ± 11.0 years. It was recognized that 46.7%
(n=35) of patients with NAFLD were obese (body mass index (BMI) ≥30.0 kg/m2) and
34.7% (n=26) – overweight (BMI 25.0 – 29.9 kg/m2). At the time of diagnosis, patients
already had serious morphological changes in liver – 44.0% (n=33) had severe stage steatosis
61.3% (n=46) – mixed type and 58.6% (n=44) had inflammatory cell infiltration. Elevated
alanine aminotransferase activity was detected in 86.6% (n=65) of patients, aspartate
aminotransferase activity – in 89.3% (n=67) of cases. At least one potentially dangerous
comorbidity occurs in 56.0% (n=42) of patients. Respondents mainly had type 2 diabetes
mellitus, it occurred in 20.0% (n=15) of patients, hypercholesterolemia – in 48.0% (n=36)
of patients, arterial hypertension – in 37.3% (n=28) of patients. Physically active 7 times a
week were 32.0% (n=24) of patients, 2 – 3 times a week – 20.0% (n=15) of patients, 1 – 2
times a week – 32.0% (n=24) of patients. Patients were more often engaged in physical
activities 1 – 3 times a week.
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ePOSTER ABSTRACTS
Corresponding author’s email: cerini4@inbox.lv
Conclusions: Patients with non-alcoholic fatty liver disease in Latvia are mostly middleaged people of both genders with predominantly sedentary lifestyle. Most of them have
obesity and diseases associated with non-alcoholic fatty liver disease.
ePOSTER ABSTRACTS
170
Screen 5: YI-MR-128
RESVERATROL IMPROVES HEPATIC NITRIC OXIDE
SYNTHESIS AND ATTENUATING ENDOTHELIAL
DYSFUNCTION IN NON-ALCOHOLIC FATTY LIVER
DISEASE
Balasubramaniyan Vairappan* 1, Sundhar Mohandas1
Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research,
Pondicherry, India
1
Introduction: Endothelial nitric oxide synthase (eNOS) deficient mice have shown to
increase early stage of non-alcoholic statohepatitis (NASH) pathogenesis. Resveratrol
treatment has been suggested to bear protective effects on liver injury of various aetiologies.
Indeed, the role of resveratrol in modulating hepatic nitric oxide (NO) synthesis and
related molecular mechanism involved in non-alcoholic fatty liver disease (NAFLD)
remains unidentified.
Aims: The purpose of this study was to evaluate the effect of resveratrol on high-fat diet
(HFD) induced endothelial dysfunction and associated fatty liver disease in mice.
Material and Methods: CD-1 mice (n=10/group) were studied for 90 days. Three
groups were studied. 1) control, 2) HFD (Dyets Inc. USA) and 3) HFD + resveratrol
(Sigma, USA; 10mg/kg b.w. daily by gastric lavage, for 7 days)
Results: Compared to naive mice, HFD supplementation significantly (p<0.001)
increased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST),
interleukin (IL)-1β, tumour necrosis factor (TNF) α and asymmetric dimethylarginine
(ADMA). Resveratrol treatment to HFD treated mice shows significantly (p<0.05)
reduced the above parameters. Furthermore, HFD fed mice show significantly (p<0.05)
increased hepatic protein expression of eNOS, iNOS and neuregulin-1 (NRG-1) when
compared to control. Resveratrol treatment to HFD fed mice significantly decreased
the expression of eNOS and iNOS but NRG-1 expression was unaltered. Resveratrol
treatment significantly (P<0.05) increased hepatic NO levels in HFD fed mice.
Conclusions: Our study is the first indication of evidence that the significant improvement
of NO and decreased NOS inhibitor by resveratrol in NAFLD and provide a future
therapeutic approach for NAFLD patients with endothelial dysfunction.
