Complications of Cirrhosis


1316

Splanchnic hypercoagulability in cirrhosis correlates with portal hypertension and is exacerbated by bacterial infections

Sebastian Raffa1,3, Juan Carlos Reverter2, Susana Seijo3,4, Juan G. Abraldes3,4, Dolors Tassies2, Annalisa Berzigotti3,4, Juan Carlos Garcia-Pagan3,4, Jaime Bosch3,4;

1Liver transplantation unit, Fun-dación Favaloro, Buenos Aires, Argentina; 2Hemotherapy and Hemostasis Department, Hospital Clinic, Barcelona, Spain; 3Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Barcelona, Spain; 4Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain

Background and aims: Cirrhosis has been recently shown to be a pro-thrombotic condition. This may be due to a relative unbalance between endogenous pro- and anti-coagulants and pro-and anti-fibrinolytic factors. This may explain the high incidence of portal vein thrombosis in cirrhosis. We hypothesized that this would be particularly evident in the hepato-splanchnic vascular bed and that it might be favored by bacterial infections. Patients and methods: Sixty-nine patients (pts) with cirrhosis were prospectively studied at the time of HVPG measurements. Sixteen pts were infected and 53 were not. All pts had simultaneous measurements in hepatic venous and peripheral blood of: Procoagulant factors (I, II, V, VII, VIII, IX, X, XI, XII), von Wille-brand antigen (vWF-Ag), anticoagulant factors: Antithrombin (AT), protein C and S, Markers of coagulation activation: D-dimer, plasmin-antiplasmin complex (PAP), plasminogen activator inhibitor (PAI), prothrombin fragment F1+2 (F1+2), factor VIIa (F-VIIa), activated Factor XII (F.XIIa) and endogenous throm-bin potential (ETP) with/without thrombomodulin, Microparti-cles, tissue factor and platelet-activating factors: Soluble P-selectin and soluble CD40 ligand (CD40Ls). These measurements were also done in portal venous blood in 13 pts undergoing TIPS. To compare continuous variables, Mann-Whitney U or Wicoxon tests were used. Correlation between continuous variables was done with Spearman rank test. The level of statistical significance was set at a P < 0.05. Results: Patients had a median age of 54.3 years old, 61% were males and cirrhosis was due to HCV (45%), alcohol (33%) and others (22%). Markers of coagulation activation (PAI, F-VIIa, F1+2, XIIa), vWF-Ag and Microparticles in non-infected cirrhotic patients were significantly and linearly correlated with HVPG, MELD and Child-Pugh score. Microparticles (31.6 vs. 25.9 nM/Eq, P=0.001) and CD40Ls (144 vs. 115 pg/ml, P= 0.002) were higher in hepatic venous blood than in peripheral blood. Levels of F1 +2 (1.7 vs. 1.6 nmol/L; P= 0.03), Microparticles (47 vs. 28.8 nM/Eq; P= 0.03) and ETP with thrombomodulin (272 vs. 258 nM; P= 0.02) were significantly higher in portal venous blood than in peripheral blood. Coagulation activation markers and platelet activation markers (CD40Ls and P selectin) were significantly higher in infected cirrhotics, despite a similar Child-Pugh and HVPG. Conclusions: Markers of coagulation activation, and thus the procoagulant state of cirrhosis, increase in correlation with the degree of liver failure and portal hypertension. This is more evident in the splanchnic territory and is further exacerbated during bacterial infections.

Disclosures:

Juan Carlos Garcia-Pagan - Grant/Research Support: GORE

Jaime Bosch -Advisory Committees or Review Panels: Intercept pharma; Consulting: Chiasma, Gilead Science, Norgine, ONO-USA; Grant/Research Support: Gore

The following people have nothing to disclose: Sebastian Raffa, Juan Carlos Reverter, Susana Seijo, Juan G. Abraldes, Dolors Tassies, Annalisa Berzigotti

1317

The circulating level of the endocannabinoid-related molecule oleoyl-ethanolamine (OEA) correlates with clinical complications and 1 -year survival in patients with cirrhosis

Maurizio Baldassarre1,2, Marco Domenicali1,2, Ferdinando A. Giannone1,2, Maristella Laggetta1,2, Flaminia Fanelli1,2, Marco Mezzullo1,2, Uberto Pagotto1,2, Mauro Bernardi1,2, Paolo Caraceni1,2;

1Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy; 2Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi University Hospital, Bologna, Italy

Background. Anandamide (AEA), the most studied endo-cannabinoid (EC) has been implicated in the pathogenesis of fatty liver disease, hepatic fibrogenesis, and many cardio-cir-culatory disturbances occurring in advanced cirrhosis. More recently, two AEA-related molecules, like oleoyl-ethanolamine (OEA) and palmitoyl-ethanolamine (PEA), have been reported to be elevated in patients with cirrhosis. These molecules share the same synthetic and degradative pathway with AEA, but they trigger their biological effects by acting on different, non-CB receptors. Thus, we aimed to assess in a large cohort of cir-rhotic patients whether circulating PEA and OEA are associated to specific clinical features of the disease. Materials and methods. 156 cirrhotic patients (mean age 60.3±11.5; 66% male) hospitalized for an acute complications and 108 healthy subjects (mean age 59.6±11.2 years; 65% male) were enrolled. Clinical and biochemical parameters were recorded at study inclusion and 1-year survival was assessed. Circulating levels of AEA, PEA and OEA were measured through an LC/MS/MS technique. As gender has been found to greatly affect the circulating levels of EC in the general population, a Z-score for cirrhotic male and female was calculated for each molecule as follows: (observed value - mean population value)/standard deviation of the population. Results. Circulating AEA, OEA and PEA were all significantly increased in cirrhotic patients as compared to healthy subjects. As female present higher circulating EC than male in both healthy and cirrhotic populations, the Z-score was calculated for each molecule. Normalized OEA and PEA, but not AEA, correlated with the MELD score. Contrary to AEA and PEA, OEA was significantly associated with arterial hypotension, ascites, hepatic encephalopathy, bacterial infection, and renal failure. Finally, at Cox regression, OEA Z-score was more accurate to predict 1-year survival than MELD and Child-Pugh classes [OR(95%CI) 1,94 (1,34–2,80)]. Conclusions. Beside AEA, the two AEA-related molecules, OEA and PEA, are up-regulated in patients with cirrhosis. However, the circulating OEA level is also associated with specific complications of cirrhosis and performs as an independent predictor of survival. As OEA has been recently found to induce vasorelax-ation of mesenteric artery branches in non cirrhotic rats, partially by activating the vanilloid receptor, and to enhance AEA activity by lowering its reuptake and degradation, the patho-physiological role of OEA in advanced cirrhosis should be further investigated.

Disclosures:

Mauro Bernardi - Consulting: CLS Behring GhmB; Speaking and Teaching: CLS Behring GhmB, PPTA Europe

The following people have nothing to disclose: Maurizio Baldassarre, Marco Domenicali, Ferdinando A. Giannone, Maristella Laggetta, Flaminia Fanelli, Marco Mezzullo, Uberto Pagotto, Paolo Caraceni

1318

The G-1T polymorphism in the farnesoid X receptor predisposes to spontaneous bacterial peritonitis in cirrhotic patients with ascites

Hans Dieter Nischalke1, Philipp Lutz1, Cordula Berger1, Frank Grünhage2, Beate Appenrodt2, Frank Lammert2, Jacob Natter-mann1, Tilman Sauerbruch1, Christian P. Strassburg1, Ulrich Spen-gler1;

1 Department of Internal Medicine I, University of Bonn, Bonn, Germany; 2Department of Medicine II, Saarland University Medical Center, Homburg, Germany

Background and Aims: The farnesoid X receptor (FXR) has been shown to be involved in bacterial translocation in mice. In humans with liver cirrhosis, bacterial translocation from the intestine can result in spontaneous bacterial peritonitis (SBP). We hypothesized that the rs56163822 G-1T polymorphism in the FXR gene (NR1H4) might be related to the occurrence of SBP. Methods: We collected blood for genotyping and clinical data of 267 cirrhotic patients with ascites and 226 healthy controls. Standard clinical and laboratory data were recorded with particular interest for the occurrence of SBP. The NR1H4 rs56163822 polymorphism as well as the known genetic risk factors for SBP in the NOD2 (rs2066844, rs2066845, rs2066847) and TLR2 (rs4696480) gene were determined on the LightCycler system. Results: In our cohort 101 (38%) patients with liver cirrhosis and ascites had SBP. Distribution of NR1H4 rs56163822 genotypes (GG/GT) matched the Hardy-Weinberg equilibrium (Cirrhosis with ascites: 96.6%/3.4%; healthy controls: 96.5%/3.5%). Patients with SBP had a significantly higher frequency of the heterozygous (GT) genotype (6.9%) than patients without SBP (1.2%, OR=6.1, p=0.012). A multivariate Cox-regression analysis confirmed the NR1 H4 GT genotype as an independent predictor of SBP (OR=6.9, p=0.022). Conclusion: We found that the G-1T polymorphism in the FXR gene is a new independent risk factor for SBP in cirrhotic patients. This result demonstrates that FXR is possibly involved in intestinal bacterial translocation in human disease. FXR modulators might be a new target for prophylaxis of SBP without the risk of inducing resistance to antibiotics.

