studies

950A AASLD ABSTRACTS HEPATOLOGY, October, 2015
1516
Linkage and interaction between portal hemodynamics
and serum sodium concentration in cirrhosis
Hitoshi Maruyama, Takayuki Kondo, Tadashi Sekimoto, Soichiro
Kiyono, Osamu Yokosuka; Department of Gastroenterology and
Nephrology, Chiba University Graduate School of Medicine,
Chiba, Japan
Background/Aim: Although a hyponatremia is frequently
observed in patients with cirrhosis, the prognostic influence
with respect to the presence of concomitant portal hemodynamic
abnormality has yet to be determined. The study aimed
to examine the linkage between portal hemodynamics and
hyponatremia, and their interactions on the prognosis of cirrhosis.
Methods: This study was based on the subgroup analysis
using medical records collected in the prospective study
regarding the influence of portal hemodynamics on clinical
outcomes from November 2007 to November 2012. Clinical
findings including portal hemodynamic parameters measured
by Doppler ultrasound and serum sodium concentrations were
examined with respect to the prognosis. Following patients
were excluded: i) with hepatocellular carcinoma (HCC) diagnosed
by contrast-enhanced CT or magnetic resonance imaging,
or a treatment history of HCC, ii) receiving medications
with vasoactive drugs such as β-blockers, antiviral therapy, or
interventional procedures such as a transjugular intrahepatic
portosystemic or peritoneo-venous shunt, prior to or during,
the study period. Results: There were 153 cirrhosis patients
(62.2 ± 12.0 years; median observation period, 34.1 m). Sixteen
patients were accompanied with hyponatremia (Na <
135 mEq/L), who showed a significantly greater frequency of
possessing a splenorenal shunt (SRS; p = 0.0068), and 137
patients without hyponatremia. Serum sodium concentrations
were significantly lower in patients with a SRS than in those
without (p = 0.0193). An increased prothrombin time-international
normalized ratio was a significant predictive factor for
developing hyponatremia a year later (8/96; Hazard ratio
14.415; p = 0.028). The cumulative survival rate was significantly
lower in patients with hyponatremia (46.7% at 1 and
3 years) than in those without (91.8% at 1 year, 76.8% at 3
years; P < 0.001), and that was significantly lower in patients
who had developed hyponatremia after one year (100% at 1
year, 62.5% at 3 years) than those who had not (100% at 1
year, 89.0% at 3 years; P < 0.001). In addition, the cumulative
survival rate was significantly worse in patients with both hyponatremia
and a SRS (20% at one year) than in others (91.8%
at 1 year, 76.3% at 3 years, and 63.1% at 5 years in patients
with neither hyponatremia nor a SRS, p < 0.0001; 77.4% at 1
year, 72.6% at 3 years and 58.1% at 5 years in patients with
hyponatremia or a SRS, p = 0.014). Conclusions: There was
a close linkage between the serum sodium concentration and
portal hemodynamic abnormality, a presence of SRS, and their
interaction may negatively influence the prognoses in cirrhosis.
Disclosures:
The following authors have nothing to disclose: Hitoshi Maruyama, Takayuki
Kondo, Tadashi Sekimoto, Soichiro Kiyono, Osamu Yokosuka
1517
Ammonia Produces Pathological Changes And Activation
In Human Hepatic Stellate Cells And Is A Target For
Therapy In Portal Hypertension
Francesco De Chiara, Rajiv Jalan, Vairappan Balasubramaniyan,
Fausto Andreola, Massimo Malago, Massimo Pinzani, Rajeshwar
Mookerjee, Krista Rombouts; UCL, London, United Kingdom
Background: Hepatic stellate cells (HSC) are vital to hepatocellular
function and the liver’s response to injury. They share
a phenotypic homology with astrocytes that are central in the
pathogenesis of hepatic encephalopathy, a condition in which
hyperammonemia plays a pathogenic role. This study tested
the hypothesis that ammonia modulates human HSC activation
in vitro and in vivo, and evaluated whether ammonia lowering,
by using L-ornithine phenylacetate (OP), modifies HSC activation
in vivo and reduces portal pressure in a bile duct ligation
(BDL) model. Methods: Primary human HSCs were isolated
and cultured. Proliferation (BrdU), metabolic activity (MTS),
morphology (TEM, light and immunofluorescence microscopy),
HSC activation markers by protein analysis, and changes in
oxidative status (ROS) and endoplasmic reticulum (ER) were
evaluated to identify effects of ammonia challenge (50 mM,
100 mM, 300 mM) over 24-72hrs. Changes in plasma ammonia
levels, markers of HSC activation, portal pressure, hepatic
eNOS activity and expression of its regulatory proteins were
quantified in hyperammonemic BDL animals, and after OP
treatment. Results: Pathophysiological ammonia concentrations
caused significant and reversible changes in cell proliferation,
metabolic activity and activation markers of hHSC
in vitro. Highly significant alterations in cellular morphology,
characterised by cytoplasmic vacuolisation, ER enlargement
and ROS production, pro-inflammatory gene expression were
observed together with HSC-related activation markers such as
α-SMA, myosin IIa, IIb, and PDGF-Rβ. Treatment with OP significantly
reduced plasma ammonia (BDL 199.1mmol/L±43.65
vs. BDL+OP 149.27mmol/L±51.1, P