171
ePOSTER ABSTRACTS
Corresponding author’s email: balamaniyan@gmail.com
Screen 6: YI-MR-179
SPLEEN DIMENSIONS EVALUATED BY ULTRASOUND
ARE INVERSELY ASSOCIATED WITH LYSOSOMAL ACID
LIPASE ACTIVITY IN PATIENTS WITH NON-ALCOHOLIC
FATTY LIVER DISEASE
ePOSTER ABSTRACTS
Licia Polimeni* 1, Daniele Pastori1, Francesco Baratta1, Giulia Tozzi2, Fiorella
Piemonte2, Francesco Violi1, Francesco Angelico3, Maria Del Ben1
1
Department of Internal Medicine and Medical Specialties, Sapienza University, 2Unit for
Neuromuscular and Neurodegenerative Diseases, Children’s Hospital and Research Institute
“Bambino Gesù”, 3Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
Corresponding author’s email: licia.polimeni@uniroma1.it
Introduction: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic
liver disease. Lysosomal Acid Lipase (LAL) is a key enzyme in lipid metabolism and a
reduction of its activity may contribute to intracellular lipid accumulation in adult NAFLD.
Splenomegaly is a typical feature of both Wolman Syndrome and Cholesterol Ester Storage
Disease, the two genetic forms of LAL deficiency. A less severe reduction of LAL activity
has been suggested as an under-recognized cause of NAFLD. Ultrasonography (US)
determination of spleen dimensions is accurate.
Aims: The aim of this study was to determine if spleen biometry evaluated by US is
associated with LAL activity in a population of NAFLD patients.
Material and Methods: The study has been performed in 252 consecutive patients with
a liver US positive for NAFLD. Spleen longitudinal diameter and area were measured
during US. Splenomegaly was defined as a spleen area >45 cm2 and /or longitudinal
diameter >12 cm. LAL activity was measured with dried blood spot method (Lalistat2,
nmol/spot/h).
Results: Mean age was 55.1 ± 10.8 years and 38.1% of patients were women. US showed
splenomegaly in 33 patients (13,1%). From the lower to the highest quartile of spleen
area a significant decrease of LAL activity (0.95 vs 0.87 vs 0.77 vs 0.78 nmol/spot/h; p<
0.05), age (57.9 vs 56.2 vs 55.9 vs 55.1 years; p=0.001) and prevalence of statin users
(42.9 vs 41.4 vs 25.9 vs 19.6 %; p< 0.05) were found; on the contrary, BMI (28.3 vs
30.2 vs 31.2 vs 31.3 kg/m2; p< 0.01) and waist circumference (103.0 vs 105.0 vs 109.0 vs
172
107.0 cm; p< 0.01) significantly increased. LAL activity was significantly reduced in
subjects with splenomegaly than in those with normal spleen (0.71 vs 0.88 nmol/spot/h;
p<0.05). Linear bivariate regression analysis showed an inverse correlation between LAL
activity and spleen diameter (r=-0.16; p=0.01) and between LAL activity and spleen area
(r=-0.21; p=0.002). Multivariable linear regression analysis showed that age (p=0.002)
and LAL activity (p=0.01) were inversely associated with spleen area. In the same model,
BMI was directly associated to spleen area (p=0.003).
Conclusions: Our data show an inverse correlation between spleen dimensions evaluated
by US and LAL activity in a population of NAFLD patients. LAL activity is significantly
reduced in patients with splenomegaly than in those without. Our findings suggest that
spleen enlargement may be a feature of NAFLD patients with reduced LAL activity.
ePOSTER ABSTRACTS
Figure:
173
Saturday 14 May 2016
Screen 1: YI-MR-148
ePOSTER ABSTRACTS
CYTOKERATIN 18 FRAGMENT LEVEL IS A USEFUL
BIOMARKER IN PREDICTING STEATOSIS AND NASH BUT
NOT FIBROSIS
Sanchit Budhiraja* 1, 1, Ashok K. Jain1, Vinod K. Dixit1, Sunit K. Shukla1, Ashutosh
Jain2, Pankaj K. Asati1
1
Gastroenterology, 2Internal Medicine, Institute of Medical Sciences, Banaras Hindu University,
Varanasi, India
Introduction: Non alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease
(from minor steatosis to cirrhosis). Differentiating various stages of the disease is important
for therapeutic decision making and prognostic outcomes. The gold standard for the
diagnosis and staging of NAFLD is liver biopsy. Cytokeratin 18 fragment (CK18-F) levels
are a marker of hepatocyte apoptosis.