Disclosures:

Christian P. Strassburg -Advisory Committees or Review Panels: Novartis, Roche; Speaking and Teaching: Novartis, Merz, MSD, Falk Pharma

The following people have nothing to disclose: Hans Dieter Nischalke, Philipp Lutz, Cordula Berger, Frank Grünhage, Beate Appenrodt, Frank Lammert, Jacob Nattermann, Tilman Sauerbruch, Ulrich Spengler

1319

Expression microarray reveals an extensive defect in the interferon (IFN)-independent activation of antiviral genes in patients with alcoholic cirrhosis

Emmanuel Weiss1,2, Magali Fasseu1, Pierre-Emmanuel Rautou3, Laure Elkrief3, Catherine Paugam-Burtz1,2, Dominique Valla1,3, Didier Lebrec1,3, Pierre de la Grange4, Richard Moreau1,3;

1Team Innate Immunity and Cellular Stress in Liver Diseases, Biomedical Research Center Bichat-Beaujon CRB3, Inserm U773,, Paris, France; 2Anesthesiology and Critical Care Medicine, Beaujon Hospital, Clichy, France; 3Liver Unit, Beaujon Hospital, Clichy, France; 4Genosplice Technology, St Louis Hospital, Paris, France

Background/aims: Bacterial translocation and subsequent release of bacterial products such as lipopolysaccharide (LPS) are known to be involved in the progression of alcoholic liver disease (ALD). In murine models of ALD, canonical antiviral type 1 IFN pathways have been shown to be protective against alcohol-induced liver injury. Since LPS induces type 1 IFN and antiviral IFN-stimulated genes (ISGs) in immune cells from healthy subjects, we hypothesized that these inductions could be defective in patients with alcoholic cirrhosis. Thus, we investigated the LPS antiviral response in peripheral blood mononu-clear cells (PBMCs) from these patients. Methods: MRNAs were obtained from “healthy” and “cirrhotic” PBMCs stimulated or not by LPS for 4 h. We performed a microarray expression study and used RT-qPCR to validate results. The protein levels of the type 1 IFN (IFN-α and IFN-β) were measured in the supernatant using ELISA technique. Results: LPS did not induce any type 1 IFN at the mRNA and protein levels in both cirrhotic and “healthy” PBMCs. Importantly, the expression microarray revealed that LPS significantly increased the expression of 208 ISGs in “healthy” cells showing that LPS is able to induce an IFN-independent antiviral program. In contrast, LPS failed to increase the expression of any ISG in cirrhotic cells. The differential LPS-induced ISG expression between “healthy” and cirrhotic cells was confirmed by RT-qPCR. Interestingly, in cirrhotic cells, defective ISGs included those involved in microbial nucleic acid recognition such as endosomal RNA sensors (TLR3, TLR7), cytosolic RNA (RIG-1, MDA5 of the RLR family) and DNA (ZBP1, MB21D1) sensors. Among defective ISGs there were also transcription factors (IRF1, STAT1); IFN-inducible GTPases (GBP4, MX1); proteins with tetratricopeptide repeats (IFIT3, IFIT5); tripartite-motif (TRIM14, TRIM21); 2′-5′-oligoadenylate synthetases (OAS1, OAS2); TREX1, MOV10 among others. Since mTOR inhibition and histone deacetylase (HDAC) inhibition are known to stimulate ISGs in certain cells, we investigated the effects of rapamycin (mTOR inhibitor) and trichostatin A (TSA, a HDAC inhibitor) in cirrhotic cells. In fact, neither rapamycin nor TSA were able to restore ISG expression in LPS-stimulated cirrhotic cells; instead each drug further decreased ISG expression in these cells. Conclusions: This study shows for the first time that patients with alcoholic cirrhosis have a marked defect in the LPS induction of an IFN-independent activation of antiviral genes. This defect is enhanced by mTOR inhibition or the alteration of epigenetic state through HDAC inhibition.

Disclosures:

Dominique Valla - Board Membership: Sequana Medical; Independent Contractor: IRIS; Speaking and Teaching: Mayoly Spindler, MSD, Janssen Pharmaceuticals

Pierre de la Grange - Management Position: GenoSplice

The following people have nothing to disclose: Emmanuel Weiss, Magali Fasseu, Pierre-Emmanuel Rautou, Laure Elkrief, Catherine Paugam-Burtz, Didier Lebrec, Richard Moreau

1320

WITHDRAWN

  

1321

The increased risk of nosocomial infection in cirrhotic patients is independent from the severity of the liver disease

Manuela Merli1, Cristina Lucidi1, Valerio Giannelli1, Vincenza Di Gregorio1, Barbara Lattanzi1, Gianna Iacovone1, Kameliya Koryukova1, Mario Venditti2, Oliviero Riggio1;

1 Gastroenterology, Sapienza Università di Roma, Roma, Italy; 2Department of Infectious Disease, Sapienza Università di Roma, Roma, Italy

A nosocomial infection is reported in 15–20% of hospitalized cirrhotic patients. The aim of the present prospective study was to assess the predisposing factors for this class of infections in cirrhotic patients. Consecutively hospitalized cirrhotic patients, hospitalized at our University Hospital in the last 2 years were enrolled. Patients with a diagnosis of infection within the first 48 hours from the admission were excluded. Nosocomial infections were diagnosed when the infection occurred after the first 48 hours. A nosocomial infection was diagnosed in 43 patients (66% males; median age 62 years; 70% Child B-C, MELD score 15) out of 238 hospitalized cirrhotic patients. The main sites of infection were: urinary tract (38%), respiratory tract (20%) and ascites (18%). Multidrug resistant bacteria were isolated in 51% of cases. Patients who developed a nosocomial infection versus those who did not were more likely to show a worse liver function (MELD 15±8 vs 12±4; p<.01), to have a diagnosis of protein malnutrition (20% vs 7%, p=0.05), to have been affected by other infections in the last year (37% vs 19% p<0.01), to have less available space in the hospital room (44% vs 27%; p<.01) and to have undergone a higher number of invasive procedures (2.7±2 vs 1.7±1.1; p=0.01). The length of hospitalization before the diagnosis of infection ranged around 15 days (4–76). The hospital stay was longer in patients with infection even when the time preceding the diagnosis of the infection was considered (21±13 vs 8±10; p<0.01). At multivariate analysis, hospitalization in a room with an additional bed (p=.004; OR 2.5; CI 1.1–5), the number of invasive procedures (p=.002; OR 6; CI 2.6–14), and a longer hospitalization time (p=.06; OR 1.9; IC 0.99–1.1) were selected as independent predictors for the development of nosocomial infections. Our study shows that a large number of invasive procedures, an inadequate space between the beds and a longer hospital stay are factors significantly related to the development of nosocomial infections independently from the severity of the liver disease in cirrhotic patients. Attempt precautions against bacterial infections are of particular relevance in cirrhotic patients.

Disclosures:

The following people have nothing to disclose: Manuela Merli, Cristina Lucidi, Valerio Giannelli, Vincenza Di Gregorio, Barbara Lattanzi, Gianna Iacovone, Kameliya Koryukova, Mario Venditti, Oliviero Riggio

1322

Hyponatremia in patients with acute-on-chronic liver failure (ACLF): an analysis of the CANONIC study

Andres Cardenas1, Elsa Solà2, Ezequiel Rodriguez2, Rogelio Bar-reto2, Isabel Graupera2, Marco Pavesi3, Filippo Morando4, Paolo Caraceni5, Alexander L. Gerbes6, Vicente Arroyo2, Pere Gines2;

1GI Unit, Hospital Clinic, Barcelona, Spain; 2Liver Unit, Hospital Clinic, Barcelona, Spain; 3Data Management Center CLIF Consortium, Hospital Clinic, Barcelona, Spain;4 Department of Medicine, University of Padova, Padova, Italy; 5Department of Clinical Medicine, University of Bologna, Bologna, Italy; 6Liver Center, Munich, Klinikum of the LMU, Munich, Germany

Background & Aims: Hyponatremia is a poor prognostic marker in patients with cirrhosis. The aim of the study was to assess if hyponatremia also has prognostic value in patients with ACLF, a syndrome in patients with cirrhosis associated with systemic inflammatory reaction and characterized by acute decompensation, organ failure, and poor short-term survival. Methods: We performed an analysis of the EASL-CLIF Consortium CANONIC database in 1343 consecutive patients admitted to 29 European centers with acute decompensation of cirrhosis, with and without associated ACLF (303 and 1040, respectively). Results: At enrollment, prevalence of hyponatremia (serum sodium <130meq/L) was higher in ACLF patients compared to those without ACLF (24% vs. 12% respectively, p<0.001). The incidence of hyponatremia during hospitalization was also higher in ACLF patients compared to those without ACLF (22% vs 11%, p<0.001). ACLF and leukocyte count were independent risk factors of hyponatremia. Hyponatremia was a prognostic factor both in the group of patients with ACLF as well as in those without ACLF. The outcome of patients with hyponatremia was clearly dependent of the presence or absence of ACLF. In fact, patients with hyponatremia and ACLF had a 3-month transplant-free survival of only 35.8% compared to 70.5% in those with hyponatremia without ACLF (p<.001 )(Figure). Corresponding values in patients without hyponatremia were 58.7% and 88.9%, respectively, p<0.001. Conclusions: The prevalence and incidence of hyponatremia are higher in patients with ACLF compared to those with acute decompensation of cirrhosis without ACLF and is independently associated with the systemic inflammatory reaction characteristic of ACLF. Patients with hyponatremia and ACLF have a worse outcome than those with hyponatremia but without ACLF. In cirrhosis, outcome of patients with hyponatremia is dependent on its association with ACLF.

image

Disclosures:

Andres Cardenas - Board Membership: Frontline Gastroenterology- BMJ publishing group; Consulting: Uptodate; Stock Shareholder: Limmedx LLC

Vicente Arroyo - Speaking and Teaching: GRIFOLS

Pere Gines - Advisory Committees or Review Panels: Ferring ; Grant/Research Support: Sequana Medical, Grifols

The following people have nothing to disclose: Elsa Solà, Ezequiel Rodriguez, Rogelio Barreto, Isabel Graupera, Marco Pavesi, Filippo Morando, Paolo Caraceni, Alexander L. Gerbes

1323

A Sensitive Procalcitonin Assay Improves the Diagnosis of Bacterial Infections in Patients with Cirrosis

Sebastian Marciano1,2, Leila Haddad1, Alfredo Martinez3, Maria L. Posadas-Martínez4, Federico Piñero1, Gonzalo J. Mora Lazo1, Laura Nazaret Guerrero3, Ezequiel Ridruejo2, Oscar G. Mandó2, Diego H. Giunta4, Adrian Gadano1;

1 Liver Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; 2Liver Unit, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno “CEMIC”, Buenos Aires, Argentina; 3Clinical Analisys Department, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno “CEMIC”, Buenos Aires, Argentina; 4Internal Medicine Research, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

Introduction: Differentiation of infected and not infected cirrhotic patients is challenging, usually leading to antibiotic overpre-scription. Procalcitonin (PCT) might be a useful tool for the diagnosis of bacterial infections in this setting. Aims: To evaluate the performance of a sensitive PCT assay for the diagnosis of bacterial infections in patients with cirrhosis. Methodology: Cirrhotic patients aged > 18 years consecutively evaluated in the Emergency Department between 01/11/10 and 01/06/12 with suspected bacterial infection (pre-defined, data not shown) were considered for eligibility. Patients receiving therapeutic antibiotics at screening or over the previous 7 days and/or receiving immunosuppressors were excluded. Blood cultures, urinary cultures and chest roentgenograms were performed in all patients. In patients with ascites or hydrothorax, fluid samples were obtained for chemical analysis and cultures. Blood samples for PCT determination were collected and stored at admission. Patients were followed for a period of 30 days or until death. Two hepatologists blinded to the PCT result independently determined whether the patient had a bacterial infection or not, using predefined criteria. PCT was measured by electrochemiluminescense (Elecsys BRAHMS; range 0.02–100 ng/ml.) Results: 103 episodes in 84 patients were included. Median age 62 years (interquartile range 11). 65 (63%) men.

