studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1255A
2150
Cross-sectional and longitudinal agreement of magnetic
resonance imaging proton density fat fraction with
pathologist grading of hepatic steatosis in adults with
nonalcoholic steatohepatitis in a multi-center trial
Michael S. Middleton 1 , Elhamy Heba 1 , Catherine A. Hooker 1 ,
Brent A. Neuschwander-Tetri 2 , Mustafa R. Bashir 3 , Kathryn
Fowler 4 , Kumar E. Sandrasegaran 11 , Elizabeth M. Brunt 5 , David
E. Kleiner 6 , Edward Doo 7 , Mark L. Van Natta 8 , James Tonascia 9 ,
Rohit Loomba 10 , Claude B. Sirlin 1 ; 1 Radiology, UCSD, San Diego,
CA; 2 Medicine, Saint Louis University, St. Louis, MO; 3 Radiology,
Duke University, Durham, NC; 4 Radiology, Washington University,
St. Louis, MO; 5 Pathology and Immunology, Washington University,
St. Louis, MO; 6 Center for Cancer Research, NIH, Bethesda,
MD; 7 Liver Disease Research Branch, NIH, Bethesda, MD; 8 Epidemiology,
Johns Hopkins University, Baltimore, MD; 9 Biostatistics
and Epidemiology, Johns Hopkins University, Baltimore, MD;
10 Medicine, UCSD, San Diego, CA; 11 Radiology, Indiana University,
Indianapolis, IN
Materials and Methods Magnetic resonance imaging (MRI)
was offered at baseline and end of treatment (EOT) to adults
participating in the Farnesoid X Receptor Ligand Obeticholic
Acid in NASH Treatment (FLINT) trial. Proton density fat fraction
(PDFF), a non-invasive MRI biomarker for hepatic steatosis,
was estimated using an advanced gradient-recalled-echo
sequence that avoids or corrects confounding factors that can
cause hepatic fat quantification to be inaccurate or scanner
dependent. Imaging quality control was managed centrally
by the NASH CRN Radiology Coordinating Center. Histologic
steatosis grade, scored centrally by the NASH CRN Pathology
Committee, served as the reference standard for PDFF.
Cross-validated receiver operating characteristic (ROC) analyses
were performed. Results Of 283 adults enrolled in FLINT,
113 had MRI and biopsy at baseline, 85 had MRI and biopsy
at EOT, and 78 had MRI and biopsy at both time points. MRIs
were obtained at seven clinics using MRI scanners from three
manufacturers, operating at one of two field strengths. Timing
of MRIs ranged from 29 days before to 89 days after
biopsy. At baseline, 34% of biopsies had steatosis grade 0
or 1, 39% had grade 2, and 27% had grade 3 with corresponding
mean(SD) PDFF(%) of 9.8(3.7), 18.1(4.3), and
30.1(8.1), respectively. The area under ROC (AUROC) from
logistic regression using PDFF as a surrogate for classifying
steatosis grade 2+ vs. < 2 was 0.95 (95% CI: 0.91, 0.98) and
for classifying steatosis grade 3 vs. < 3 was 0.96 (95 % CI:
0.93, 0.99). PDFF cut-off values at 90% specificity were 16.3%
for grade 2+ and 21.7% for grade 3 discrimination; sensitivities
were 83% and 84%, respectively. At EOT, 42% of paired
biopsies had improvement in steatosis grade, 49% had no
change, and 9% had worsening with corresponding mean(SD)
change from baseline in PDFF(%) of -7.4(8.7), 0.3(6.3) and
7.7(6.0), respectively. The AUROC using PDFF change to classify
steatosis grade improvement and worsening, respectively,
were 0.81 (95% CI: 0.71, 0.91) and 0.81 (95% CI: 0.63,
0.99). Cut-off values for PDFF change at 90% specificity were
-5.1% for improvement and +5.6% for worsening; sensitivities
were 58% and 57%, respectively. Conclusions In a multi-center
setting, MRI PDFF showed high agreement with histologic
hepatic steatosis grades on scanners at different sites using
different scanner manufacturers and of different field strengths.
Importantly, change in PDFF accurately classified change in
72-week histologic hepatic steatosis grade. These findings support
wider use of MRI PDFF in multi-center trials as a biomarker
for hepatic steatosis at baseline, and for change in hepatic
steatosis with treatment.