Aims: The aim of this study was to evaluate the role of serum cytokeratin 18 fragment
level (CK18-F) in predicting steatosis, significant NASH and fibrosis when compared to
the gold standard i.e liver biopsy.
Material and Methods: 88 patients with biopsy proven NAFLD were enrolled.
Histological findings were classified according to the NAFLD activity score (NAS)
proposed by the Nonalcoholic Steatohepatitis Clinical Research Network. In addition
to basic serum biochemical profile, serum CK18-F level was measured using M30
Apoptosense ELISA. Patients with diabetes mellitus and significant alcohol consumption
were excluded.
Results: Of the 88 patients, 59 (67%) had a NAS score of ≥5 suggesting histopathological
NASH and 33% patients had a score of <5. The mean level of CK18-F was significantly (p
0.024) higher (382±138 U/L) when significant steatosis (steatosis grade 2 or 3 on NAS)
was present as compared to when there was no/mild steatosis [(320±106.8 U/L) (steatosis
grade 0 or 1 on NAS scoring)]. There was a statistically significant difference in the level
174
of CK18-F in the group with NASH (NAS ≥5) when compared to the group with no
NASH (NAS<5). Even though the CK18-F level was higher in the group with fibrosis
grade 1-2 (381.9±139.22 U/L) as compared to the group with no fibrosis (334.6±117.05
U/L), this was not statistically significant (P 0.087). The AUROC for detection of NASH
for CK18-F was 0.82. A value of 304 U/L was 83.1 % sensitive and 82.8% specific for
the diagnosis of significant NASH. The AUROC for fibrosis detection using CK18-F was
0.62. A value of 325.5 was 62% sensitive and 61% specificity for diagnosis of fibrosis.
Conclusions: Measurement of serum CK18-F was useful in prediction of significant
steatosis and NASH but not fibrosis.
ePOSTER ABSTRACTS
Figure:
175
Screen 2: YI-MR-165
ePOSTER ABSTRACTS
NATURAL EXTRACTS ABOLISH LIPID ACCUMULATION
IN CELLS HARBOURING NON-FAVOURABLE PNPLA3
GENOTYPE
Ángela Rojas* 1, Jose A Del Campo2, Rosario Maldonado3, Paloma Gallego4, Juan
Bautista4, Manuel Romero-Gómez1
1
Unit for Clinical Management of Digestive Diseases and CIBERehd, Inter-Centre Unit of
Digestive Diseases and CIBERehd, Virgen Macarena – Virgen del Rocío University Hospitals,
INSTITUTE OF BIOMEDICINE OF SEVILLE, UNIVERSITY OF SEVILLE, SEVILLA,
SPAIN., 2Unit for Clinical Management of Digestive Diseases and CIBERehd, 3Clinical and
Experimental Pharmacology Research Unit, , Valme University Hospital, Sevilla, 4Biochemistry
and molecular biology, University of Seville, Seville, Spain
Corresponding author’s email: angela_rojas16@hotmail.com
Introduction: Hepatic steatosis is characterized by the excessive triglycerides accumulation
as lipid droplets in the cytoplasm of hepatocytes, which result from an imbalance between
uptake, synthesis, export, and oxidation of fatty acids. G-allele of PNPLA3 favours the
increase of triglycerides accumulation.
Aims: In this study, we examined the effect of quercetin and other natural extracts from
mushroom (M) and artichoke (A) on reducing lipid accumulation in hepatic cells.
Material and Methods: Hepatocytes (Huh7.5) were treated with oleic acid 1mM (OA)
containing with or without quercetin and soluble extracts to observe the lipid accumulation
by Oil Red O stain, the intracelular triglycerides (TG) concentration by Nile Red and the
LD size measured by Imaging Software cell^F. Reverse transcription polymerase chain
reaction (RT-PCR) was used to measure sterol regulatory element binding proteins-1
(SREBP-1), peroxisome proliferator-activated receptor (PPARα) and γ and cholesterol
acyltransferase (ACAT) expression. . PNPLA3 (rs738409) genotype was determined by
RT-PCR Taqman probes.