Mean MELD 18.5 (±1.95), 61% Child C. 29 (28.2%) patients were considered infected, 74 (71.8%) not infected. The most frequent infections were spontaneous bacterial peritonitis 13 (45%) and spontaneous bacteremia 7 (24%). Median PCT in the infected group was 0.45 ng/ml (interquartile range 1.07) and 0.061 ng/ml in the not infected group (interquartile range 0.05), p < 0.001. AUROC: 0.95 (CI 95%, 0.91–0.99). With a cutoff value of 0.098 the following results were obtained for the diagnosis of bacterial infection: Sensitivity 97% (95% CI 86–100%), Specificity 82% (95% CI 72–94%), Negative Predictive Value 98% (95% CI 94–100%), Positive Predictive Value 68% (95% CI 51–88%), Efficiency of 0.86 (95% CI 79%>96%). PCT was still statistically associated with infection after adjusting for age, prothrombin time, Child, creatinine and fever (p < 0.001). Conclusion: We found a great accuracy of PCT for the diagnosis of bacterial infections in patients with cirrhosis. We believe this is of particular interest to rule out bacterial infections and avoid antibiotic over-prescription.

Disclosures:

The following people have nothing to disclose: Sebastian Marciano, Leila Haddad, Alfredo Martinez, Maria L. Posadas-Martínez, Federico Piñero, Gonzalo J. Mora Lazo, Laura Nazaret Guerrero, Ezequiel Ridruejo, Oscar G. Mandó, Diego H. Giunta, Adrian Gadano

1324

Increased apoptotic activity is associated with hospital mortality and disruption in lipid homeostasis in acute-on-chronic liver failure

Mark McPhail1,2, Evangelos Triantafyllou2, Debbie Shawcross2, Charalambos G. Antoniades1,2, Mattew R. Lewis3, Elizabeth Want3, Vishal C. Patel2, Yasmin Pasha1, (Robin) Daniel Abeles2, William Bernal2, Elaine Holmes3, Julia Wendon2, Simon D. Taylor-Robinson1;

1 Hepatology & Gastroenterology, Imperial College London, London, United Kingdom; 2Institute of Liver Studies, King's College Hospital, London, United Kingdom; 3Computational and Systems Medicine, Imperial College London, London, United Kingdom

Background Apoptosis is an important mechanism of hepato-cyte cell death in acetaminophen acute liver failure (AALF), sepsis and by lipoapoptosis in non-alcoholic steatohepatitis (NASH). In AALF and NASH peripheral blood levels of apoptotic and necrotic markers (total and caspase cleaved cytoker-atin-18) reflect underlying severity of disease. Acute-on-chronic liver failure (ACLF) is associated with reduction in high and low density lipoprotein (HDL,LDL) and phosphocholine (PC) concentrations but whether this reflects increased apoptotic activity is not known. Methods Fifty nine patients with cirrhosis (33 ACLF(12 died; 21 survived); 26 compensated (CLD)) and 7 healthy controls (HC) were studied. Median age was 55(23–65) years with 41 male, 18 female. The aetiology of cirrhosis was alcohol(32), viral(6), NASH (7), autoimmune(10) and other(4). Peripheral blood plasma was tested on admission for levels of total and caspase-cleaved cytokeratin 18 (M30,M65). Global metabolic and lipid of plasma was performed by 1 H nuclear magnetic resonance spectroscopy (NMR) and reverse phase ultra performance liquid chromatography mass spec-trometry (UPLCMS). Multivariate analysis was performed by orthogonal projection to least squares (OPLS) and univariate analysis by Spearman rank correlation and Kruskall-Wallis test. Results Levels of M30 were elevated in both CLD and ACLF compared with HC (p<0.01 HC v CLD; p<0001 HC v ACLF). Similarly the plasma levels of M65 were also highest in ACLF patients compared with CLD and HC (p<0.0001 ACLF v HC; p<0.01 CLD v HC). M30/M65 ratios were lowest in DC compared to other groups (p<0.0001 HC v CLD; p<0.001 HC v ACLF). M30 and M65 were correlated with MELD score (M30 v MELD r=0.40, p=0.002; M65 v MELD r=0.39, p=0.004). On OPLS modelling M65 (but not M30) levels correlated negatively with the LDL (p(corr)=-0.87,p<0.001) and PC(p(corr)=-0.79,p<0.001) resonances on 1H NMR. Of the identified lipids on UPLCMS LPC(16:0) at 518.3 m/z was negatively correlated with M30 (r=-0.30,p=0.010) and M65 (r=-0.39,p=0.002) levels and also predicted hospital survival (AUROC 0.76 (95%CI 0.66–0.84),p<0.001). M65 levels performed less well at outcome prediction (AUROC 0.66 (95%CI 0.54–0.76), p=0.02). M30 and M30/M65 ratio were not independently associated with outcome. Conclusion ACLF is associated with an increase in levels of both total and caspase cleaved cytokeratin-18 which correlates with increasing MELD score and reduced LDL and LPC levels in peripheral blood. This suggests that hepatocyte death mediated by lipo-apoptotic mechanisms is an important component in the progression of severe disease and poor outcome in ACLF.

Disclosures:

Debbie Shawcross - Advisory Committees or Review Panels: Norgine; Speaking and Teaching: Norgine

Yasmin Pasha - Grant/Research Support: Merz Pharmaceuticals GmbH, Frankfurt, Germany

Julia Wendon - Consulting: Pulsion, Excalenz

The following people have nothing to disclose: Mark McPhail, Evangelos Tri-antafyllou, Charalambos G. Antoniades, Mattew R. Lewis, Elizabeth Want, Vishal C. Patel, (Robin) Daniel Abeles, William Bernal, Elaine Holmes, Simon D. Taylor-Robinson

1325

An objective immune function biomarker demonstrates lower immune function in cirrhotic patients and higher infection risk

Siddharth Sood1, Julie Pavlovic1, Paul Gow1, Peter W. Angus1, Kumar Visvanathan2, Adam Testro1;

1 Liver Transplant Unit Victoria, University of Melbourne, Austin Health, Melbourne, VIC, Australia; 2Innate Immune Laboratory, University of Melbourne, St Vincents Hospital, Melbourne, VIC, Australia

Background: Patients with cirrhosis are immunosuppressed, but quantifying this is difficult. Identifying patients at most risk of infection would allow clinicians to individualize treatment, monitoring, transplant selection and antimicrobial prophylaxis. Many immune biomarkers need significant processing and aren't feasible outside research. CST007 (Cellestis Ltd, Melbourne, Australia) is a new whole blood assay measuring IFNγ production after combined stimulation of adaptive and innate immune systems. It requires minimal processing with results potentially available within a day, and is based on the widely available QFN-gold assay. We explored CST007 in cirrhotics to objectively quantify their net immune function and subsequent infection risk. Methods: Pre-transplant cirrhotics (n=50) were compared with matched healthy controls (n=50). Higher IFNγ suggest a more robust immune system. Results were compared against markers of disease severity and prospectively against documented infection. The census date was defined as date of infection, transplant, death or 31st May 2013. Results: Pre-transplant cirrhotics had a mean CST007 less than half that of controls (215.3 v 573.3 IU/ml, p<0.0001). There was correlation between increasing MELD and diminishing immune response by CST007 r2=0.2, p=0.001. 23 patients had bloods immediately pre-transplant and were unable to be followed longitudinally. Of the remaining 27, 2 died, 8 await transplant and 17 underwent transplant an average 79 days later (range 11–275). 37% (10 of 27) had an infection prior to census. As expected, patients with lower immune responses (<215.3 IU/ml) had higher infection risk HR 3.59 (95%CI:0.96–13.37), infection free survival curve (Figure 1, p=0.057). Conclusion: Although CST007 is under development as an immune biomarker in the transplantation setting, it may have use in clinical practice for identifying cirrhotics at highest risk of sepsis.

Figure 1

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Disclosures:

Siddharth Sood - Grant/Research Support: Cellestis Ltd

Peter W. Angus - Grant/Research Support: Gilead Sciences

The following people have nothing to disclose: Julie Pavlovic, Paul Gow, Kumar Visvanathan, Adam Testro

1326

Nosocomial Index Infections Portend Worse Outcomes Compared to Health-Care Associated Index Infections in a Multi-Center Hospitalized Cirrhosis Cohort (NACSELD)

Jasmohan S. Bajaj1, Jacqueline G. O'Leary2, K. Rajender Reddy3, Florence Wong4, Heather M. Patton5, Scott W. Biggins6, Benedict Maliakkal8, Michael B. Fallon7, Guadalupe Garcia-Tsao11, Ram M. Subramanian14, Manish Thapar10, David Koch12, Charmaine Stewart9, Raza Malik13, Leroy Thacker15, Patrick S. Kamath16;

1 Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA; 2Baylor Medical Center, Dallas, TX; 3University of Pennsylvania, Philadelphia, PA; 4University of Toronto, Toronto, ON, Canada; 5University of California, San Diego, San Diego, CA; 6University of Colorado, Denver, CO; 7University of Texas, Houston, TX; 8Univer-sity of Rochester, New York, NY; 9University of Minnesota, Minneapolis, MN; 10Drexel University, Philadelphia, PA; 11Yale University, New Haven, CT; 12Medical University of South Carolina, Charleston, SC; 13Beth Israel Deaconess Medical Center, Boston, MA; 14Emory University, Atlanta, GA; 15Biostatistics, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA; 16Mayo Clinic School of Medicine, Rochester, MN

Nosocomial infections in cirrhosis increase mortality in single-center studies but multi-center data are lacking. Aim: To evaluate the outcomes of cirrhotics with index nosocomial compared to non-nosocomial infections in the NACSELD cohort. Method: NACSELD is a 15-center collaboration that prospectively collects data on infected cirrhotic inpatients in which demographics, infection/cirrhosis details, outcomes [death, length-of-stay(LOS), organ failures [hepatic encephalopathy(HE), dialysis, ventilation or shock with >2=acute on chronic liver failure:(ACLF)] were recorded. Nosocomial infections(NI) developed >48 hours after admission in pts admitted without infections. Infection details & outcomes were compared between groups, & multi-variable analysis was performed. Results: 424 cirrhotics (age 56 yrs, 57% men, 20.5 MELD, 29% alcoholic) were enrolled. While 84% were admitted due to healthcare-associated infections, 16% were admitted without infections (HE 45%, high creatinine 30%, ascites Rx 20%, others 5%) who then developed index NIs. NI patients had a higher admission MELD (23 vs 20,p=0.04) but similar demographics, alcoholic etiology, admission vitals, sodium & albumin compared to non-NI pts. Infections: most prevalent overall were UTI (28%), SBP(24%), bacteremia(14%), Skin(13%)& respiratory(10%). Gram positives were seen in 34%, negative in 29%, fungi in 5% & no isolate in 24% overall. A significantly higher percent of NI were UTI(45 vs 25%, p<0.0001) & C.difficile(13 vs 3%,p=0.002). SBP(11 vs 26%,p=0.005) & skin infections(2 vs 15%, p=0.003) were significantly less NI than non-NI. Pneumonia, bacteremia & others were similar. NI pts had higher % of fungi (15 vs 2%,p=0.001), similar numbers of gram positives and negatives, but fewer without isolates (13 vs 26%,p=0.03). NI pts had higher van-comycin-resistant Enterococcus (13 vs 5%, p=0.03) & fluoro-quinolone resistance (18 vs 9%, p=0.03) but similar MRSA (8 vs 5%) compared to non-NI. Outcomes: NI pts had a significantly higher rate of death (30 vs 17%,p=0.01), HE (71 vs 53%,p=0.009), shock (31 vs 16%,p=0.003), dialysis (47 vs 23%,p<0.0001), ventilation (31 vs 13%,p=0.004), ACLF (51 vs 27%,p<0.0001) & LOS (17 vs 7 days, p<0.0001) compared to non-NI. On multi-variable analysis, NI were significantly associated with mortality (OR 1.9), higher MELD (OR: 1.1) & WBC counts (OR: 1.02). Conclusions: Cirrhotics who develop an index NI after admission without an infection are at risk for higher rate of organ failure, ACLF and death compared to those admitted for an infection despite controlling for cirrhosis severity in this multi-center prospective cohort.