Disclosures:
Michael S. Middleton - Consulting: Bracco; Grant/Research Support: Gilead,
Isis, Genzyme, Pfizer, Siemens, Bayer, Synageva, Merck, Janssen; Stock Shareholder:
General Electric
Brent A. Neuschwander-Tetri - Advisory Committees or Review Panels: Nimbus
Therapeutics, Bristol Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus,
Scholar Rock
Elizabeth M. Brunt - Consulting: Synageva; Independent Contractor: Rottapharm
Rohit Loomba - Advisory Committees or Review Panels: Galmed Inc, Tobira Inc,
Arrowhead Research Inc; Consulting: Gilead Inc, Corgenix Inc, Janssen and
Janssen Inc, Zafgen Inc, Celgene Inc, Alnylam Inc, Inanta Inc, Deutrx Inc; Grant/
Research Support: Daiichi Sankyo Inc, AGA, Merck Inc, Promedior Inc, Kinemed
Inc, Immuron Inc, Adheron Inc
Claude B. Sirlin - Grant/Research Support: GE, Pfizer, Bayer, Guerbet, Siemens
The following authors have nothing to disclose: Elhamy Heba, Catherine A.
Hooker, Mustafa R. Bashir, Kathryn Fowler, Kumar E. Sandrasegaran, David E.
Kleiner, Edward Doo, Mark L. Van Natta, James Tonascia
2151
Non-invasive Diagnosis of Non-alcoholic Steatohepatitis
(NASH) using a Panel of Fatty Acids
Donjeta Gjuka 1 , Xiaoling Song 2 , Wonbeak Yoo 1 , Suk Young
Yoo 3 , Jing Wang 3 , Michael B. Fallon 4 , George N. Ioannou 5 , Stephen
A. Harrison 6 , Laura Beretta 1 ; 1 Molecular and Cellular Oncology,
MD Anderson Cancer Center, Houston, TX; 2 Fred Hutchinson
Cancer Research Center, Seattle, WA; 3 Bioinformatics and Computational
Biology, The University of Texas MD Anderson Cancer
Center, Houston, TX; 4 Division of Gastroenterology, The University
of Texas Health Science Center at Houston, Houston, TX; 5 Division
of Gastroenterology, Veterans Affairs Puget Sound Health Care
System and University of Washington, Seattle, WA; 6 Department
of Medicine, Brooke Army Medical Center, Houston, TX
Introduction: Non-alcoholic fatty liver disease (NAFLD) is rapidly
becoming the most common form of liver disease worldwide.
NAFLD represents a spectrum of disease states ranging
from isolated steatosis to non-alcoholic steatohepatitis (NASH).
Diagnosis of NASH is important as this form of the disease
has been shown to progress to cirrhosis and hepatocellular
carcinoma. To date, liver biopsy is required for the diagnosis
of NASH. Methods: We measured 46 fatty acids in sera from
106 patients with NAFLD who underwent biopsy at Brooke Military
Hospital in San Antonio (n=75) and the Veterans Affairs
Puget Sound Health Care System in Seattle (n=31). For fatty
acid profiling, total lipids were extracted from 100 μL of serum,
the phospholipid fraction was isolated by one-dimensional
thin-layer chromatography and methyl esters of phospholipid
fatty acids were prepared using direct transesterification and
separated by gas chromatography. Results: Levels of 15:0,
17:0 and 16:1n7t negatively correlated with NAFLD activity
scores (NAS) and hepatocyte ballooning scores, while levels
of 18:1n7c strongly correlated with fibrosis scores and significantly
discriminated patients with mild fibrosis and patients
with intermediate or advanced fibrosis. Levels of 18:1n7c also
correlated with liver inflammation. In addition, 15:0 and 17:0
levels negatively correlated with fasting glucose and AST, while
levels of 16:1n7c, 18:1n7c and 22:5n3 positively correlated
with AST, ferritin and albumin, respectively. None of the six
fatty acids correlated with BMI. Inclusion of age, ferritin, AST
or AST-to-Platelet ratio Index (APRI) scores improved the performance
of the fatty acid panels in detecting patients with NAS
≥5 or patients with intermediate to severe fibrosis. The panel
composed of 15:0, 16:1n7t, 18:1n7c, 22:5n3, age, ferritin
and APRI best predicted intermediate or advanced fibrosis in
NAFLD patients, with an area under ROC curve (AUROC) of
0.92 and a 82% sensitivity at 90% specificity. Conclusion: The
comprehensive analysis of fatty acid composition through the
different stages of NAFLD and their correlation to histological