studies

516A AASLD ABSTRACTS HEPATOLOGY, October, 2015
(2). Model parametrization was completed using measured
viscosity from gallbladder bile of patients treated with UDCA
and quantitative 3D-reconstruction of stacked high resolution
microscopy of healthy human and PSC livers. Bile viscosity and
osmotic water inflow are modelled as functions of UDCA dose
according to effects (1) and (2) above. Results: This quantitative
model allows the assessment of the mechanical consequences
of UDCA treatment in a dose-dependent manner and predicts
intrahepatic fluid pressure as a function of the physical properties
of bile and the geometrical properties of the tissue. For
healthy liver, the model reproduces the insensitivity of biliary
pressure to UDCA dose. In PSC, a pronounced dose-response
curve is predicted by our model: biliary pressure is decreasing
at UDCA dose increments, reaches a minimum and then rapidly
increases beyond baseline upon further dose increments. The
optimal UDCA dose corresponding to the maximum pressure
reduction can be quantified as a function of the physical and
geometrical parameters that may vary from patient to patient.
Conclusions: This study provides a hydrodynamic explanation
of the clinical dose-response of UDCA in PSC. Further, it confirms
tolerance to high doses of the compound in normal liver.
Mechanistically, the UDCA-induced increase in water inflow
has pressure-lowering (bile dilution) and pressure-increasing
(increased fluid volume in need of drainage) consequences.
Thus, the model advocates individualized dose-optimization
based on the patient-specific biliary micro-geometry, thereby
potentially rendering UDCA treatment safer and more widely
applicable.
Disclosures:
The following authors have nothing to disclose: Oleksandr Ostrenko, Fabian
Segovia-Miranda, Mario Brosch, Wiebke Erhart, Kirstin Meyer, Georg Kretzschmar,
Christoph Jüngst, Frank Lammert, Marino Zerial, Clemens Schafmayer, Lutz
Brusch, Jochen Hampe
618
In PSC with dominant bile duct stenosis, multi-resistant
bacteriobilia is associated with reduced survival
Christian Rupp 1 , Hannah Salzer 1 , Konrad A. Bode 2 , Karl Heinz
Weiss 1 , Wolfgang Stremmel 1 , Peter Sauer 1 , Daniel Gotthardt 1 ;
1 Internal Medicine IV, University Hopsital Heidelberg, Heidelberg,
Germany; 2 Department of Infectious Diseases, University of Heidelberg,
Heidelberg, Germany
Background & Aims: Primary sclerosing cholangitis (PSC) is
a chronic cholestatic liver disease, characterized by sclerosis
and destruction of the biliary system. The course of diseases is
often complicated by biliary infections. We aimed to analyze
the frequency and influence of cholangitis with multi-resistant
bacteria in PSC patients. Methods: Patients who were admitted
to our Department during the time period of 1987 and
2014 with well-defined diagnosis of PSC were analyzed in
regard to multi-resistant bacteria in bile cultures. Comparison
between frequencies was done using Chi-Square-test or Fisher’s
exact test where appropriate. Continuous data were compared
with the nonparametric Wilcoxon rank-sum test. Actuarial
transplantation-free survival was estimated using Kaplan-Meier
product limit estimator. Differences between the actuarial estimates
were tested with the log rank test. Results: We identified
20/244 (8.3) patients with multi-resistant bacteriobilia.
