studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1075A
1778
Early elevation in serum IFN-λ3 is responsible for progressive
liver failure caused by acute infection of Hepatitis
E virus genotype 4
Jong-Hon Kang 1 , Kazumoto Murata 2 , Yoshiyasu Karino 3 , Takeshi
Matsui 1 , Itaru Ozeki 3 , Kazuaki Takahashi 4 , Masahiro Arai 4 ,
Masashi Mizokami 2 ; 1 Center for Gastroenterology, Teine Keijinkai
Hospital, Sapporo, Japan; 2 The Research Center for Hepatitis and
Immunology, National Center for Global Health and Medicine,
Tokyo, Japan; 3 Department of Hepatology, Sapporo Kosei General
Hospital, Sapporo, Japan; 4 Department of Medical Sciences,
Toshiba General Hospital, Tokyo, Japan
Background / Aims: Acute sporadic infection of hepatitis E virus
(HEV) has been emerging in non-endemic countries because of
increasing clinical impacts. Hepatitis E virus (HEV) of genotype
(Gt) 4 was showed to be more responsible for development of
acute liver failure (ALF) compared with Gt 3 in our previous
report (abstract ID; 745, AASLD 2014). However, the relationships
between genotypic differences and disease severity have
been obscure. Interferon (IFN)-λ3 has been recognized as one
of markers for innate immune responses against viral infection,
such as HCV infection. The aim of this study is to clarify the
mechanism of disease progression in acute HEV of Gt 4 infection
by the analysis of serum IFN-λ3 levels. Methods: Among
98 patients with sporadic and autochthonous hepatitis E diagnosed
in Hokkaido, Japan, a total of 43 patients in whom early
sera were sampled during the day 2 to 14 after the onset were
enrolled. Acute HEV infection was diagnosed upon the detection
of HEV RNA by PCR or anti-HEV antibody (IgM) in sera by
enzyme linked immune-sorbent assay (ELISA). HEV genotypes
(Gt) were determined by comparison of a 326-nt sequence
within ORF1 of HEV genome. IFN-λ3 levels were measured
by chemiluminescence ELISA and HEV RNA were quantified
by real time PCR for the same sera obtained from the patients.
Acute liver failure (ALF) was defined to be a case with longer
prothrombin time (INR>1.5). Results: Out of 43 patients with
acute HEV (32 males, median age 56 years) thus collected, 15
developed ALF, in which 2 presented hepatic coma. HEV Gt
4 was determined in 27 patients, Gt 3 in 13, co-infection with
Gt 3+4 in 1, and not determined in 2. IFN-λ3 level was 11.5
(1.5-120.4) pg/ml at Day 4.5 (1-13) in median. In Gt 4 cases,
median peak levels in AST and ALT were higher than those with
Gt 3, respectively, and, as previously reported, Gt 4 infection
was correlated with development of ALF in comparison with Gt
3 (14/15 vs. 1/15, p=0.002, OR 16.2[95%CI, 1.9-140.1]).
Serum IFN-λ3 levels were higher in Gt 4 cases than those in Gt
3 cases (15.9 vs. 5.0 pg/ml, p=0.001), despite of no difference
in sampling timing of sera between Gts. Among 27 cases
with Gt 4 infection, IFN-λ3 levels were higher in ALF cases than
in self-limited (26.3 vs. 12.8 pg/ml, p=0.046), and IFN-λ3 levels
revealed correlation with HEV RNA titrations in sera in Gt 4
(r=0.701, p=0.008). Conclusion: Our study may implicate the
pathological roles of IFN-λ3 in acute hepatitis E especially ALF
due to HEV Gt 4 infection, and serum IFN-λ3 would be a useful
predictive marker for disease-severities.