Results: Quercetin prevents stetosis decreasing the intracellular concentration of lipids,
the lipids droplets size and the levels of intracellular TG through the down-regulation of
SREBP-1c, PPARγ and ACAT1 expression levels however it increases PPARα expression.
The natural extracts suppressed OA-induced lipid accumulation (figue 1) and the
176
intracellular TG. Also, they tend to decrease the hepatic lipogenesis through SREBP-1c,
besides the activation of lipolysis through the increasing the expression of PPARα.
Conclusions: Quercetin has the same ability to the water-soluble extracts suppressing
significantly the intracellular lipid accumulation in a steatosis model induced by OA.
These components tend to reduce SREBP-1c expression, finally leading to inhibit hepatic
lipogenesis. The increased activation of PPAR”” inducing lipolysis and together the
reduction of lipogenesis could be postulated to be responsible for decreased hepatic fat
content. In this report, we found some component in the natural extracts which has a
regulatory effect on lipid accumulation and shown the evidence evaluating the mechanisms
of action hepatic lipid metabolism in different experimental setting: in vitro, in vivo, and
in human trials.
ePOSTER ABSTRACTS
Figure:
177
Screen 3: YI-MR-132
ePOSTER ABSTRACTS
PRIMARY CARE SEQUENTIAL USE OF FIB-4 AND
THE ENHANCED LIVER FIBROSIS TEST TO STRATIFY
PATIENTS WITH NAFLD DOUBLES CIRRHOSIS
DETECTION AND REDUCES REFERRALS OF PATIENTS
WITH MILD DISEASE
Ankur Srivastava* 1, 2, 3, Ruth Gailer4, 5, Shirin Demma1, Sudeep Tanwar1, 6, Alex
Warner5, Deepak Suri2, 7, Sarah Morgan5, Karen Sennett8, Douglas Thorburn1, 3,
Julie Parkes1, 9, Emmanouil Tsochatzis1, 3, William Rosenberg1, 3 and Camden and
Islington Liver Working Group
1
Department of Hepatology, UCL INSTITUTE OF LIVER AND DIGESTIVE HEALTH,
2
Department of Hepatology, University College London Hospital, 3Hepatology and Liver
Transplantation, Royal Free London, 4Primary Care and Population Health, University
College London, 5Primary Care, Camden Clinical Commissioning Group, 6Department of
Gastroenterology, Barts Health, 7Department of Gastroenterology,Whittington Hospital, 8Primary
Care, Islington Clinical Commissioning Group, London, 9Public Health Sciences and Medical
Statistics, University of Southampton, Southampton, United Kingdom
Corresponding author’s email: ankur.srivastava@nhs.net
Introduction: Identifying patients with NAFLD who may develop cirrhosis in primary
care is difficult. Patients with advanced fibrosis remain undiagnosed until presenting with
decompensated cirrhosis, whilst many with mild disease are referred to busy specialist
clinics. In March 2014, Camden & Islington (C&I) London boroughs commisioned a
primary care risk stratification pathway using FIB-4 followed by ELF test for indeterminate
cases.
Aims: At 18 months, we evaluated pathway effectiveness data to assess impact on cirrhosis
detection.
Material and Methods: Patients with NAFLD & abnormal transaminases were eligible
for pathway entry. Patients were stratified to low risk (FIB-4<1.30; or FIB-4 1.30-3.25 &
ELF<9.5) or high risk (FIB-4>3.25; or FIB-4 1.30-3.25 & ELF>9.5) indicative of ≥F3
fibrosis. High-risk patients were recommended for referral. For primary care outcomes,
the C&I electronic database was interrogated for aggregate data. For secondary care
178
Results: At 18 months, 844 patients were managed on the pathway. 245 patients (29.4%)
required ELF test (FIB-4 1.30-3.25). Overall, 663 (78.6%) were stratified as <F3 fibrosis,
and 181 patients (21.4%) as high risk of ≥F3 fibrosis. To date, hospital data are available
for 81 cases. 33 patients are awaiting investigations or have normal LFTs (ineligible). For
eligible patients, ≥F3 fibrosis was diagnosed in 24/48 (50%) patients compared to 7/116
(6.0%) non-pathway and 6/85 (7.1%) pre-pathway referrals. For 8/11 (72.7%) cirrhotics
detected via the pathway, CLD was not evident from clinical examination, bloods or
imaging. To allow direct comparison to pre-pathway, 1 year analysis showed 283% &
250% increases in ≥F3 fibrosis and cirrhosis detection respectively (figure 1).
