studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 659A
a risk for hepatic fibrosis, a concern in light of Phase III clinical
trials of pharmacologic Mttp inhibitors.
Disclosures:
The following authors have nothing to disclose: Elizabeth P. Newberry, Susan
M. Kennedy, Yan Xie, Hui Jiang, Anping Chen, Daniel S. Ory, Nicholas O.
Davidson
912
intrahepatic expression levels of bile acid transporters
are inversely correlated with histological progression of
non-alcoholic fatty liver disease
Kazuya Okushin 1 , Takeya Tsutsumi 2 , Kenichiro Enooku 1 , Hidetaka
Fujinaga 1 , Akira Kado 1 , Kyoji Moriya 3 , Hiroshi Yotsuyanagi 2 ,
Kazuhiko Koike 1 ; 1 Department of Gastroenterology, Graduate
School of Medicine, The University of Tokyo, Tokyo, Japan;
2 Department of Infectious Diseases, Graduate School of Medicine,
The University of Tokyo, Tokyo, Japan; 3 Department of Infection
Control and Prevention, Graduate School of Medicine, The University
of Tokyo, Tokyo, Japan
Background & Aims Non-alcoholic fatty liver disease (NAFLD)
is increasing in the world including Asian countries. NAFLD
contains a disease spectrum ranging from simple steatosis to
nonalcoholic steatohepatitis (NASH). The latter is considered
as a progressive disease, of which pathogenesis remains
largely unclear. Recently, bile acid (BA) metabolism is focused
as a therapeutic target of NASH. The aim of this study was to
identify changes of bile acid metabolism in NAFLD patients
in terms of disease progression. Methods From November
2011 to June 2014, we prospectively enrolled patients with
clinically suspected NAFLD at The University of Tokyo Hospital.
Patients taking ursodeoxycholic acid were excluded in this
study. Disease progression was evaluated by NAFLD activity
score (NAS). Intrahepatic expression levels of genes related
to BA metabolism were determined by quantitative PCR and
immunohistochemistry. This study was approved by the ethics
committees of The University of Tokyo and all patients gave
informed written consent for the study according to the Declaration
of Helsinki. Results Seventy-eight patients (male: female
= 49: 29) histologically diagnosed as NAFLD by significant
steatosis, namely the percentage of hepatocytes showing fatty
changes was ≥ 5% and coincidence with Matteoni classification,
were analyzed. Expression levels of farnesoid X receptor
(FXR) and liver receptor homolog 1 (LRH1), key molecules
associated with BA metabolism, were significantly decreased
along with NAS increase only in female. Small heterodimer
partner (SHP), a downstream transcriptional repressor of FXR,
was similarly changed but only in male. On the other hand,
the level of cholesterol 7 alpha-hydroxylase (CYP7A1), a key
enzyme of BA synthesis, was not changed with the elevation of
NAS in both genders. However, expression levels of an export
transporter, bile salt export pump (BSEP), and an uptake transporter,
Na + /taurocholate cotransporter (NTCP), were significantly
down-regulated as the NAS increases in both genders.
Another export transporter, multidrug resistance-associated
protein 2 (MRP2) was also significantly down-regulated but
only in female. Decreases in protein levels were confirmed by
immunohistochemistry on both BSEP and MRP2. Conclusions
Expression levels of BA export transporters, BSEP and MRP2,
were inversely correlated with NAS in the liver of NAFLD
patients. This down-regulation are supposed to cause excessive
increase of BA levels in hepatocyte, leading to hepatocyte injuries.
Although the mechanism underlying the down-regulation
remains to be elucidated, our findings in patients might lead to
the development of new therapeutic options for NASH.
Disclosures:
The following authors have nothing to disclose: Kazuya Okushin, Takeya Tsutsumi,
Kenichiro Enooku, Hidetaka Fujinaga, Akira Kado, Kyoji Moriya, Hiroshi
Yotsuyanagi, Kazuhiko Koike
913
Non-invasive quantitative decline in liver fat content on
MRI and histologic response in nonalcoholic steatohepatitis:
A secondary analysis of MOZART trial
Janki R. Patel 1 , Ricki Bettencourt 2,3 , Jeffrey Y. Cui 2 , Joanie
Salotti 4,2 , Jonathan Hooker 5 , Archana Bhatt 2 , Carolyn Hernandez
2 , Phirum Nguyen 2 , Hamed Aryafar 5 , William Haufe 5 , Catherine
A. Hooker 5 , Lisa M. Richards 2,4 , Claude B. Sirlin 5 , Rohit
Loomba 2,4 ; 1 Department of Internal Medicine, University of California,
San Diego, La Jolla, CA; 2 NAFLD Translational Research
Unit, University of California, San Diego, La Jolla, CA; 3 Division of
Epidemiology, University of California, San Diego, La Jolla, CA;
4 Division of Gastroenterology, Department of Medicine, University
of California, San Diego, La Jolla, CA; 5 Liver Imaging Group,
Department of Radiology, University of California, San Diego, La
Jolla, CA
Background: Magnetic resonance imaging-estimated proton
density fat fraction (MRI-PDFF) has been shown to be a non-invasive,
accurate and reproducible imaging-based biomarker
for assessing steatosis change and treatment response in nonalcoholic
steatohepatitis (NASH) clinical trials. However, there
are no data on the amount of decline in liver fat shown on MRI-
PDFF that corresponds to histologic response in the setting of a
clinical trial in NASH. We aimed to quantitatively compare the
amount of change in liver fat using MRI-PDFF between histologic
responders vs. histologic non-responders. Methods: This study is
a secondary analysis of the MOZART trial, a randomized, placebo-controlled,
double-blind trial, which included 50 patients
with biopsy-proven NASH to assess efficacy of ezetimibe 10
mg orally daily in reducing liver fat as measured by MRI-PDFF.
All patients enrolled in the trial underwent biochemical testing,
liver biopsy, and MRI at baseline and of those who had both
liver biopsy and MRI-PDFF at weeks 0 and 24 were included in
this analysis. Patients were classified as histologic responders
if they had ≥2 point reduction in NAFLD Activity Score (NAS)
without any increase in fibrosis stage and as histologic non-responders
if they did not meet this criterion. We performed a
head-to-head comparative analysis of histologic responders
and histologic non-responders, and associated quantitative
changes in liver fat as measured via MRI-PDFF. Results: Of the
35 patients who underwent paired liver biopsy and MRI-PDFF
assessment, 10 demonstrated histologic response. Histologic
responders and non-responders had similar baseline demographic
and histological characteristics, with a median age
of 60.5 years and 70% female vs. median age of 49 years
and 64% female, respectively. Compared to histologic non-responders,
histologic responders had a statistically significant
reduction in net MRI-PDFF of -4.1% ± 4.9 vs. +0.6% ± 4.1 (P
< 0.036) with a mean percent change of -29.3% ± 33.0 vs.
+2.0% ± 24.0 (P < 0.004), respectively. Histologic responders
had a significant decrease in hepatic steatosis (P = 0.007) and
hepatocellular ballooning (P = 0.025) compared to histologic
non-responders, and no significant changes were seen in lobular
inflammation and fibrosis scores within or between groups.
Conclusion: Utilizing paired MRI-PDFF and liver histology data
from MOZART Trial, we demonstrate that a 29% reduction in
liver fat on MRI-PDFF is associated with histologic response in
NASH. These novel data can be incorporated into designing
future NASH clinical trials, especially those utilizing change in
liver fat quantified by MRI as an end-point.