Disclosures:

Jasmohan S. Bajaj - Advisory Committees or Review Panels: Salix, Merz, otsuka, ocera, grifols, american college of gastroenterology; Grant/Research Support: salix, otsuka, grifols

Jacqueline G. O'Leary- Consulting: Vertex, Gilead

K. Rajender Reddy - Advisory Committees or Review Panels: Genentech-Roche, Merck, Janssen, Vertex, Gilead, BMS, Novartis, Idenix; Grant/Research Support: Genentech-Roche, Merck, BMS, Ikaria, Gilead, Hyperion, Janssen, AbbVie

Florence Wong - Consulting: Gore Inc; Grant/Research Support: Grifols

Michael B. Fallon - Advisory Committees or Review Panels: Bayer/Onyx; Grant/Research Support: Ikaria Therapeutics, Gilead, ANADYS, Mochida, Eaisi, Research Triangle Institute

The following people have nothing to disclose: Heather M. Patton, Scott W. Biggins, Benedict Maliakkal, Guadalupe Garcia-Tsao, Ram M. Subramanian, Man-ish Thapar, David Koch, Charmaine Stewart, Raza Malik, Leroy Thacker, Patrick S. Kamath

1327

Predictive factors for an improvement in hepatic encephalopathy with hyperammonemia by occlusion of portosystemic shunts in patients with liver cirrhosis

Takashi Matsuda, Tsuyoshi Ishikawa, Takuya Iwamoto, Isao Sakaida;

Department of Gastroenterology and Hepatology, Yam-aguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan

Aims: Liver cirrhosis (LC) is often complicated with hepatic encephalopathy (HE) caused by hyperammonemia, which is considered to be closely related to shunt formation and impaired liver function. In the present study, we investigate the effect of balloon-occluded retrograde transvenous obliteration (B-RTO), which has been reported as an interventional method for the treatment of gastric varices (GV), on hyperammonemia due to portosystemic shunts (PSS), and this study evaluates predictive factors for an improvement in hyperammonemia by B-RTO in cirrhotic patients with portal hypertension. Methods:

B-RTO procedures were performed at our hospital for 44 cirrhotic patients (mean age=68.0 years; female/male=19/25; hepatitis B virus/hepatitis C virus (HCV)/alcohol/nonalcoholic steatohepatitis/others=1/19/14/7/3, Child-Pugh's (C-P) class A/B/C=21/22/1; indication GV/HE=37/7) between May 2009 and April 2013. Routine hematological and biological tests were analyzed before and at 1 month after the procedure. Results: Shunt occlusion resulted in a decrease in extrahepatic collateral blood flow and an increase in portal venous flow. B-RTO dramatically improved various hepatic function parameters, including total bilirubin, albumin, cholinesterase, indocyanine green retention rate at 15 min, prothrombin activity, and anti-thrombin activity, and C-P score was consequently reduced from 6.6 to 6.0 points (p<0.01). The procedure also led to a decrease in ammonia levels from 56.8 to 46.3 μmol/L (p=0.03) and an increase in branched chain amino acids/tyro-sine molar ratio from 3.7 to 4.2 (p<0.01) accompanied by decreased tyrosine levels from 119.2 to 106.4 μmol/L (p<0.01), indicating a beneficial effect of B-RTO on HE. In addition, ammonia levels at the left renal vein (LRV) and right hepatic vein before B-RTO were 81.4 and 28.3 μmol/L, respectively, and those at LRV were markedly reduced to 61.0 μmol/L by the operation, suggesting a decreased outflow of ammonia to systemic circulation via collateral vessels by hemodynamic changes following the procedure. Predictive factors for a decrease in ammonia levels were statistically sex=male, age>70 years, etiology=HCV, C-P class=A, and feeding vein of GV=left gastric vein. Furthermore, data-mining method revealed that preoperative ammonia levels were most significantly associated with an improvement in hyperammonemia. Conclusions: Shunt occlusion has a beneficial effect on HE due to PSS with higher levels of ammonia through decreased collateral blood flow, increased portal venous flow, and ameliorated metabolic function of the liver for elder, male, HCV-related LC patients classified as C-P class A.

Disclosures:

The following people have nothing to disclose: Takashi Matsuda, Tsuyoshi Ishikawa, Takuya Iwamoto, Isao Sakaida

1328

Coronary Artery Disease in Patients with Liver Cirrhosis: A Matched Case-Control Study

Jihyun An, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, Dong Jin Suh;

Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea

Background: There are conflicting data regarding whether liver cirrhosis has a preventive or aggravating effect on atherosclerotic lesions in the coronary arteries. The purposes of this study are to compare the prevalence of significant coronary artery stenosis in general populations and to identify the clinical and laboratory factors related to coronary artery stenosis in cirrhotic patients. Methods: This study included both a prospective cohort of 816 cirrhotic patients [median age 53, 80% male, 75% HBV-positive, Child-Pugh class A/B/C (31 %/42%/27%)] with angiographic results of coronary computed tomography (CT) as their pre-liver transplant evaluation obtained at the Asan Medical Center and 2,477 healthy controls, matched 4:1 with 621 cirrhotic patients for determining the risk factors of coronary artery disease (CAD), such as age, gender, hypertension, diabetes, hyperlipidemia, and smoking. No study subjects had a previous history of CAD or of angina symptoms. Significant coronary artery stenosis was defined as luminal narrowing greater than 50%. Logistic regression analysis was used to identify the variables associated with significant stenosis in cirrhotic patients. Results: The overall prevalence of significant coronary stenosis was 7.6% (n=62) for all 816 cirrhotic patients. In these patients, diabetes was the most important risk factor for significant stenosis (Odds ratio [OR] 3.07, 95% confidence interval [CI] 1.74–5.41; P<0.05). Age, hypertension, and the serum creatinine level was also related to significant stenosis (OR 1.07, 95% CI 1.03–1.11; 2.13, 1.16–3.91; and 1.22, 1.02–1.38, respectively, Ps<0.05). However, hyper-lipdemia, smoking, gender, and body mass index were not usually related to significant stenosis seen on coronary CT. Among the etiologies of cirrhosis, only their alcohol drinking was significant (OR 2.78, 95% CI 1.37–5.66; P<0.05). Other clinical-laboratory parameters, including platelet count, prothrombin time, Child-Pugh class, and MELD score, were not associated with significant coronary stenosis. Importantly, significant coronary stenosis was significantly lower in the cirrhotic cohort when compared with the matched sample (5.2% [32/621] vs. 7.7% [190/2,477]; P<0.05). Conclusions: Significant coronary artery stenosis was relatively lower in patients with cirrhosis than in the general population and was not related to liver function and coagulation parameters but to traditional cardiovascular risk factors in cirrhotic patients. Our data suggest that routine or preoperative cardiac evaluation of patients with liver cirrhosis is worthwhile based on the current guidelines for the non-cirrhotic populations.

Disclosures:

Han Chu Lee - Grant/Research Support: Medigen Biotechnology Co., Novartis, Roche, Bayer HealthCare, Bristol-Myers Squibb, INC research, Boehringer Ingel-heim, Taiho Pharmaceutical Co., Yuhan Co.

The following people have nothing to disclose: Jihyun An, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Dong Jin Suh

1329

Diastolic cardiac dysfunction is a predictor of dismal prognosis in patients with liver cirrhosis

Jiannis Vlachogiannakos1, Dimitrios Karagiannakis1, Georgios Anastasiadis2, Anastasios Karlaftis1, Irene Vafiadis-Zouboulis1, Spiros D. Ladas1;

1Academic Department of Gastroenterology, Medical School, University of Athens, Laiko General Hospital, Athens, Greece; 2Department of Cardiology, Laiko General Hospital, Athens, Greece

Background - Aim: Left ventricular diastolic dysfunction (LVDD) constitutes the prominent characteristic of cirrhotic cardiomy-opathy, but its relevance to the clinical course of cirrhosis has not been clearly elucidated. The aim of our study was to evaluate the relationship of LVDD with the severity and the etiology of liver disease and to investigate its effect on the long-term prognosis of patients with cirrhosis. Methods: We enrolled 45 cirrhotics [33 (73.3%) males; mean age 57.2±12.4 years; 21 (46.6%) alcohol-related; 22 (48.9%) decompensated cirrhosis], after excluding those with known heart or pulmonary diseases, hypertension, recent gastrointestinal bleeding, clinical or laboratory signs of active infection and hepatocellular carcinoma. Cardiac function was estimated by conventional and Tissue Doppler (TDI) echocardiography and the diagnosis of LVDD was based on the latest guidelines of the American Society of Echocardiography. All patients were prospectively fol-lowed-up for a period of 2 years. Death was the end-point of the study. Results: LVDD was found in 17 out of 45 patients (38%). Its prevalence wasn't found to significantly differ between patients with alcoholic cirrhosis and those with cirrhosis of other etiologies (6/21, 28.5% vs 11/24, 45.8%; p=0.208). No significant differences were found in Child-Pugh score and MELD score in patients with LVDD compared to those without LVDD (C-P score: 6.4±1.6 vs 6.5±2.1, p=0.828; MELD score: 11 ±3.5 vs 11.7±4.6, p=0.605). At the end of follow up, 13 patients had died; 8 had LVDD (8/17, 47%) and 5 had not (5/28, 17.8%). The actuarial probability of reaching the end-point was significantly increased in patients with LVDD (p=0.032, log rank: 4.607). More precisely, the survival rates of LVDD patients were 92%, 73%, 60% and 44% at months 6, 12, 18 and 24 respectively, whereas in patients without LVDD were 95%, 91%, 86% and 80% at the same periods of time. Hepatorenal syndrome was the leading cause of death in patients who had developed LVDD. In the multivariate analysis, low levels of albumin (p=0.003) and the presence of LVDD (p=0.034) were independently associated with increased mortality. Conclusions: LVDD is a frequent complication of liver cirrhosis, independently of the etiology and the stage of liver disease. Its development seems to be associated with a poor prognosis in patients with cirrhosis.