Conclusions: Early analysis of the C&I NAFLD pathway suggests risk-stratification using
FIB-4 & ELF in primary care increases advanced liver disease detection, and reduces
referrals of patients with <F3 disease. The pathway displays early promise in addressing an
important clinical challenge.
Figure:
179
ePOSTER ABSTRACTS
outcomes, hospital records were reviewed at Royal Free London, UCLH & Whittington
Hospital of all referred patients. The primary endpoint was “consultant’s final fibrosis
assessment” – a binary outcome: Advanced fibrosis/Cirrhosis vs. lesser degree/no fibrosis
based on composite of liver histology (when available), imaging, fibroscan, bloods &
clinical judgement. Diagnostic performance was compared to pre-pathway (2012-2013)
& those referred on and off the pathway since March 2014.
ePOSTER ABSTRACTS
Disclosure of Interest: A. Srivastava: : None Declared, R. Gailer: : None Declared, S.
Demma: : None Declared, S. Tanwar: : None Declared, A. Warner: : None Declared, D.
Suri: : None Declared, S. Morgan: : None Declared, K. Sennett: : None Declared, D.
Thorburn: : None Declared, J. Parkes: Sponsored Lectures (National or International):
Conflict with: Siemens Healthcare Diagnostics,, E. Tsochatzis: : None Declared, W.
Rosenberg: Grant: Conflict with: Siemens Healthcare Diagnostics,, Consultant: Conflict
with: Siemens Healthcare Diagnostics,, Sponsored Lectures (National or International):
Conflict with: Siemens Healthcare Diagnostics,
180
Screen 4: YI-MR-145
TOWARDS A NON-INVASIVE DIAGNOSIS OF
NON-ALCOHOLIC STEATO HEPATITIS (NASH)
Corresponding author’s email: natalia.rosso@csf.units.it
Introduction: Nonalcoholic steatohepatitis (NASH) is a common, often “silent”, liver
disease. The major feature in NASH is fatty liver, along with inflammation and fibrosis.
Liver biopsy, the gold standard for its diagnosis, was established almost a century ago.
Surprisingly, reliable non-invasive diagnostic tools have not been developed yet.
Aims: Validate in vivo, proteins identified in silico as biomarkers for NASH diagnosis.
Material and Methods: CD44, SPARC, EGFR and IGF2, were identified by in silico
studies as candidate biomarkers for being secreted factors with clinical relevance.
A cohort of 45 adult morbid obese consenting patients (BMI> 35 kg/m2; 17 males and
28 females, age range: 19-63) undergoing bariatric surgery was enrolled. Wedge liver
biopsy was performed and blood samples were collected. Exclusion criteria were alcohol
consumption, viral hepatitis infection, known chronic liver disease. Liver histology was
classified by Brunt’s score and patients were divided according to fibrosis stage: F0 (n=3),
F1 (n=35), F2 (n=7). Plasmatic concentration of candidate biomarkers was measured by
ELISA, at the moment of the surgery (T0) and during the follow-up at 6 and 12 months
after bariatric surgery. Lean healthy subjects were used as controls in the follow-up study.
Results: Our cohort of patients showed to have alterations of glucose homeostasis (63.8%);
hypercholesterolemia (44%); hypertriglyceridemia (27.6%) and altered transaminases
levels (19.1%). As expected, correlation analysis of these parameters with the degree of
fibrosis do not provide any predictive value about the hepatic fibrosis stage.
Regarding our biomarkers, plasmatic levels of IGF2 correlated inversely with the fibrosis
score (p<0.01) while EGFR levels showed a direct correlation with fibrosis stage (p<0.01).
