studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 853A
increase in hepatic IL-6 and IL-1β expression and neutrophil
infiltration as showed by CAE staining, which were associated
with TLR4 up-regulation. In the HIF-1α -/- mice, alcohol exposure
disrupted intestinal structure integrity as shown by H&E staining
of ileal sections. 16s RNA analysis of the cecal and fecal
samples from HIF1α -/- mice exposed to alcohol showed an elevated
dysbiosis. PCR analysis revealed that alcohol exposure
decreased the expression of tight junction gene, occludin, and
CRAMP, P-gp, and ITF, which are HIF-1α transcription target
genes and important for gut microbiota homeostasis and intestinal
barrier integrity. Ex vivo assay demonstrated that HIF1α
-/-
increased alcohol-induced ileal permeability. Conclusions:
Our results demonstrated that intestinal HIF-1α is required for
the adaptation response to alcohol exposure-induced changes
in intestinal microbiota and barrier function leading to elevated
endotoxemia and hepatic steatosis and injury.
Disclosures:
Craig J. McClain - Consulting: Vertex, Gilead, Baxter, Celgene, Nestle, Danisco,
Abbott, Genentech; Grant/Research Support: Ocera, Merck, Glaxo SmithKline;
Speaking and Teaching: Roche
The following authors have nothing to disclose: Tuo Shao, Liming Liu, Fengyuan
Li, Lihua Zhang, Wenke Feng
1306
Fibroblast growth factor 21 is critically involved in alcohol-induced
hepatic lipid metabolism and adipose tissue
lipolysis in mice
Cuiqing Zhao 1 , Liming Liu 1 , Ying Yang 1 , Craig J. McClain 1,2 ,
Wenke Feng 1 ; 1 Department of Medicine/GI, University of Louisville,
Louisville, KY; 2 Robley Rex VAMC, Louisville, KY
Purpose: Fibroblast growth factor 21 (FGF21) is a novel
metabolic regulator produced primarily in the liver that regulates
hepatic fat metabolism in various models of metabolic
syndromes. Alcoholic liver disease (ALD) is characterized by
hepatic lipid accumulation. Here, we sought to determine
the role of FGF21 in mice exposed to alcohol and to discern
underlying mechanisms. Methods: Male FGF21 knockout (KO)
and control (WT) mice were fed either the Lieber DeCarli diet
containing 5% alcohol (AF) or an isocaloric diet (PF). For the
chronic alcohol exposure, mice were fed for 4 weeks. For the
chronic-binge alcohol exposure, mice were fed for 12 days,
followed by a single dose of alcohol (5g/kg) or isocaloric
maltose dextrin treatment by gavage. Mice were sacrificed
6 hours later. One group of AF mice were administered with
recombinant human FGF21 (rhFGF21) for the last 5 days.
Liver steatosis and inflammation and epididymal white adipose
tissue (eWAT) lipolysis were investigated. Results: Alcohol
exposure induced plasma FGF21 elevation. FGF21 knockout
exacerbated chronic alcohol-induced hepatic steatosis and
liver injury, which was associated with increased activation
of genes involved in lipogenesis mediated by SREBP1c and
decreased expression of genes involved in fatty acid (FA)
β-oxidation mediated by PGC1α. Chronic alcohol exposure
induced a moderate adipose tissue lipolysis in eWAT. rhFGF21
administration reduced alcohol-induced hepatic steatosis and
inflammation in WT mice. Surprisingly, in the chronic-binge
model, alcohol consumption-induced fatty liver is blunted in
the KO mice. Chronic-binge alcohol exposure-induced in situ
hepatic lipogenesis and FA β-oxidation were comparable to
that in chronic alcohol-exposed mice. However, FGF21 deficiency
markedly reduced chronic-binge alcohol exposure-induced
eWAT lipolysis, which may contribute to hepatic FA
uptake. Further analysis showed that in the KO mice alcohol
induced significant elevation in systemic catecholamine, which
is known to promote adipose lipolysis. rhFGF21 administration
increased alcohol- induced fat loss in parallel with an increase
of circulating norepinephrine concentration in KO mice. Conclusion:
Our results demonstrated that the role of FGF21 in ALD
is alcohol exposure model dependent. Lack of FGF21 exacerbates
chronic alcohol exposure-induced fatty liver, and this
exaggeration is overridden in chronic-binge alcohol exposed
mice through a reduction of adipose lipolysis mediated by
systemic catecholamine release involving sympathetic nervous
system activation. Pharmacologic strategies targeting hepatic
FGF21 elevation and reduction in adipose tissue lipolysis are
warranted.