Disclosures:

The following people have nothing to disclose: Jiannis Vlachogiannakos, Dimitrios Karagiannakis, Georgios Anastasiadis, Anastasios Karlaftis, Irene Vafiadis-Zouboulis, Spiros D. Ladas

1330

An Evidence-based Algorithm for Correcting Vitamin D Deficiency in Patients with Advanced Liver Disease Awaiting Transplantation

Emily A. Schonfeld1, Alexis Pappas1, Shai Posner3, Jonathan Barsa2, Kian Bichoupan1, Mitchell Liverant2, Dana R. Berg2, Thomas D. Schiano1, Andrea D. Branch1;

1 Liver Diseases, Mount Sinai Hospital, New York, NY; 2Internal Medicine, Mount Sinai Hospital, New York, NY; 3Mount Sinai School of Medicine, Mount Sinai Hospital, New York, NY

Aim/Background: Patients with advanced liver disease have a high risk of bone fracture and are often vitamin D deficient. The aim of this study is to produce evidence-based guidelines for correcting vitamin D deficiency in patients awaiting liver transplantation. Methods: This ongoing open-label prospective clinical trial is enrolling adult liver transplantation candidates (ClinicalTrials.gov, NCT01575717). Supplemental vitamin D3 is given according to a tiered dosing schedule: 4000 IU/day of vitamin D3 if baseline 25-hydroxyvitamin D [25(OH)D] is < 15 ng/mL and 2000 IU/day if baseline 25(OH)D is > 15 and < 25 ng/mL. Hyperparathyroidism and hypercalcemia are exclusion criteria. 25(OH)D is measured at baseline, 3, and 6 months. Monthly calls are made to provide reminders and monitor adherence. The dose of supplements is doubled if 25(OH)D remains < 25 ng/mL after 3 months in adherent patients. Linear regression is being used to analyze the relationship between natural MELD and the incremental change in 25(OH)D per 1000 IU/day of nutritional vitamin D. Interim Results: To date, 40/63 (63%) of the patients screened for the study had baseline 25(OH)D < 25 ng/mL. Among 26 patients with 3-month follow-up data, median (range) baseline values are: age = 58.5 yr (25–70), MELD = 15 (6–28), and 25(OH)D = 17.2 ng/ml (8.1–24.3). The majority of the patients have HCV (61%), while the rest have NASH or cryptogenic liver disease (19%), PBC (8%), alcoholic liver disease (8%), and HBV (4%). 15/26 (58%) have HCC. Over 3 months, 25(OH)D increased from 10.3 ng/ml to 31 ng/ml in 11 patients taking 4000 IU/d of vitamin D3 (p < 0.01) and from 20.5 ng/mL to 28.5 ng/ml in 15 patients taking 2000 IU/day of vitamin D3 (p < 0.01). Importantly, the change in 25(OH)D/1000 IU/day was similar in the two dosage groups (4.0 and 4.4 ng/mL/1000 IU/day) and it was independent of dose (p=0.56). There was a striking inverse relationship between the MELD score and the change in 25(OH)D/1000 IU/day (R square = 0.32). Based on our data, the change in 25(OH)D for an individual patient = 7.630 + 0.009*(dose in IU/day) - 1.136*(MELD). Conclusions: We present a useful algorithm for calculating the dose of nutritional vitamin D required to raise 25(OH)D levels and correct vitamin D deficiency in patients with advanced liver disease. Controlling for the MELD score, the dose-response relationship between nutritional vitamin D and 25(OH)D demonstrated a linear relationship regardless of baseline 25(OH)D. Each unit of the MELD score increased the required dose of vitamin D3 by 130 IU/day (DA031095, DK090317, CA152514).

Disclosures:

Thomas D. Schiano -Advisory Committees or Review Panels: vertex, salix, merck, gilead, pfizer; Grant/Research Support: massbiologics, itherx

Andrea D. Branch - Grant/Research Support: Kadmon, Gilead, Janssen

The following people have nothing to disclose: Emily A. Schonfeld, Alexis Pap-pas, Shai Posner, Jonathan Barsa, Kian Bichoupan, Mitchell Liverant, Dana R. Berg

1331

Implications of long-term carvedilol administration for portal hypertension-related renal dysfunction: follow-up from a randomised controlled trial

Joanna A. Leithead1,6, James W. Ferguson1,6, Dhiraj Tripathi1,6, Narendra Kochar1, George Therapondos1, Norma C. McAvoy1, Adrian J. Stanley3, Ewan Forrest2,3, William S. Hislop4, Peter R. Mills5, Peter C. Hayes1;

1Hepatology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; 2Victoria Infirmary, Glasgow, United Kingdom; 3Glasgow Royal Infirmary, Glasgow, United Kingdom; 4Royal Alexandra Hospital, Paisley, United Kingdom; 5Gart-navel Hospital, Glasgow, United Kingdom; 6Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom

Carvedilol has a greater portal hypotensive effect than propanolol in patients with cirrhosis and is effective in the primary prophylaxis of oesophageal variceal haemorrhage. 4-weeks of carvedilol administration has previously been shown not to affect natriuresis or creatinine clearance. The aim of this study was to examine the implications of long term carvedilol administration on portal hypertenstion-related renal dysfunction. Methods: 100 patients who participated in a randomised controlled trial of carvedilol versus variceal band ligation (VBL) for the prevention of first variceal bleed with adequate documentation from at least one followup clinic attendance were included (Tripathi et al, Hepatology 2009). 56 patients were randomised to carvedilol and 44 to VBL. The following markers of portal hypetension-related renal dysfunction were examined: ascites, hyponatraemia, serum creatinine (SCr). Results: There was no difference in the prevalence of diuretic controlled ascites or severe ascites at baseline between the carvedilol (25.5%, 16.4%) and VBL arms (29.5%, 20.5%) (p=0.714). Similarly the prevalence of hyponatraemia (31.7% vs 50.0%, p=0.098) was the same. The median SCr was 82 (70–99) μmol/l in the carvedilol patients and 87 (74–100) μmol/l in the VBL patients (p=0.238). 16.7% of patients without ascites at baseline developed ascites, 31.8% demonstrated an increase in ascites severity/diuretic dosage, 17.0% without hyponatraemia developed hyponatraemia, and 31.3% had a sustained increase in SCr >10% from baseline during a median followup time of 1.3 (IQR 0.5–3.1) years. There was no difference in the probability of development of ascites (p=0.907), increase in ascites severity/diuretic dosage (p=0.299) or development of hyponatraemia between the 2 randomisation arms (p=0.816). Median SCr at 1 month after randomisation was the same for both groups (p=0.435). In patients with no ascites at baseline (p=0.878), or diuretic controlled ascites (p=0.913), there was no difference in the probability of a rise in SCr >10% from baseline. However, in the patients with refractory ascites there was trend towards an increased probability of a rise in SCr >10% when randomised to carvedilol (6-month estimated cumulative incidence 66.7% vs 12.5%, p=0.053). In this group survival was comparable for the carvedilol and VBL arms (p=0.995). Conclusion: Overall patients receiving carvedilol for prevention of first variceal bleed are not at increased risk of portal hypertension-related renal dysfunction. Nevertheless, in patients with refractory ascites there may be an increased incidence of SCr rise, and caution should be employed in this subgroup.

Disclosures:

James W. Ferguson - Advisory Committees or Review Panels: Astellas, Novartis

Peter C. Hayes - Advisory Committees or Review Panels: Roche, Roche, Jannsen, Gilead, ?ONO, Norgine; Grant/Research Support: Novartis; Speaking and Teaching: Roche, MSD, Roche, MSD, Pfiser, Gore, Falk, Ferring

The following people have nothing to disclose: Joanna A. Leithead, Dhiraj Tripathi, Narendra Kochar, George Therapondos, Norma C. McAvoy, Adrian J. Stanley, Ewan Forrest, William S. Hislop, Peter R. Mills

1332

Prognostic value of diffusion-weighted MRI in cirrhotic patients with and without minimal encephalopathy

Motoh Iwasa, Hirohide Miyachi, Yoshinao Kobayashi, Yoshiyuki Takei;

Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan

Aims: Hepatic encephalopathy (HE) has recently been proposed to represent low-grade cerebral edema related to an osmotic imbalance in astrocytes. In cirrhotic patients, an increase in glutamine resulting from ammonia metabolism and decreases in myo-inositol are observed on magnetic resonance (MR) spectroscopy. The changes in osmolytes are considered to be suggestive of brain edema. Hyponatremia is a frequent complication in patients with advanced cirrhosis; it also affects the osmotic balance in brain cells, owing to a reduction in the osmolality of the extracellular fluid. Diffusion-weighted MRI allows assessment of intra- and extracellular water content in the brain. Knowledge of apparent diffusion coefficient (ADC) abnormalities in the presence coexistence of HE and hyponatremia remains limited, so this study measured ADC in various regions of the brain in patients with cirrhosis and investigated the significance of ADC for quantifying low-grade HE and predicting overt HE. Methods: This study examined 40 patients with liver cirrhosis. Cirrhosis grade was Child-Pugh A in 12 patients, B in 25 and C in three. The control group comprised 24 healthy sex- and age-matched subjects. Diffusion-weighted imaging was conducted using single-shot echo-planar imaging. Results: No patients showed signs of overt HE. Among the 40 cirrhotic patients, 10 showed impairment on neuropsychologi-cal tests and were therefore included in the minimal HE group. In cirrhotic patients with minimal HE, mean ADC was significantly increased in white matter such as the frontal (P<0.01) and parietal (P<0.05) lobes when compared to patients with no HE. No significant difference in brain ADC was found between patients with no HE and healthy subjects. Higher ADC in the white matter was associated with hyperammonemia (P<0.01) and low serum sodium (frontal, P<0.05; parietal, P<0.01). In addition, in cirrhotic patients with minimal HE, mean serum sodium level was significantly decreased when compared to patients with no HE. Median follow-up was 11 months, and 10 patients exhibited an episode of overt HE during follow-up. According to Kaplan-Meier analysis, ADC for frontal and parietal-lobe white matter represent risk factors for overt HE (P<0.05). Conclusions: The present results support the hypothesis that astrocyte swelling induced by an increase in intracel-lular glutamine or a decrease in extracellular sodium and low-grade cerebral edema affect neuronal excitability and neu-rotransmission, resulting in the clinical picture of HE. ADC appears to offer a reliable tool for quantifying low-grade HE and high ADC represents a risk factor for the development of overt HE.