181
ePOSTER ABSTRACTS
Pablo J. Giraudi1, Sabrina E. Gambaro1, Carla M. Chackelevicius* 1, Michela
Giuricin2, Deborah Bonazza3, Fabrizio Zanconati4, Nicolò de Manzini2, Claudio
Tiribelli1, 5, Silvia Palmisano2, Natalia Rosso1
1
Centro Studi Fegato, Fondazione Italiana Fegato, 2Chirurgia Generale, Università degli Studi di
Trieste, Ospedale di Cattinara, 3School of Anatomic Pathology, University of Udine and Trieste;
Department of Medical, Surgical and Health Sciences, University of Trieste, 4UCO Anatomia
e Istologia Patologica, 5Università degli Studi di Trieste, Clinica Patologie del fegato, Cattinara
Teaching Hospital, Trieste, Italy
Data at T0, allow to discriminate healthy subjects from subjects with middle stage of
fibrosis (scores 1 and 2). During the follow-up, we observed improvement of plasma level
of CD44, IGF2 and EGFR, which reached values similar to healthy subjects at 12 months,
when; the metabolic pattern also improved.
Conclusions: Our study looks like a promising first step towards the development of
future non-invasive diagnostic tools to distinguish even first phases of NASH.
Acknowledgements: U05SPFRA14 – fondi FRA 2014 (CdA dd. 19.12.2014) and FIF.
PJG was sponsored by Fondazione Umberto Veronesi (Grants 2015), SEG by Proyecto
297 CTGAS (CUPB91C12000000001) and CMC by MAE
ePOSTER ABSTRACTS
182
Screen 5: YI-MR-151
ANGIOPOIETIN-LIKE4 IS ASSOCIATED WITH LIPID
METABOLISM AND SEVERE FIBROSIS IN NON-DIABETIC
PATIENTS WITH NON ALCOHOLIC FATTY LIVER DISEASE
Corresponding author’s email: crosso3@cittadellasalute.to.it
Introduction: Non-alcoholic fatty liver disease (NAFLD) results from an imbalance
between lipid deposition and removal, driven by increased lipid flow and de novo
lipogenesis (DNL) in insulin resistance (IR). The angiopoietin-like4 (ANGPTL4) is
involved in the regulation of lipid metabolism through the inhibition of lipoprotein lipase,
leading to systemic hypertriglyceridemia and hepatic steatosis.
Aims: Our aim was to explore the association between ANGPTL4, lipid metabolism,
monocyte chemoattractant protein-1 (MCP-1) and liver damage in a well characterized
group of non-diabetic NAFLD patients.
Material and Methods: We enrolled 54 subjects, 45 patients with biopsy proven NAFLD
and 9 healthy controls (CT). Adipose tissue IR (AT-IR) indices in fasting condition were
derived from free fatty acids (FFAs) levels and tracer studies (D2 glycerol): AT-IR1: FFAs
x insulin (INS) and AT-IR2: glycerol Ra x INS. Plasma FFAs composition was assessed
by GC-MS and the ratio palmitic/linoleic acid (16:0/18:2), which has been associated
with DNL, has been calculated. ANGPTL4 and MCP-1 plasma levels were measured by
Multiplex Assay based on the Luminex technology. Liver histology was score according
to Kleiner.
Results: Plasma levels of ANGPTL4 were similar to CT when NAFLD were analyzed as
a whole group, but was 22% higher in obese vs non-obese NAFLD. Overall, ANGPTL4
resulted positively associated with plasma levels of FFAs and triglycerides (r=0.49, p<0.01;
r=0.30, p=0.03), liver fat (r=0.40, p<0.01) and lipolysis (r=0.28, p=0.04). Compared to
183
ePOSTER ABSTRACTS
Chiara Rosso* 1, Milena Marietti1, Melania Gaggini2, Chiara Saponaro2, Gian
Paolo Caviglia1, Fabrizia Carli2, Emma Buzzigoli2, Rami I. K. Jouness1, Maria
Lorena Abate1, Antonina Smedile1, Giorgio Maria Saracco3, Amalia Gastaldelli2,
Elisabetta Bugianesi1
1
Medical Sciences, UNIVERSITY OF TURIN, Torino, 2Cardiometabolic Risk Unit, CNRInstitute of Clinical Physiology, Pisa, 3Department of Oncology, UNIVERSITY OF TURIN,
Torino, Italy
CT, NAFLD subjects had increased AT-IR and 16:0/18:2 ratio that were significantly
related to ANGPTL4 levels (AT-IR1 r=0.51, p<0.01 and AT-IR2 r=0.37, p=0.04;
16:0/18:2 ratio r=0.32, p=0.02). MCP-1 levels were increased by 40% in NAFLD vs CT
and directly related to ANGPTL4 levels (r=0.46, p<0.01). Among histological features,
ANGPTL4 was increased by 30% in the presence of inflammation and by 60% in severe
fibrosis but was unchanged by degree of ballooning. At regression analysis, ANGPTL4
levels were associated with the degree of fibrosis independent of BMI, ATIR and MCP-1.
