studies

946A AASLD ABSTRACTS HEPATOLOGY, October, 2015
the effects of bile acid signaling on the HPA axis. Methods:
Sprague Dawley rats were fed cholestyramine for 3 days
prior to sham or bile duct ligation (BDL) surgery; corticosterone
levels, hypothalamic corticotropin releasing hormone
(CRH) expression, and serum and hypothalamic bile acid levels
were assessed. Apical sodium-dependent bile acid transporter
(ASBT)- and glucocorticoid receptor (GR)-specific Vivo
morpholinos were infused in the lateral ventricle (1mg/kg/
day) for 3 days, followed by injection of the bile acids cholic
acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid
(CDCA), taurocholic acid (TCA) or glycochenodeoxycholic
acid (GCDA) into the 3 rd ventricle (20 pmol) and HPA activity
was assessed after 6 hr. Hypothalamic neurons were treated
with various bile acids (10 mM) with or without the GR antagonist
RU486 or after ASBT knockdown, and CRH expression
and secretion was assessed. Bile acid uptake was assessed
with the fluorescent bile acid derivative cholyl-lysyl fluorescein
(CLF). The ability of bile acids to activate GR was assessed ex
vivo using a commercially available competition assay and in
vitro by subcellular localization of GR. Results: Cholestyramine
attenuated the HPA axis suppression and increase in hypothalamic
bile acid levels observed during cholestasis. Treatment of
hypothalamic neurons with various bile acids suppressed CRH
expression and secretion in vitro. In vivo, HPA axis suppression
was only evident after injection of conjugated bile acids
(TCA or GCDA). Uptake of CLF was evident in hypothalamic
neurons but was inhibited in ASBT-silenced neurons. TCA- or
GCDA-driven suppression of hypothalamic CRH expression
and circulating corticosterone could be prevented in vitro and
in vivo by inhibiting ASBT-mediated bile acid uptake. Both TCA
and GCDA compete for GR binding sites with endogenous
ligands in an ex vivo competition assay and caused nuclear
translocation of GR in vitro. Inhibiting GR activation in vitro
and in vivo prevented bile acid-driven suppression of the HPA
axis. Conclusions: Taken together our data support the hypothesis
that during cholestatic liver injury, bile acids gain entry to
the brain, are transported into neurons through the ASBT transporter
and can activate GR to suppress the HPA axis. These
data also support the broader hypothesis that bile acids may
act as central modulators of hypothalamic peptides that may be
altered during liver disease.
Disclosures:
The following authors have nothing to disclose: Matthew McMillin, Gabriel A.
Frampton, Stephanie Grant, Matthew A. Quinn, Sharon DeMorrow
1508
Characteristics, indications and outcomes in cirrhotic
patients with portal hypertension undergoing endoscopic
retrograde cholangiography: a case-control
study
Ricardo Macías-Rodríguez, Jose Luis Rodriguez-Garcia, Astrid
Ruiz-Margáin, Aldo Torre; Gastroenterology, INCMNSZ, Mexico,
Mexico
Background: Endoscopic retrograde cholangiography (ERC)
is a useful tool for diagnostic and therapeutic biliary tract diseases.
In patients with cirrhosis, portal hypertension leads to
clinical and biochemical alterations which can exert higher
risk for complications related to ERC. However, scarce data
regarding ERC in cirrhosis are available in medical literature.
Aim:to evaluate the indications, general characteristics and
outcomes of ERC in patients with cirrhosis and portal hypertension.
Methods: This was a case-control study including 37
patients (71 procedures) with cirrhosis and portal hypertension
(C) and 37 age and sex-matched controls without cirrhosis
(NC), undergoing ERC and evaluated 30 days post-ERC. Characteristics
related to ERC (cannulation, sphincterotomy, stenting
and complication rate) and cirrhosis (Child-Pugh and MELD
scores; presence of ascites, hepatic encephalopathy (HE) and
esophageal varices) were recorded. Mann-Whitney’s U and X 2
were used as appropriate.Logistic regression and ROC analysis
with Youden index were used to analyze complications
in cirrhotics. Results: Main etiology of cirrhosis was hepatitis
C infection (22%). Patients were classified as Child A/B/C
(4/18/15), mean MELD was 17.8±6. Complications of cirrhosis
were ascites (46%), esophageal varices (63%; large
esophageal varices 43.7%) and HE (16%). Main differences
in baseline characteristics between groups showed changes
inherent to cirrhosis in biochemical parameters(higher bilirubin
and lower PT, platelets, sodium and albumin). Main indication
in C and NC group for ERC was choledocholithiasis in 46%
and 48%, respectively p=0.816. Cannulation rate was the
same in both groups, (97%, p=1.000). Biliary sphincterotomy
was performed more frequently in NC patients compared to
C (60 vs 35%, p=0.036); there was no difference in complications
related to ERC between C and NC (10% vs 8%,
p=0.677). Factors related to complications in cirrhosis were
lower alkaline phosphatase levels(230± 71 vs 619± 550mg/
dL) and sphincterotomy rate(71 vs 20% for complication and
no complication subgroup, p=0.010). In the multivariable analysis
only sphincterotomy was independently associated to the
presence of complications (OR 9.8[1.7-56.3], p=0.011). ROC
analysis yielded a MELD score>16 to best predict complications
after ERC in cirrhosis (Se 71.4%, Sp 57.8%, AUC 0.616).
Conclusion:Outcomes after ERC in patients with cirrhosis are
similar to non-cirrhotics despite of the alteration in coagulation
parameters and the presence of disease-specific complications,
however a more cautiously approach in patients with cirrhosis
undergoing sphincterotomy and MELD>16 is needed.
Disclosures:
The following authors have nothing to disclose: Ricardo Macías-Rodríguez, Jose
Luis Rodriguez-Garcia, Astrid Ruiz-Margáin, Aldo Torre
1509
Efficacy of Ornithine Phenylacetate (OP) in lowering
plasma ammonia after upper gastrointestinal bleeding
(UGIB) in cirrhotic patients: a multicenter, randomized,
double blind trial
Meritxell Ventura-Cots 1 , German Soriano 3,4 , Macarena Simon-Talero
1 , Maria Torrens 1 , Albert Blanco 2 , Jose Antonio Arranz 2 , Mar
Concepción 3 , Edilmar A. Alvarado 3 , Cristina Gely 3 , Eva Roman 3 ,
Joan Genescà 1,4 , Juan Cordoba 1,4 ; 1 Liver Unit, Hospital Vall d’Hebron,
Barcelona, Spain; 2 Metabolopathies Unit, Hospital Vall
d’Hebron, Barcelona, Spain; 3 Department of Gastroenterology,
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 4 Instituto
de Salud Carlos III, CIBEREHD, Madrid, Spain
OP has been proposed to decrease ammonia in uncontrolled
studies. Methods: Thirty-eight consecutive cirrhotic patients,
aged between 18-85 years and with a creatinine level lower
than 1.5 mg/dL were enrolled within 24 h of an UGIB. Patients
were randomized (1:1) to receive OP (10g/24h continuous
infusion for 5 days) or placebo, in addition to the usual treatment,
and followed up for 28 days. Ammonia and related
metabolites were assessed by HPLC and mass spectroscopy.
The hypothesis was that OP would produce a 25μmol/L venous
ammonia difference in the means between the groups during
the first 24h. Secondary outcomes included: plasma ammonia
changes at any time point, pharmacokinetic profile, hepatic
encephalopathy and clinical outcome, and confirmation of
safety and tolerability of OP. Treatment groups were compared
using a one-sided exact Wilcoxon rank-sum test. Results: a