image

Disclosures:

The following people have nothing to disclose: Motoh Iwasa, Hirohide Miyachi, Yoshinao Kobayashi, Yoshiyuki Takei

1333

Falsely Elevated Ammonia Levels: Predictive Factors

Jennifer A. Cuthbert2, Ibrahim A. Hashim1;

1Pathology, UT Southwestern, Dallas, TX; 2Internal Medicine, UT Southwestern, Dallas, TX

Aim: To determine factors contributing to falsely elevated blood ammonia levels and to identify time parameters indicating the potential for pseudo-hyperammonemia. Methods: We investigated the effect of plasma enzymes, blood cell counts and processing delays on the extent of in vitro ammonia production. Results of ammonia levels determined over a 12 month period were reviewed and time limits for reliable ammonia levels derived. Results: Time-dependent increases in in vivo ammonia concentration were observed. Median percentage increase in ammonia levels was 36, 81, 142, 212, and 409 % at 2, 4, 8, 12 and 24 hours post venepuncture respectively. The rate of increase in ammonia concentration varied among specimens and strongly correlated with gamma-glutamyl transferase levels (r = 0.9) and to a lesser extent with alanine aminotransferase levels (r = 0.7). During the 12 month period, January- December 2012, 3,747 ammonia tests were ordered. Samples for quality assurance (n = 62), that were lipemic and analysed elsewhere (n = 51) or unsatisfactory e.g. hemolyzed (n = 9) were excluded from the analysis. Under routine sampling and conditions for the remaining 3,625 tests, normal and elevated results were comparably distributed if the time from venepuncture to result confirmation was < 120 minutes. Thus, for an elapsed time of 90 - 119 minutes, 49 samples (42%) had a normal ammonia level and 68 samples had an elevated ammonia level (58%). When the elapsed time was 120 - 149 minutes, only 20 (26%) had a normal level and 56 (74%) were elevated. This difference was statistically significant (p = 0.028, Pearson chi-square). Delays during analysis performance and in transportation to the laboratory contributed to potential pseudo-hyperammonemia in a small number of samples (2.65%). Limitations: Single center study Conclusions: Delays in either transportation to the laboratory after collection or before completion of analysis has the potential to falsely elevate ammonia levels and cause pseudo-hyperammonemia. Elevated gamma-glutamyl transferase levels in samples provided the best correlation with in vitro ammonia production. Unexpectedly elevated ammonia levels need to be evaluated for errors in sampling handling.

Elapsed Time Effect on Results and Contributing Factors

CategoryTotal elapsed time < 120 minsTotal elapsed time > 120 min P value*
Normal ammonia Elevated ammonia Total1,548(99%) 1,981 (96%) 3,529 (97%)18(1%) 78 (4%) 96 (3%)1.566(43%) 2,059 (57%) 3,625< 0.001
In laboratory to result: < 90 mins > 90 mins3,482 (99%) 47(1%)9 (9%) 87 (91%)3,492(96%) 134 (4%)< 0.001
Collection to in laboratory: < 30 mins > 30 mins3,391 (99%) 38(1%)87 (91%) 9 (9%)3,578 (99%) 47 (1%)< 0.001

The following people have nothing to disclose: Jennifer A. Cuthbert, Ibrahim A. Hashim

1334

Ascitic Fluid Lactoferrin evaluation in the Diagnosis of Spontaneous Bacterial Peritonitis

Harshad Devarbhavi1, Ravi R. Kumar2, Anita R. Bijoor2, Keyur A. Sheth1, Mallikarjun Patil1, Adarsh Ck1;

1Department of Gastroen-terology, St. John's Medical College Hospital, Bangalore, India; 2Department of Biochemistry, St. John's Medical College Hospital, Bangalore, India

Disclosures:

The following people have nothing to disclose: Harshad Devarbhavi, Ravi R. Kumar, Anita R. Bijoor, Keyur A. Sheth, Mallikarjun Patil, Adarsh Ck

Background: The diagnosis of spontaneous bacterial peritonitis (SBP) is based on the presence of > 250 polymorphonuclear cells (PMN)/mm3 in ascitic fluid (AF)of cirrhotic patients. Alternative methods for detection of SBP have been explored with mixed results. A single study that assessed the utility of AF lactoferrin (AFLAC) in 22 patients with SBP found it promising. (Gas-troenterology 2008;135:803). This result has not been validated. We aimed to assess the accuracy of AFLAC in a cohort of patients with SBP and compared it with cirrhotic ascites without SBP. Methods: We analyzed the AFLAC in 30 consecutive patients with cirrhosis and SBP (> 250 PMN cells/mm3) vs. cirrhosis and no SBP. AFLAC concentration was estimated using enzyme-linked immunosorbent assay (Human Lactoferrin ELISA; Kamiya Biomedical Company, Seattle, WA 98168) Results: The baseline clinical and biochemical features in the two groups were similar. Alcohol was the commonest cause of cirrhosis (83%). The median PMN count in the SBP group and non-SBP group was 1134 cells/ml and 59 cells/ml respectively. The SBP group showed a median AFLAC concentration of 2320 ng/mL (25th-75th percentiles, 1300–3600) compared with an AFLAC concentration of 47 ng/mL ( 25th-75th percentiles, 32–85) in non-SBP group. A cut-off level 538 ng/ml in AF yielded a sensitivity and specificity of 93.3% and 100% for SBP with a ROC 0.986. The Spearman correlation co-efficient for AFLAC and AF PMN count was 0.809 (<0.001). Conclusion: AF lactoferrin is a highly accurate test for the diagnosis of SBP with a C-stat of 0. 986 and a significant correlation coefficient. Larger studies and wider experience will establish the utility of AFLAC.

* Pearson chi-square

Disclosures:

1335

Impact of cytoreductive therapy on the outcome of patients with myeloproliferative neoplasms and hepato-splanchnic vein thrombosis

Carine Chagneau-Derrode1, Lydia Roy2,3, Joelle Guilhot3, Odile Goria4, Isabelle Ollivier-Hourmand5, Christophe Bureau6, Laetitia Rouleau1, Florence Tartarin3, Kamal Zekrini7, Dominique Valla7, Christine Silvain1, Victor de Ledinghen8, Frederic Oberti9, Marie Line Debette-Gratien10, Jean-Baptiste Nousbaum15, Alexandre Lou-vet12, Xavier Causse13, Eric Nguyen-Khac14, Alexandra Heurgué-Berlot19, Jean-Pierre Bronowicki18, Helene Barraud18, Rodolphe Anty20, Georges-Philippe Pageaux16, Dominique G. Larrey16, Dominique Thabut21, Nicolas Carbonell22, Anne Minello17, Armand Abergel23, Jean Jacques Kiladjian11, Aurelie Plessier7;

1hepatology, university hospital poitiers, Poitiers, France; 2hema-tology, university hospital poitiers, poitiers, France; 3INSERM CIC0802, university hospital, poitiers, France; 4hepatology, university hospital rouen, rouen, France; 5hepatology, university hospital caen, caen, France; 6hepatology, university hospital purpan, toulouse, France; 7hepatology, university hospital beaujon, clichy, France; 8hepatology, university hospital haut leveque, bordeaux, France; 9hepatology, university hospital angers, angers, France;10hepatology, university hospital limoges, Limoges, France; 11hematology, university hospital saint louis, paris, France; 12hepatology, university hospital lille, lille, France; 13hepatology, university hospital orleans, orleans, France; 14hepatology, university hospital amiens, amiens, France; 15hepatology, university hospital brest, Brest, France; 16hepatology, university hospital montpellier, mont-pellier, France; 17hepatology, university hospital dijon, dijon, France; 18hepatology, university hospital nancy, nancy, France;19hepatology, university hospital reims, reims, France; 20hepatology, university hospital nice, nice, France;21 hepatology, university hospital pitie salpetriere, paris, France; 22hepatology, university hospital saint antoine, paris, France; 23hepatology, university hospital clermond ferrand, Clermond Ferrand, France

Introduction : Myeloproliferative neoplasms (MPNs) are the commonest cause of splanchnic vein thrombosis (SVT), their prevalence being approximately 30% in portal vein thrombosis (PVT) and 40% in Budd-Chiari syndrome (BCS).There is no consensus regarding the use of cytoreductive therapy in patients with MPNS and SVT. Methods and results : In this retrospective multicentric French study, we studied the prognostic factors predicting the survival without major event in a cohort of 109 MPN patients (BCS, n=46; PVT n= 63). The major events (occurring more than one month after acute phase of SVT) were: vascular events (de novo thrombosis, hemorrhage) or liver-related complications (refractory ascites, hepato renal syndrome, hepatic encephalopathy and transplantation). Among the 46 BCS patients, 33 (72%) experienced at least one major event: new or extensive SVT (n=7), refractory ascites (n=13), severe liver dysfunction (n=2), hepatic encephalopathy (n=1), hepatorenal syndrome (n = 1), liver transplantation (n=5), pulmonary embolism (n=2), extensive thrombosis of jugular vein (n=1), cerebral hemorrhage (n=1). Median event free survival from diagnosis of SVT was 9.4 months (IC95: 4.1–36.4). Absence of cytoreductive therapy (p <0.0001), platelet count above 250109/L at diagnosis of BCS (p=0.099) and gender (p=0.110) were the 3 variables associated with a higher risk of major event after BCS in univariate analysis. With Cox regression model, absence of cytoreductive therapy after BCS diagnosis was the only independent prognostic factor associated with an increased risk of subsequent major event (p <0.0001). A similar trend was observed for platelet count above 250109/L (p = 0.051). Among the 64 patients with PVT, 26 (40%) patients experienced at least one major event: extensive PVT (n=13), variceal bleeding (n=10), refractory ascites (n=1) and cerebral thrombosis (n=2). Median event free survival (EFS) was 59.8 months (IC95: 35.9-NA), confirming the better overall prognosis of PVT compared to BCS. Initiation of cytoreductive therapy after the diagnosis of PVT was also significantly associated with a lower risk of subsequent major event (p= 0.011) in univariate analysis, as esophageal varices (grade < 2) (p=0.117). In a multivariate model, only cytoreductive therapy remained an independent prognostic factor (p= 0.048). Conclusion : This study provides for the first time, the evidence for a beneficial role of cytoreductive therapy in SVT patients with underlying MPN, in particular for reducing the risk of severe liver-related complications and significantly improving EFS in both BCS and PVT, regardless of MPN characteristics.

