studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1279A
coholic Fatty Liver Disease (NAFLD), where the average BMI
is higher than in Europe and Asia, is limited. We examined
predictors of liver stiffness measurement (LSM) change and
the effect of a combined testing strategy employing NAFLD
Fibrosis Score (NFS) and VCTE. Methods: A prospective cohort
of 161 biopsy-proven NAFLD patients evaluated with VCTE
using an M probe and NFS at baseline and a repeat VCTE
at 6 months. Unreliable VCTE readings were defined as a
failure to obtain 10 valid measurements or an interquartile
range (IQR) > 30%. Results: 121 (75.2%) patients had reliable
VCTE. The mean body mass index (BMI) of the total cohort
was 33.5 km/m 2 ; 32.2 and 37.2 in those with reliable and
unreliable VCTE (p < 0.0001). The optimal BMI cutoff for an
unreliable exam is BMI 37 kg/m 2 (odds ratio 6.76 95% CI
(3.06 – 15.4). The area under the receiver operating curve
(AUROC) for the detection of F3-F4 fibrosis by VCTE is 0.92
(95% CI: 0.85–0.96) with an optimal LSM cutoff of 9.9 kPa
(sensitivity 95%, specificity 77%). Conversely, the AUROC for
the association between NFS and advanced fibrosis for the
whole cohort was 0.77 (95% CI:0.63–0.97). In the detection
of F3-F4 fibrosis in patients with reliable VCTE, the AUROC for
VCTE is superior to that of NFS (0.92 vs. 0.77, p=0.01). VCTE
led to a lower F3-F4 fibrosis misclassification rate (13% versus
17%) A low risk VCTE result was obtained for 63 patients with
F0-F2 fibrosis. However, 13 of these patients had indeterminate
NFS; a combined strategy correctly classifies fewer (50)
low-risk patients. The median LSM improvement after 6 months
was 11.1% (IQR= -13.0% - 37.8%) and 37 patients (45%)
experienced a 20% improvement. A 5% weight loss was associated
with improved LSM (p = 0.009). Conclusion: Reliable
VCTE exams are useful to rule out advanced fibrosis in the U.S.
NAFLD patients. However, 25% have unreliable studies using
an M probe. Weight loss improves liver stiffness in the short
term, likely by addressing steatosis and not fibrosis. Further
data using the XL probe and adjustment for hepatic steatosis
will be important.
Disclosures:
The following authors have nothing to disclose: Elliot B. Tapper, Michelle Lai
2198
Functional inhibition of spleen tyrosine kinase ameliorates
different stages of alcoholic liver disease in mice
Terence N. Bukong, Arvin Iracheta-Vellve, Aditya Ambade, Karen
Kodys, Gyongyi Szabo; Medicine, University of Massachusetts
Medical School, Worcester, MA
Background: The spectrum of alcoholic liver disease (ALD)
includes steatosis triggered by acute alcohol binge drinking,
chronic alcoholic hepatitis and cirrhosis, the latter a leading
cause of mortality with limited therapies available. Because
alcohol targets different signaling pathways in the liver, identification
of a master regulatory target capable of modulating
multiple signaling processes is attractive. The aim of this study
was to evaluate the role of spleen tyrosine kinase (SYK), a
non-receptor tyrosine kinase, given its central modulatory role
of multiple pro-inflammatory signaling pathways previously
identified in the pathomechanism of ALD. Methods: Three different
models of ALD were assessed in mice: 3-day binge,
10-day acute-on-chronic and 5 weeks chronic alcohol Lieber-DeCarli
diet. Some mice received daily dose of SYK inhibitor
(R406) [5-10mg/kg]. Liver and serum samples were assessed
by western blot, ELISA, EMSA, qPCR and histology. Results:
Liver Syk protein expression was increased by acute-on-chronic
and chronic but not acute alcohol administration. However,
we found a significant elevation of activated Syk and its downstream
targets, phosphorylated(p)-SYK Y525/526 , p-ERK1/2 and
p-p38, in livers of alcohol-fed mice compared to controls in
all 3 models. In all models, alcohol administration led to liver
injury and inflammation demonstrated by significant increases
in ALT, p-ERK1/2, NF-κB binding, TNF-α, MCP1, and IL-1β protein
expression compared to controls. In vivo administration of
a functional SYK inhibitor attenuated alcohol-induced hepatic
injury and inflammation indicated by significantly reduced ALT,
p-ERK1/2, p-p38, NF-κB binding, TNF-α, MCP1, E-Selectin,
IL-1β expression compared to vehicle treated ethanol-fed mice.
