studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 597A
Estimated fibrosis stage by TE at baseline and SVR24
Disclosures:
Marc Bourlière - Advisory Committees or Review Panels: Schering-Plough,
Bohringer inghelmein, Schering-Plough, Bohringer inghelmein, Transgene; Board
Membership: Bristol-Myers Squibb, Gilead, Idenix; Consulting: Roche, Novartis,
Tibotec, Abott, glaxo smith kline, Merck, Bristol-Myers Squibb, Novartis, Tibotec,
Abott, glaxo smith kline; Speaking and Teaching: Gilead, Roche, Merck, Bristol-Myers
Squibb
Veronique Loustaud-Ratti - Board Membership: Gilead, Roche, Schering Plough
MSD; Speaking and Teaching: Roche, Schering Plough MSD, Janssen, Bristol
meyers squibb, gilead, Abbvie
Sophie Metivier - Speaking and Teaching: Roche, BMS, Janssen, Merck, Gilead,
abbvie
Vincent Leroy - Board Membership: Abbvie, BMS, Gilead; Consulting: Janssen,
MSD; Speaking and Teaching: Abbvie, BMS, Gilead, Janssen, MSD
Armando Abergel - Consulting: gilead, msd, bms; Speaking and Teaching: abbvie
Robert P. Myers - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead
Sciences, Inc.
Raul E. Aguilar Schall - Employment: Gilead Sciences, Inc.
Robert H. Hyland - Employment: Gilead Sciences, Inc; Stock Shareholder: Gilead
Sciences, Inc
Mani Subramanian - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Lawrence Serfaty - Board Membership: BMS, Gilead; Consulting: Merck; Speaking
and Teaching: Roche, Janssen, Merck, Janssen, BMS, Gilead
Victor de Ledinghen - Board Membership: Janssen, Gilead, BMS, Abbvie; Speaking
and Teaching: AbbVie, Merck, BMS, Gilead
778
A Hepatic Stellate Cell Secreted Protein Signature that
Has Potential for use in the Non-invasive Detection of
Fibrosis and Fibrogenic Activity in Chronic Liver Diseases
Daniel L. Motola 1 , Chan Zhou 1 , Samuel York 1 , Yujin Hoshida 2 ,
Alan Mullen 1 , Raymond T. Chung 1 ; 1 MGH, Boston, MA; 2 Division
of Liver Diseases,, Icahn School of Medicine at Mount Sinai, New
York, NY
Background: Emerging clinical data highlight that the degree
of hepatic fibrosis correlates with clinical outcomes in patients
with liver disease (Ekstedt et al Hep. 2015). However, there
remains no reliable method for detection of fibrosis, other
than liver biopsy, which carries potential morbidity. Furthermore,
non-invasive methods such as Fibroscan do not predict
early stages of fibrosis well. Accordingly, development
of non-invasive techniques to detect hepatic fibrosis and its
progression is critically needed. It is well-known that activated
hepatic stellate cells (HSCs) deposit extracellular collagen
matrix and directly contribute to fibrosis. Furthermore, studies
reveal direct correlation between HSC number and degree of
hepatic fibrosis. Therefore, we hypothesize that HSC-derived
secreted proteins can be used as functionally relevant, non-invasive
biomarkers to characterize disease stage and identify
high-risk patients. Methods: We performed RNA-sequencing
of primary human activated HSCs to comprehensively characterize
their secreted protein gene expression profile, as these
proteins have potential to be detected systematically. Through
bioinformatic analysis, we identified genes that are specifically
expressed by activated HSCs compared to whole liver and
36 other human tissues (dbGaP). Further, to identify candidates
of greater biological relevance we focused on: 1. genes
enriched in activated versus quiescent HSCs, 2. those directly
regulated by TGFβ, defined by upregulaton of expression by
TGFβ and proximity to SMAD3 sites, and 3. genes within
super-enhancers (presence of H3K27ac marks 10kb upstream
of transcription start site). We cross-referenced candidates to
a previously published 186-gene set that predicts outcomes of
patients with HCC or hepatitis-C related early-stage cirrhosis.
Additionally, we compared candidates to recently published
and unpublished data sets corresponding to stellate signatures.
Results: We identified a total of 218 genes enriched in activated
HSCs. Of these 90 are upregulated by TGFβ, of which
62 have associated SMAD3 sites, suggesting direct regulation.
Further, 10 candidates are found within super-enhancers, 5
of which are TGFβ-regulated and contain SMAD3 sites. All 5
genes are implicated in liver fibrosis and may serve as putative
biomarkers. Finally, we found that our 218 HSC-specific gene
signature is unique and associated with negative clinical outcomes
in patients with HCC and hepatitis C-related cirrhosis.
Conclusion: Taken together, this work provides a functionally
relevant list of genes and proteins that have potential as serum
biomarkers in the non-invasive assessment of hepatic fibrogenic
activity.
Disclosures:
Raymond T. Chung - Grant/Research Support: Gilead, Mass Biologics, Abbvie,
Merck, BMS
The following authors have nothing to disclose: Daniel L. Motola, Chan Zhou,
Samuel York, Yujin Hoshida, Alan Mullen
779
Diagnostic disparity of FIB4, APRI and AAR in predicting
liver fibrosis in HDV/HBV co-infected patients
Varun K. Takyar 1 , David E. Kleiner 2 , Kenneth J. Wilkins 3 , Pallavi
Surana 1 , Ohad Etzion 1 , Jay H. Hoofnagle 1 , T. Jake Liang 1 , Theo
Heller 1 , Christopher Koh 1 ; 1 Liver Diseases Branch, NIH, Bethesda,
MD; 2 Laboratory of Pathology, NCI, Bethesda, MD; 3 Office of the
Director, NIDDK, Bethesda, MD
Introduction: Information on staging of liver fibrosis is essential
in managing chronic hepatitis B (HBV), C (HCV) and D (HDV)
virus infections. Simple, non-invasive methods for the assessing
fibrosis originally designed for HCV have proven usefulness
in HBV. However, their accuracy and utility have not been
evaluated in HDV, which involves dual virulent pathogens and
accelerated hepatic fibrosis. Aims: To evaluate the utility of
well established non-invasive biomarkers of fibrosis in HDV
infection. Methods: Non-invasive biomarkers of liver disease
(aspartate aminotransferase (AST)/alanine aminotransferase
(ALT) ratio (AAR), AST-to-platelet ratio index (APRI), Fibrosis-4
(FIB-4) index) were correlated with liver histology in HCV, HBV
and HDV infected subjects. Laboratory measurements were
obtained within 24-hours of liver biopsy. Fibrosis scores (Ishak
and Knodell) were mapped to a F0-4 equivalent scale. After
normalization, Mann-Whitney U test used to assess statistical
differences of area under the receiver operator curve (AUROC)
between the 3 biomarkers. Results: Out of 2682 unique viral
hepatitis liver biopsies,1043 index pre-treatment liver biopsies
with biomarkers were analyzed. The mean age was 45.4+/-
12.4 at the time of biopsy; 688 (66%) male and 646 (61.9%)
Caucasian. Of these, 706 (68%) were HCV, 276 (26%) were
HBV and 61 (6%) were HDV. Histologically, HDV had the
greatest percentage of advanced fibrosis (29%) and necroinflammation
(35%) compared to HCV (11% and 6%, respectively)
and HBV (16% and 7%, respectively). In HCV, FIB-4 had
the best area under the receiver operating characteristic curve