Disclosures:

Isabelle Ollivier-Hourmand - Speaking and Teaching: MSD

Christophe Bureau - Speaking and Teaching: Gore

Dominique Valla - Board Membership: Sequana Medical; Independent Contractor: IRIS; Speaking and Teaching: Mayoly Spindler, MSD, Janssen Pharmaceuticals

Victor de Ledinghen - Advisory Committees or Review Panels: Merck, Janssen, Gilead, Echosens, Boehringer Ingelheim, Abbvie; Grant/Research Support: Roche, Gilead, Janssen; Speaking and Teaching: Roche, Echosens

Frederic Oberti - Speaking and Teaching: LFB, gore

Xavier Causse - Board Membership: Gilead, BMS, MSD, Janssen-Cilag; Speaking and Teaching: Roche, Gilead, BMS, Janssen-Cilag

Jean-Pierre Bronowicki - Consulting: Merck, Janssen, Boehringer Ingelheim, Gilead, BMS, Bayer, Novartis, GSK, Merck, Janssen, Boehringer Ingelheim, Gilead, BMS, Bayer, Novartis, GSK; Speaking and Teaching: Roche, Merck, Janssen, BMS, Bayer, Roche, Merck, Janssen, BMS, Bayer

Georges-Philippe Pageaux - Advisory Committees or Review Panels: Roche, Roche, Roche, Roche; Board Membership: Astellas, Astellas, Astellas, Astellas

Dominique G. Larrey - Board Membership: ROCHE, MSD, TIBOTEC/JANSSEN, ABBOTT, BOEHRINGER, BMS, GILEAD; Consulting: BAYER, SANOFI, PFIZER, SERVIER, HELSINN, MMV, BIAL, TEVA; Grant/Research Support: Roche, Boehringer, BMS, GILEAD; Independent Contractor: ABBOTT

Armand Abergel - Board Membership: MSD; Grant/Research Support: ROCHE, MSD; Speaking and Teaching: JANSSEN, MSD

The following people have nothing to disclose: Carine Chagneau-Derrode, Lydia Roy, Joelle Guilhot, Odile Goria, Laetitia Rouleau, Florence Tartarin, Kamal Zekrini, Christine Silvain, Marie Line Debette-Gratien, Jean-Baptiste Nousbaum, Alexandre Louvet, Eric Nguyen-Khac, Alexandra Heurgué-Berlot, Helene Barraud, Rodolphe Anty, Dominique Thabut, Nicolas Carbonell, Anne Minello, Jean Jacques Kiladjian, Aurelie Plessier

1336

Covert Hepatic Encephalopathy Diagnosis With The New Stroop App (EncephalApp) Using Age-Based Cutoff Values

Jasmohan S. Bajaj1, Douglas M. Heuman1, Leroy Thacker3, Richard K. Sterling1, R. Todd Stravitz1, Arun J. Sanyal1, Velimir A. Luketic1, Nicole Noble1, Melanie White1, Ariel Unser1, Pamela Monteith1, Puneet Puri1, James Wade2;

1 Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA; 2Biostatistics, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA; 3Psychiatry, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA

Diagnosis of covert/minimal hepatic encephalopathy (CHE) is difficult; the older Stroop App needed updates to make it CHE-specific,streamline timing, result transmission & get norms. Therefore a new App iteration (EncephalApp) was created. Aim: to validate EncephalApp for the CHE diagnosis using age-based cut-offs. Methods: Cirrhotics and healthy controls underwent cognitive testing using standard batteries (Number connection-A/B,NC-A/B, digit symbol DS, block design BD; >2 impaired two standard deviations(SD) beyond controls =CHE) and then tested on the new App. The App has two parts; Stroop Off in which the subject needs to press the correct color in which # signs are presented while On state is to press the correct color in which words meaning red,green or blue are presented in discordant colors i.e.if “red” is presented in green color, the correct answer is green. Time to complete 5 Off runs(OffTime) and On(OnTime) were recorded; a lower time indicates good performance. Number of trials to achieve 5 correct runs was also recorded. OffTime+OnTime >2 SD above controls was considered impaired on EncephalApp. Sensitivity and specificity were performed for EncephalApp using standard tests are gold standard.Results: 100 controls (age 43±14 yrs, education 15±2 yrs, 50% >45 yrs age) & 75 cirrhotics (35% prior HE, MELD 9, 60%HCV) underwent EncephalApp & standard testing. Controls performed significantly better than cirrhotics on standard tests (NC-A 23 vs 43s, NC-B 59 vs 114s, DS 78 vs 53, BD 42 vs 22, all p<0.0001) & EncephalApp OffTime+OnTime (132 vs 206 s p<0.0001). 40% of pts had CHE on standard tests. OffTime+OnTime was correlated with age (r=0.6, p<0.0001) but not education in controls, therefore their App results were analyzed separately for those > or <45 yrs. OffTime+OnTime(±SD) in controls <45 yrs was 119±13 sec & 146±22 sec in those>45 yrs. Therefore 2 SD impaired beyond controls was >145 sec in pts <45 yrs &>190 sec in >45 yrs on OffTime+OnTime. Cirrhosis group: OffTime+OnTime was higher in pts with prior OHE compared to no OHE (230 vs 171s p=0.001) and was correlated with MELD (r=0.5,p=0.004) but not age/education. Number of trials to achieve 5 correct Off (5 vs 6) or On (5 vs 6) were not different between OHE/no OHE. CHE diagnosis: Using the age-adjusted cutoffs, 52% of pts had impaired App performance. CHE was more in prior OHE (94% vs no OHE 30%,p=0.0001). Using standard tests as reference sensitivity of these age-variable cut-off was 90% while specificity was 78%.Conclusion: The new age-based cut-offs for Encepha-lApp_Stroop are highly sensitive for covert HE screening and could be used to guide future dedicated testing in cirrhosis.

Disclosures:

Jasmohan S. Bajaj - Advisory Committees or Review Panels: Salix, Merz, otsuka, ocera, grifols, american college of gastroenterology; Grant/Research Support: salix, otsuka, grifols

Douglas M. Heuman - Consulting: Bayer, Grifols, Genzyme; Grant/Research Support: Exilixis, Novartis, Bayer, Bristol Myers Squibb, Scynexis, Ocera, Mannkind, Salix, Globeimmune, Roche, SciClone, Wyeth, Otsuka, Ikaria, UCB, Celgene, Centocor, Millenium, Osiris; Speaking and Teaching: Otsuka, Astellas

Richard K. Sterling - Advisory Committees or Review Panels: Merck, Vertex, Salix, Bayer, BMS, Abbott; Grant/Research Support: Merck, Roche/Genentech, Pfizer, Medtronic, Boehringer Ingelheim, Bayer, BMS, Abbott

R. Todd Stravitz - Grant/Research Support: Exalenz Biosciences, LTD

Arun J. Sanyal - Advisory Committees or Review Panels: Gore, Gilead, Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Bayer-Onyx, Genentech, Norgine, GalMed, Novartis, Echosens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept, Ikaria, Takeda, Gilead; Independent Contractor: UpToDate

Velimir A. Luketic - Grant/Research Support: Intercept, Merck, Idenix, Vertex, Gilead, BMS, Novartis, abbvie, Genfit, Takeda

Puneet Puri - Advisory Committees or Review Panels: Health Diagnostic Laboratory Inc.; Consulting: NPS Pharmaceuticals Inc.

The following people have nothing to disclose: Leroy Thacker, Nicole Noble, Melanie White, Ariel Unser, Pamela Monteith, James Wade

1337

Rifaximin is Associated with Decreased Incidence of Spontaneous Bacterial Peritonitis in Cirrhotics with Ascites

Susanne Shokoohi2, Adam Zivony1, T Domi Le1, Atif Zaman1, Janice Jou1;

1Medicine, Gastroenterology, Oregon Health and Science University, Portland, OR; 2Medicine, Oregon Health and Science University, Portland, OR

Background: Rifaximin is a non-absorbable antibiotic used for the treatment of hepatic encephalopathy (HE). Given its limited systemic absorption and antibacterial spectrum, rifaximin is an intriguing candidate medication for spontaneous bacterial peritonitis (SBP) prophylaxis as well. The potential effect of rifaximin on the incidence of SBP in patients with cirrhosis and ascites is unclear. The aim of this study was to assess the association of rifaximin with SBP in cirrhotic patients. Methods: Adult cirrhotic patients with ascites, seen in hepatology clinic at least twice from 2005–2012, and taking rifaximin, lactulose, or both medications were included. Patients with prior episodes of SBP or on antibiotics for other reasons were excluded. Electronic medical records were reviewed to abstract demographics and clinical information pertaining to the patients liver disease and diagnosis of SBP. Cases of SBP were defined by an ascitic neu-trophil count of >250 cells/μL and were determined by primary review of laboratory diagnostic paracentesis cell counts. The proportion of SBP was assessed in patients receiving rifaximin with or without lactulose as compared to those patients receiving lactulose only. Logistic regression was used to model the effect of rifaximin on the incidence of SBP. Results: Overall, 139 cirrhotic patients were included. There were 79 patients who received rifaximin and 60 patients who received lactulose alone for the treatment of HE. The average duration of follow-up was 20.2 months in the rifaximin group and 18.8 months in the lactulose group. The average age for the rifaximin group was 53.5 and for the lactulose group was 58.2. The average MELD score for the rifaximin group and lactulose group were 15.2 and 13.6 respectively. The proportion of SBP was 3.8% (n=3) in the rifaximin group as compared to 20% (n=12) in the lactulose group, which was statistically significant (OR 0.16, 95% CI 0.03–0.65, P=0.004). When adjusting for age, gender, MELD score, serum sodium, and etiology of liver disease, rifaximin remained a statistically significant preventative factor in the incidence of SBP (OR 0.12, 95% CI 0.03–0.49, P=0.003). Conclusions: Rifaximin is associated with decreased incidence of SBP in patients with HE and ascites. It may be possible to consolidate therapy for HE and SBP prophylaxis by using rifaximin. Further studies are needed to confirm these findings and to explore the potential role for rifaximin in secondary prophylaxis of SBP.

