studies

1294A AASLD ABSTRACTS HEPATOLOGY, October, 2015
2228
Relationships between very low density lipoprotein
profiles and pathological processes in nonacoholic fatty
liver disease: insights from the Cardiovascular Health
Study
Zhenghui G. Jiang 1 , Ian H. de Boer 2 , Rachel H. Mackey 3 , Majken
K. Jensen 4 , Michelle Lai 1 , Russel Tracy 3 , Simon C. Robson 1 , Lewis
Kuller 5 , Kenneth Mukamal 6 ; 1 Gastroenterology and Hepatology,
Beth Israel Deaconess Medical Center, Harvard Medical School,
Boston, MA; 2 Nephrology, University of Washington, Seattle, WA;
3 Pathology, University of Vermont College of Medicine, Burlington,
VT; 4 Nutrition, Harvard School of Public Health, Boston, MA;
5 Epidemiology, University of Pittsburgh Graduate School of Public
Health, Pittsburgh, PA; 6 General Internal Medicine, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, MA
Background: Nonalcoholic fatty liver disease (NALFD) significantly
impacts the production of very low density lipoprotein
(VLDL) from the liver. As a result circulating VLDL profile
may serve as a marker for NAFLD disease severity. Herein,
we aim to determine the impact on VLDL profiles from three
key pathological processes in NAFLD: insulin resistance, liver
synthetic function and inflammation. Methods: We examined
cross-sectional associations of markers for insulin sensitivity,
inflammation, and liver synthetic function with VLDL particle
(VLDL-P) subclass concentration and size among 1,850 participants
in the Cardiovascular Health Study. Results: Insulin resistance
(lower Matsuda index and 1/HOMA-IR) was associated
with larger mean VLDL size and higher concentrations of large
VLDL-P. Markers of liver synthetic function (albumin, fibrinogen
and factor VII) were positively associated with concentrations
of total and subclass VLDL-P. CRP and IL-6, markers for inflammation,
demonstrated a nonlinear relationship with both total
VLDL-P concentration and VLDL size. When mutually adjusted,
one standard deviation (SD) increment in Matsuda index and
CRP were associated with -4.9 nmol/L (-8.2 - -1.5, p = 0.005)
and -6.3 nmol/L (-11.0 - -1.6, p = 0.009) lower VLDL-P concentration
respectively. In contrast, one-SD increment in factor VII
was associated with 16.9 nmol/L (12.6 – 21.2, p < 0.001)
higher VLDL-P concentration. In addition, a one-SD increment in
the Matsuda index was associated with -1.1 nm (-2.0 - -0.3, p
= 0.006) smaller mean VLDL size, whereas CRP and factor VII
were not associated with VLDL size. Conclusion: Insulin resistance
is associated with higher VLDL-P concentration and larger
mean VLDL size, whereas both inflammation and impaired liver
synthetic function are associated with lower concentrations of
VLDL-P, but have no relationship with VLDL size. These differential
impacts on VLDL profile set the foundation for the utility of
VLDL in disease staging of NAFLD.
Adjusted regression coefficients for VLDL profiles from standardized
Matsuda index, CRP and factor VII
Regression models calculated using the Z-scores of three primary
exposures (Mastuda index, CRP, factor VII) in units of standard
deviation (SD), and covariates including age, gender, ethnicity,
BMI, alcohol, smoking history and the use of lipid lowering medications.