8 patients had vancomycin resistant enterococcus (VRE) and
12 had multi-resistant gram negative bacteria (MRGN) in bile
culture. Baseline characteristic including laboratory values
(AST, ALT, GGT, AP, Bilirubin), age at onset of PSC, concomitant
inflammatory bowel disease, overlap with autoimmune
hepatitis, dominant stenosis and Mayo Risk Score were not
different between patients with or without MR bacteria. There
was no difference in frequency of MR bacteriobilia between
patients with or without DS (14/159, 8.8% vs. 5/66, 7.6%;
p=0.8). We performed Kaplan-Meier analysis showing a markedly
reduced transplantation-free survival in PSC patients with
MR bacteriobilia (17.2 vs. 11.0 years; p=0.014). Stratification
for presence of DS revealed reduced survival in presence
of MR bacteriobilia only in patients with DS (16.7 vs. 9.9
years; p=0.001), whereas no influence was detectable in PSC
patients without DS (21.0 vs. 17.8 years; p=0.8). In multivariate
analysis, including gender, age, AIHOL, IBD, DS, number
of endoscopic interventions, MRS and MR bacteriobilia, only
IBD (HR 3.3, 95% CI 1.1-11.1; p=0.04), MRS (HR 1.5, 95%
CI 1.1-2.1; p=0.04) and MR bacteriobilia (HR 3.2, 95% CI
1.1-9.5; p=0.03) were independent risk factors for reduced
transplantation-free survival. Conclusion: In PSC patients with
dominant stenosis MR bacteriobilia is associated with reduced
survival, independent of number of endoscopic interventions.
Multi-resistant bacteria may play a role in the progression of
PSC. Optimal treatment strategies need to be established in
order to achieve eradication of MR bacteriobilia.
Disclosures:
The following authors have nothing to disclose: Christian Rupp, Hannah Salzer,
Konrad A. Bode, Karl Heinz Weiss, Wolfgang Stremmel, Peter Sauer, Daniel
Gotthardt
619
Innate Immunity Drives the Initiation of Autoimmune
Cholangitis in a Xenobiotic Murine Model of Primary
Biliary Cirrhosis
Chao-Hsuan Chang 2 , Ying-chun Chen 2 , Weici Zhang 1 , Patrick S.
Leung 1 , M. Eric Gershwin 1 , Ya-Hui Chuang 2 ; 1 Internal Medicine,
University of California, Davis, CA; 2 Department of Clinical Laboratory
Sciences and Medical Biotechnology, National Taiwan
University, Taipei, Taiwan
Background: Invariant natural killer T (iNKT) cells are important
in bridging innate and adaptive immunity by engaging
with glycolipids presented by CD1d. α-galactosylceramide
(α-GalCer) is a specific ligand for iNKT cell activation. Modification
of α-GalCer lipid chain results in the generation of
glycolipids with predominant Th1 or Th2 cytokine skewing
profiles. (2s,3s,4r)-1-O-(α- D
-galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol
(OCH) is a synthetic analog
of α-GalCer which stimulates iNKT cells to predominantly Th2.
Previous work in our group has demonstrated that iNKT cell
activation by α-GalCer resulted in profound exacerbation of
portal inflammation, bile duct damage, and hepatic fibrosis
in the 2 octynoate-BSA (2OA-BSA) xenobiotic murine model
of PBC. Here, we examined whether iNKT cells activated by
a Th2-biasing agonist OCH, can influence the development of
PBC in 2OA-BSA immunized mice. Methods: Groups of mice
were treated with either OCH or α-GalCer and serially followed
for cytokine production, markers of T cell activation,
liver histopathology and anti-mitochondrial antibodies (AMA).
In addition, groups of CD1d deleted mice and wild type mice
were immunized with 2OA-BSA and monitored for liver infiltrates
including CD4+ T cells, CD8+ T cells, NKT, NK and B
cells. IFN-γ production by liver mononuclear cells were also
compared. Results: 2OA-BSA mice treated with OCH exhibited
a Th2 biased cytokine; α-GalCer initiated a rapid IL-4
and prolonged IFN-γ production, whereas OCH induced predominant
IL-4 production. Both OCH and α-GalCer induced
high levels of AMA in 2OA-BSA immunized mice and had
exacerbated portal inflammation and hepatic fibrosis. However,
at 12 weeks post immunization, 2-OA-BSA/OCH immunized
mice had significantly higher liver total mononuclear
cell infiltrates, increased numbers of T, B and NK cells, and