Disclosures:
Craig J. McClain - Consulting: Vertex, Gilead, Baxter, Celgene, Nestle, Danisco,
Abbott, Genentech; Grant/Research Support: Ocera, Merck, Glaxo SmithKline;
Speaking and Teaching: Roche
The following authors have nothing to disclose: Cuiqing Zhao, Liming Liu, Ying
Yang, Wenke Feng
1307
Early prediction of response in patients with severe
acute alcoholic hepatitis by using Lille model on day 4
Mauricio Garcia-Saenz de Sicilia 1 , Chitharanjan Duvoor 2 , Jose
Altamirano 4,5 , Veronica Prado 3,4 , Juan Caballeria 3,4 , Andres
Duarte-Rojo 1 ; 1 Gastroenterology and Hepatology, University of
Arkansas for Medical Sciences, Little Rock, AR; 2 Internal Medicine,
University of Arkansas for Medical Sciences, Little Rock, AR; 3 Liver
Unit, Hospital Clinic, Barcelona, Spain; 4 Institut d’Investigacions
Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; 5 Vall
d’Hebron Institut de Recerca, Barcelona, Spain
BACKGROUND: Corticosteroids are the mainstay of treatment
for severe alcoholic hepatitis (SAH) associated with a lower
28-day mortality. Lille model (LM) can identify non-responders
after 7 days of treatment, however this requires longer
exposure and increases the risk of infection. We aimed to
evaluate LM at day 4(LM4) of treatment with corticosteroids
in comparison to day 7(LM7). METHODS: We performed a
retrospective analysis of a multinational cohort with SAH based
on a discriminant function (DF)>32. Response to corticosteroids
was assessed with LM7 and LM4 according to the validated
cutoff value (CUV>0.45). ROC-curves were constructed to
determine an ideal CUV for LM4, and to compare accuracy
of LM4, LM7, MELD, and ABIC. Logistic regression models
were constructed to predict 90-day mortality. RESULTS: A total
of 132 (83.9%) out of 162 patients with SAH received corticosteroids.
Mean age was 47.87±10.58, 98 (60.49%) were
males, and BMI was 27.58±6 kg/m 2 . On admission the mean
bilirubin was 17±10 mg/dL, creatinine 0.97 (0.7-1.8) mg/
dL, INR 1.92±0.63. Severity parameters on admission were
DF 58.34±33.38, MELD 24.98±8.79, and ABIC 8.18±1.56.
Although mean LM4 and LM7 were statistically different
(0.56±0.03 and 0.52±0.03, p=0.005), the proportion of
responders was similar 45%(n=53) and 49%(n=56) p=0.08,
and there was agreement in 90% of cases (k=0.80). Three
patients became responders between days 4 and 7 (all died).
Accuracy of SAH scores to predict 90-day mortality (AUROC)
was: MELD 0.687 (0.595-0.778), ABIC 0.729 (0.648-0.809),
LM4 0.686 (0.593-0.775), LM7 0.723 (0.633-0.813). In univariate
analysis LM4, SIRS, infection, hepatic encephalopathy,
and gastrointestinal bleeding predicted mortality, however, in
the multivariate analysis only LM4 (OR=4.67 [1.40-15.54])
and GIB (OR=4.94 [1.40-15.25]) remained significant, with a
trend for HE (OR=1.86 [0.96-4.55]). The operational characteristics
of LM4 and LM7 as predictors of 90-day mortality are
shown in table-1. CONCLUSION: LM4 is good as LM7 as predictor
of 90-day mortality or response to corticosteroids. Using
LM4 instead of LM7 would help decrease exposure to corticosteroids,
infection risk, and health care costs. Although there