Disclosures:
Yoshiyasu Karino - Speaking and Teaching: BMS KK
The following authors have nothing to disclose: Jong-Hon Kang, Kazumoto
Murata, Takeshi Matsui, Itaru Ozeki, Kazuaki Takahashi, Masahiro Arai,
Masashi Mizokami
1779
Expression of Krüppel-like factor 6 parallels induction of
autophagy in acute liver injury
Svenja Sydor 1 , Jan Best 1 , Paul P. Manka 1 , Sami Jafoui 1 , Martin
Schlattjan 1 , Francisco Javier Cubero 2 , Thomas Schreiter 1 , Diana
Vetter 3 , Andreas Paul 4 , Scott L. Friedman 5 , Guido Gerken 1 , Ali
Canbay 1 , Lars Bechmann 1 ; 1 Department of Gastroenterology and
Hepatology, University Hospital Essen, Essen, Germany; 2 Department
of Medicine III, Gastroenterology, Metabolic Disease and
Intensive Care, University Hospital RWTH Aachen, Aachen, Germany;
3 Department of Surgery, University Hospital Zurich, Zurich,
Switzerland; 4 Department of General- and Transplant -Surgery,
University Hospital Essen, Essen, Germany; 5 Division of Liver Diseases,
Mount Sinai School of Medicine, New York, NY
Krüppel-like factor 6 (KLF6) is a ubiquitously expressed, multifunctional
transcription factor and tumor suppressor gene regulating
hepatocyte glucose and lipid homeostasis and KLF6
down-regulation is associated with proliferation in hepatocellular
cancer. Autophagy regulates turnover of long-lived or
damaged organelles and proteins, which affects liver regeneration
by maintaining intracellular energy production. With
this study, we characterized the role of KLF6 in liver injury
and regeneration and found significant correlations with the
induction of autophagy. KLF6 expression was quantified in
liver samples from 10 patients with acute liver failure (ALF)
and 10 controls. Human liver preparations were treated with
acetaminophen (APAP) up to 30 hours in an established ex
vivo perfusion model. Furthermore, C57B/6 mice were sacrificed
8h after APAP injection (6 mice/group) and HepG2
cells were incubated with APAP for 24h. We characterized
the role of KLF6 in liver regeneration in vivo in a model of partial
hepatectomy (PHx) in wildtype (wt) or hepatocyte-specific
KLF6 knockout mice (dKLF6) (6 mice/group). We performed
an Affymetrix gene array (HT-MG4306) on liver samples of
dKLF6 and wt mice at 12h after PHx. KLF6 expression was significantly
induced in hepatocytes from ALF patients compared
to controls. APAP perfusion of liver tissue significantly induced
KLF6 expression and KLF6 was significantly upregulated in
APAP treated mice. The gene array revealed significant alterations
in autophagy related genes in dKLF6 mice compared to
wt following PHx. Hepatocyte proliferation was significantly
induced at early time points after PHx in dKLF6 mice compared
to wt. Western blot analyses of whole liver tissue from dKLF6
mice revealed reduced levels of LC3-II 72h after PHx. dKLF6
mice had decreased expression levels of autophagy related
molecules Atg7 and Beclin1 before and after PHx compared to
wt mice. HepG2 cells and murine liver tissue showed increased
LC3-II levels following APAP treatment. Here, we observed a
consistent induction of hepatic KLF6 expression in various models
of acute liver injury. Results from hepatocyte-specific KLF6
knockout mice implicate a significant role for KLF6 in early
hepatic regeneration. Furthermore, gene array data as well as
studies on mRNA and protein expression in mice, humans and
cell culture reveal a novel interaction between KLF6 and autophagy
in acutely injured hepatocytes. The underlying mechanisms
need further characterization.
Disclosures:
Jan Best - Speaking and Teaching: BTG
Scott L. Friedman - Advisory Committees or Review Panels: Pfizer Pharmaceutical;
Consulting: Conatus Pharm, Exalenz, Genfit, Exalenz Biosciences, Eli Lilly PHarmaceuticals,
Fibrogen, Boehringer Ingelheim, Nitto Corp., Immune Therapeutics,
Synageva, Roche/Genentech Pharmaceuticals, DeuteRx, Abbvie, Novartis,
RuiYi, Kinemed, Sanofi Aventis, Takeda Pharmaceuticals, Nimbus Therapeutics,
Bristol Myers Squibb, Astra Zeneca, Sandhill Medical Devices, Galmed, Northern
Biologics, Enanta Pharmaceuticals, Regado Bioscience, Raptor Pharmaceuticals,
Teva Pharmaceuticals, Zafgen Pharmaceuticals, Merck Pharmaceuticals,
Debio Pharmaceuticals; Grant/Research Support: Galectin Therapeutics, Tobira
Pharm; Stock Shareholder: Angion Biomedica, Intercept Pharma