Conclusions: ANGPTL4 is significantly associated with alterations in lipid metabolism,
AT-IR and severe hepatic fibrosis in non-diabetic subjects with NAFLD.
ePOSTER ABSTRACTS
Funded by:FP7/2007-2013under grant agreement no.HEALTH-F2-2009-241762 for the
project FLIP; PRIN2009ARYX4T. Horizon2020under grant agreement no.634413 for the
project EPoS.
184
Screen 6: MR-135
Chia-Yen Dai* 1, 2, 3, 4, Kuan-Ta Wu1, Jeng-Fu Yang1, Chung-Feng Huang2, Ching-I
Huang, 3, Chia-I Lin2, Meng-Hsuan Hsieh1, 4, Jee-Fu Huang3, 4, Wan-Long Chuang3,
4
, Ming-Lung Yu2, 3, 4, Hsien-Yi Wang5
1
Health Management Center, 2Department of Occupational and Environmental Medicine,
3
Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University
Hospital, Kaohsiung Medical University, 4Faculty of Internal Medicine, College of Medicine,
Kaohsiung Medical University , Kaohsiung, 5Department of Nephrology, Chi–Mei Medical
Center, Tainan, Taiwan
Corresponding author’s email: daichiayen@gmail.com
Introduction: Nonalcoholic fatty liver disease (NAFLD) is reported to be associated
with metabolic parameters. Limited data support the notion that lipid ratios are risk
factors for NAFLD.
Aims: The retrospective study aimed to evaluate the association between lipid ratios and
NAFLD.
Material and Methods: We have conducted a large population, cross-sectional,
retrospective study enrolling 44,767 adults who have received examination in our
department for health checkups in our tertiary medical center. The data on blood pressure,
fasting glucose, total cholesterol (TC), triglycerides (TG), and high-density lipoprotein
cholesterol (HDL-C) levels were obtained. The NAFLD severity (none, mild, moderate
and severe) was evaluated by ultrasound examinations done by expert hepatologists. By
using multivariate analyses we evaluated the odds between lipid ratios and NAFLD.
Results: Of the enrolled 44,767 subjects (mean age: 43.0±11 years, 28,744 males),
the prevalence rate of fatty liver in the present study was 53.76%. The individuals were
stratified into four subgroups based on their lipid profiles ratios (TC/HDL-C with a cutoff of 4.0 and TG/HDL-C with a cut-off of 2.0, respectively). In the subgroup with the
lowest TC/HDL-C and TG/HDL-C ratios, the prevalence of NAFLD, hypertension, and
diabetes was lower than that of the other three subgroups. Patients with higher lipid ratios
had a significantly greater risk for advanced NAFLD.
185
ePOSTER ABSTRACTS
ASSOCIATION BETWEEN SEVERITY OF NONALCOHOLIC
FATTY LIVER DISEASE AND THE RATIOS OF
CHOLESTEROL AND TRIGLYCERIDES
Conclusions: The severity of NAFLD was associated with lipid ratios. Adults with high
TC/HDL-C or TG/HDL-C ratios, or both, have a greater risk for NAFLD, especially
advanced NAFLD
ePOSTER ABSTRACTS
186
Co-organised by:
NEW PERSPECTIVES
IN HEPATITIS C VIRUS
INFECTION - THE
ROADMAP FOR CURE
23-24 SEPTEMBER 2016
PARIS, FRANCE
Thomas Berg, Germany
Raymond Chung, United States
Xavier Forns, Spain
Norah Terrault, United States
KEY DEADLINE:
Abstract submission:
27 June 2016
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