The protective effect of SYK inhibition on liver inflammation
was present in all 3 models; specifically, neutrophil activation
markers, Ly6G, MPO and E-Selectin, were decreased in the
acute-on-chronic model and macrophage activation (F4/80
and CD68) was attenuated in chronic alcohol feeding. Furthermore,
SYK inhibition resulted in a significant decrease in
hepatic steatosis indicated by Oil Red-O staining, triglyceride
levels and increases in UCP1 and PRDM16 expression in the
liver suggesting that SYK-dependent signaling is involved in
alcoholic steatosis at different levels, including lipogenesis and
lipid metabolism. Conclusions: Our data demonstrate a novel
functional role of SYK in modulating liver inflammation and
steatosis at different stages of alcoholic liver damage. This
study highlights SYK as a potential multifunctional therapeutic
target to suppress inflammation and steatosis in alcoholic liver
disease.
Disclosures:
The following authors have nothing to disclose: Terence N. Bukong, Arvin Iracheta-Vellve,
Aditya Ambade, Karen Kodys, Gyongyi Szabo
2199
The glycosylation marker M2BPGi predicts the development
of hepatocellular carcinoma in nonalcoholic
steatohepatitis
Miwa Kawanaka 1 , Hideyuki Hyogo 2 , Masahiko Koda 3 , Toshihide
Shima 5 , Yuichi Hara 6 , Hiroshi Tobita 4 , Ken Nishino 1 , Akira Hiramatsu
2 , Shuichi Sato 4 , Kazuaki Chayama 2 , Hirofumi Kawamoto 1 ,
Takeshi Okanoue 5 , Keisuke Hino 6 ; 1 General Intrenal medicine2,
Kawasaki-Hostital,Kawasaki Medical school, Okayama-city,
Japan; 2 Medicine and Molecular Sciences,Graduate School of
Biomedical Sciences, Hiroshima University, Hiroshima, Japan;
3 Department of Multidisciplinary Internal Medicine, Tottori University
School of Medicine, Yonago, Japan; 4 Gastroenterology
and Hepatology, Shimane University, School of Medicine, Izumo,
Japan; 5 Saiseikai Suita Hospital, Suita city, Japan; 6 Hepatology
and Pancreatology, Kawasaki Medical School, Kurashiki city,
Japan
[Objectives] The number of non-B non-C hepatocellular carcinoma
(HCC) cases has increased rapidly in recent years,
and the increasing in the incidence of nonalcoholic steatohepatitis
(NASH) has been an associated factor. Therefore,
non-invasive methods are important to detect NASH patients
with a high carcinogenesis risk.The present study examined
the utility of M2BPGi as an indicator of liver carcinogenesis
in NASH patients.[Subjects and methods] In this multicenter
study, 63 patients diagnosed as NASH on the basis of hepatic
histological findings and detected to have HCC (NASH-HCC)
were compared with 280 control patients who, on the basis of
liver biopsy findings, had not developed HCC for 9.8 years
after a NASH diagnosis (NASHnon-HCC) in terms of age,
sex, body mass index, ALT, AST, GTP, AST/ALT ratio, platelet
count, homeostatic assessment model of insulin resistance,
iron, ferritin, and high-sensitivity C-reactive protein, hyaluronic
acid, type IV collagen 7S, and P-III-P, glycosylation markers
(M2BPGi), and fibrosis-4 (FIB4) index, which contribute to HCC
development.[Results] Patients in the NASH-HCC group were