The following authors have nothing to disclose: Zhenghui G. Jiang, Ian H. de
Boer, Rachel H. Mackey, Majken K. Jensen, Michelle Lai, Russel Tracy, Lewis
Kuller, Kenneth Mukamal
2229
WITHDRAWN
2230
The development of hepatocellular carcinoma in Japanese
patients with biopsy-proven nonalcoholic fatty liver
disease : the relation between carriage of the PNPLA3
rs738409 C >G polymorphism and hepatocarcinogenesis
Yuya Seko 1 , Yoshio Sumida 1 , Saiyu Tanaka 2 , Hiroyoshi Taketani 1 ,
Kazuyuki Kanemasa 2 , Hiroshi Ishiba 1 , Akira Okajima 1 , Tasuku
Hara 1 , Kanji Yamaguchi 1 , Michihisa Moriguchi 1 , Kohichiroh
Yasui 1 , Hironori Mitsuyoshi 1 , Yoshito Itoh 1 ; 1 Kyoto Prefectural University
of Medicine, Kyoto, Japan; 2 Center for Digestive and Liver
Diseases, Nara City Hospital, Nara, Japan
BACKGROUND: Some patients with nonalcoholic fatty liver disease
(NAFLD) develop hepatocellular carcinoma (HCC). Carriage
of the PNPLA3 rs738409 (encoding the I148M variant)
has been reported to be associated with advanced fibrosis
and HCC related to NAFLD. Our aim was to determine the
incidence of and risk factors including PNPLA3 rs738409 polymorphism
for HCC in Japanese patients with biopsy-proven
NAFLD. METHODS: This retrospective cohort study analyzed
hepatocarcinogenesis in 341 patients with biopsy-proven
NAFLD. PNPLA3 rs738409 genotype was determined by allelic
discrimination in 133 patients. RESULTS: Of 341 patients, 205
(60.1%) were diagnosed with nonalcoholic steatohepatitis. The
PNPLA3 rs738409 genotype frequencies were CC 0.14, CG
0.46, GG 0.40. During a median follow-up period of 5.0
years, 9 patients (2.6%) developed HCC. The cumulative rate
of HCC was 1.5% at the end of the 5th year and 7.1% at the
end of the 10th year. Multivariate analysis identified PNPLA3
genotype (GG; hazard ratio [HR] 14.2, p=0.035), and platelet
count (^15x10/μl; HR 11.6, p=0.036) as predictors for the
development of HCC. PNPLA3 genotype was analysed in 9
patients with HCC, 7 were PNPLA3 GG and 2 were CG. In
patients with GG allele, the cumulative rate of HCC was 4.9%
at the end of the 5th year and 33.5% at the end of the 10th
year. The incidence of HCC was significantly higher in patients
with PNPLA3 GG allele than in those with CC and CG allele
(p=0.027). CONCLUSIONS: Severe fibrosis was a predictor
for HCC in NAFLD patients. And PNPLA3 polymorphism genotyping
was also the risk to the development of HCC. These
findings might help us HCC surveillance in NAFLD patients.
Disclosures:
Yoshito Itoh - Grant/Research Support: MSD KK, Bristol-Meyers Squibb, Dainippon
Sumitomo Pharm. Co., Ltd., Otsuka Pharmaceutical Co., Chugai Pharm
Co., Ltd, Mitsubish iTanabe Pharm. Co.,Ltd., Daiichi Sankyo Pharm. Co.,Ltd.,
Takeda Pharm. Co.,Ltd., AstraZeneca K.K.:, Eisai Co.,Pharm.Ltd, FUJIFILM Medical
Co.,Ltd., Gelaed Sciences Co., GlaxoSmithKline
The following authors have nothing to disclose: Yuya Seko, Yoshio Sumida, Saiyu
Tanaka, Hiroyoshi Taketani, Kazuyuki Kanemasa, Hiroshi Ishiba, Akira Okajima,
Tasuku Hara, Kanji Yamaguchi, Michihisa Moriguchi, Kohichiroh Yasui, Hironori
Mitsuyoshi
Disclosures:
Simon C. Robson - Grant/Research Support: Pfizer, NIH, Dainippon; Independent
Contractor: Biolegend, EMD Millipore, Mersana; Management Position:
eBioscience; Speaking and Teaching: ACP, Elsevier, ATC; Stock Shareholder:
Nanopharma, Puretech