Disclosures:

Atif Zaman - Advisory Committees or Review Panels: Bristol Meyers Squibb; Grant/Research Support: Bristol Meyers Squibb, Gilead Sciences, Merck, Ikaria

The following people have nothing to disclose: Susanne Shokoohi, Adam Zivony, T Domi Le, Janice Jou

1338

Pretreatment with rifaximin is associated with a shift from enteric to oropharyngeal pathogens in spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites, resulting in less effective prevention compared to systemic antibiotics

Philipp Lutz1,3, Marijo Parcina2,3, Isabelle Bekeredjian-Ding2,3, Kenneth Pfarr2,3, Hans Dieter Nischalke1, Jacob Nattermann1 ,3, Tilman Sauerbruch1, Achim Hoerauf1,3, Christian P. Strassburg1, Ulrich Spengler1,3;

1 Department of Internal Medicine I, University of Bonn, Bonn, Germany; 2Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany; 3German Center for Infection Research, Bonn, Germany

Background and Aims: Rifaximin is a non-absorbable antibiotic used to prevent relapses of hepatic encephalopathy (HE). Since it is also considered a candidate for prophylaxis of spontaneous bacterial peritonitis (SBP) and might have an impact on the bacterial species causing SBP, we studied the characteristics of SBP with respect to rifaximin co-medication. Methods: We prospectively checked all patients receiving a diagnostic para-centesis in our department from March 2012 to April 2013 for SBP and recorded all clinical data including previous episodes of SBP, etiology of liver disease, type of SBP prophylaxis, prior use of rifaximin, concomitant complications of cirrhosis as well as laboratory results and bacteriological findings. The patients were divided in three groups, according to the intake of no antibiotic prophylaxis, rifaximin, or systemic antibiotic prophylaxis. Results: Our study cohort comprised 159 patients with advanced liver cirrhosis (n=156, 98% with Child Pugh stage B orC). The majority were male (n=107, 67%) and suffered from liver disease due to alcohol abuse (n=98, 63%). 32 patients developed SBP, which was culture positive in 15 cases (47%). The majority of patients did not receive antibiotic prophylaxis (n=115), while 27 patients took rifaximin and 17 patients used systemic antibiotic prophylaxis (in 96% of patients chinolones). As expected, the patients differed with respect to the rates of previous HE, which was most frequent in the rifaximin group, and of previous SBP, which was most frequent in patients taking systemic prophylaxis. The three groups were comparable concerning the etiology of cirrhosis, use of other medication, laboratory exams, the MELD score and the history of other complications of liver cirrhosis. While SBP occurred in 8/27 patients (30%) on rifaximin and 24/115 (21%) without any prophylaxis, 0/17 patients on systemic antibiotic prophylaxis developed SBP (p=0.04 versus no prophylaxis and p=0.02 versus rifaximin). Laboratory and clinical parameters did not differ during episodes of SBP between the groups. Concerning microbiological findings, however, enteric bacteria were predominantly identified in the ascites of patients without any prophylaxis (9/11, 82%), while exclusively bacteria from the oropharyngeal cavity were detected in patients on rifaximin (4/4, 100%; p=0.01). Conclusion: Pretreatment with rifaximin might prevent SBP caused by enteric bacteria but not by bacteria from the oropharyngeal flora. In line with this finding, systemic antibiotics seem to be more effective in the prevention of SBP than rifaximin and should remain the standard of care till data from randomized trials are available.

Disclosures:

Marijo Parcina - Speaking and Teaching: BD Diagnostics

The following people have nothing to disclose: Philipp Lutz, Isabelle Bekeredjian-Ding, Kenneth Pfarr, Hans Dieter Nischalke, Jacob Nattermann, Tilman Sauerbruch, Achim Hoerauf, Christian P. Strassburg, Ulrich Spengler

1339

Pathogen recognition receptor polymorphisms and spontaneous bacterial peritonitis in patients undergoing liver transplantation

Saul Kane1, Jose Parungao2, Rocio Lopez4, Medhat Askar3, Nizar N. Zein1;

1Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH;2Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH; 3Allo-gen Laboratories, Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH; 4Department of Quantitative Health Science, Cleveland Clinic Foundation, Cleveland, OH

Background and Aims: Pathogen recognition receptors such as toll-like receptors (TLR) and nucleotide- binding oligomerization domain proteins (NOD) recognize distinct pathogen-associated molecular patterns on the cell surface and in the cytoplasm and are important in mediating innate immune response to infection. Polymorphisms in these molecules have been shown to confer susceptibility to a wide range of infections. We studied the effects of gene variants of TLR2, TLR4, NOD2, and TIRAP on susceptibility for SBP (spontaneous bacterial peritonitis) in our population of decompensated cirrhotics with ascites who subsequently underwent liver transplantation in our institute. Methods: A historical case control study was undertaken. Patients who underwent liver transplantation from August 2007- October 2011 and had ascites necessitating at least one paracen-tesis prior to transplantation were identified and included in the study. SBP was defined as PMNL count >250/mm3. Pertinent clinical variables were extracted from electronic medical records. Blood samples from these patients obtained in the peri-operative period were available for genotyping. SNPs of TLR2 (rs4696480, rs5743708, rs5743704, rs4986791), TLR4 (rs4986790), NOD2 (rs2066844, rs2066845), and TIRAP (rs8177374), were identified by real-time PCR. Results: A total of 125 subjects with cirrhosis and ascites who underwent liver transplant were included in the study. Average age at time of transplant was 55.7 ± 8.5 years and 71% were male. Prior to transplantation, 59 patients had SBP and 66 patients did not. On univariable analysis, higher MELD score (p = 0.029), INR (p = 0.007) and bilirubin (p = 0.034) were found to be significantly associated with SBP. There was no evidence to suggest that any of the genetic variants of TLR2, NOD2, TLR4 or TIRAP were significantly associated with SBP on univariable or multi-variable analysis (rs4696480 p = 0.48, rs5743708 p = 0.26, rs5743704 p = 0.59, rs4986791 p = 0.3, rs4986790 p = 0.4, rs2066844 p = 0.59, rs2066845 p= 0.29, rs8177374 = 0.55). Conclusions: In our study, there was no evidence to suggest that any of the gene variants of TLR2, NOD2, TLR4 or TIRAP were associated with SBP in patients with decompensated cirrhosis and ascites who subsequently underwent liver transplantation. Although prior studies in the literature show an association between TLR2 and NOD2 and SBP in the general cirrhotic population, this may not be applicable to patients who survive to transplantation.

Disclosures:

The following people have nothing to disclose: Saul Kane, Jose Parungao, Rocio Lopez, Medhat Askar, Nizar N. Zein

1340

Ischemia modified albumin (IMA) as a novel diagnostic marker of bacterial infection in hospitalized patients with cirrhosis

Ferdinando A. Giannone1,2, Marco Domenicali1,2, Maurizio Baldassarre1,2, Maristella Laggetta1,2, Lucia Napoli1, Elisabetta Beltrandi3, Roberto Motta3, Mauro Bernardi1,2, Paolo Caraceni1,2;

1Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy; 2Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi University Hospital, Bologna, Italy; 3Central Laboratory, S. Orsola-Malpighi University Hospital, Bologna, Italy

Background/Aims. Albumin carries many properties unrelated to its oncotic activity, including free radical scavenging, detoxification, and transport of many compounds. The N-terminal site of the molecule is capable to bind transition metal ions and therefore plays an important role against oxidative stress. Ischemia Modified Albumin (IMA) is the post-transcriptional alteration of the N-terminal site, reflecting the loss of the cobalt chelating function. IMA elevation has been reported in chronic and acute conditions characterized by a pro-inflammatory state. Thus, this study aimed to assess in cirrhotic patients whether circulating IMA can be considered a novel marker of bacterial infections. Methods. 133 cirrhotic patients (Child-Pugh A/B/C:27/77/29) hospitalized for acute complications of the disease and 50 age- and sex-matched healthy controls were enrolled. The plasma IMA was assessed by the ACB-assay at admission. Clinical and biochemical data were also recorded in all patients. The diagnosis of bacterial infection was diagnosed in 41 patients by microbiological and instrumental data. Major sites of infection were urinary tract (17%), lungs (15%), ascites (15%), blood (15%), and skin soft tissue (15%). Results. Plasma IMA was significantly higher in cirrhotic patients than in controls (0.51±0.12vs0.39±0.12, p<0.001). No correlations were found with MELD and Child Pugh score. IMA was similar in patients with or without gastrointestinal bleeding, renal failure, hepatic encephalopathy, and ascites. In contrast, IMA was higher in patients with bacterial infection as compared to non infected cirrhotics (n=92) (0.58±0.12vs0.48±0.10, p<0.001). ROC curve analysis showed that IMA had the same discriminating performance (AUROC 0.73) for detecting bacterial infections as C-reactive protein (CRP). Logistic regression showed that the parameters independently associated with bacterial infection were IMA, CRP, serum sodium and INR. Using these parameters, we have developed a novel score (9.852×IMA + 0.181×CRP + 1.426×INR-0.143×Na) showing a greater diagnostic performance than either IMA or CRP alone (AUROC 0.83). Conclusions. Elevation of plasma IMA level is specifically associated with bacterial infection in cirrhosis, but not with other clinical complications of the disease. Moreover, IMA showed a diagnostic performance for bacterial infection similar to that of CRP, while a score including IMA, CRP, serum sodium and INR enhanced the diagnostic performance of either IMA and CRP alone. These data prompt further investigation to assess the feasibility of IMA as a novel test to diagnose bacterial infection in the clinical ground.

Disclosures:

Mauro Bernardi - Consulting: CLS Behring GhmB; Speaking and Teaching: CLS Behring GhmB, PPTA Europe

The following people have nothing to disclose: Ferdinando A. Giannone, Marco Domenicali, Maurizio Baldassarre, Maristella Laggetta, Lucia Napoli, Elisabetta Beltrandi, Roberto Motta, Paolo Caraceni

1341

Short treatment with Rifaximin improves blood cerebral flow at transcranial Doppler and psychometric tests in cirrhotic patients with minimal hepatic encephalopathy

Gianluigi Caracciolo1, Maria Assunta Zocco1, Andrea Lupascu2, Bigida E. Annicchiarico1, Matteo Garcovich1, Maria Elena Ain-ora1, Davide Roccarina1, Francesca D'Aversa1, Daniele D. Fer-rarese1, Massimo Siciliano1, Paolo Tondi2, Antonio Gasbarrini1;

1Internal Medicine and Gastroenterology, UCSC, Rome, Italy; 2Internal Medicine and Angiology, UCSC, Rome, Italy

Background: Minimal hepatic encephalopathy (MHE) includes a number of cognitive deficits such as alterations of psychomotor speed and executive functions, detectable in patients with liver cirrhosis only by psychometric or electrophysiological techniques. It has been shown that a long term treatment with rifaximin improves psychometric tests, quality of life and driving ability in these patients. Cerebral blood flow seems to be decreased in patients with chronic liver disease and cerebral vascular resistance indices (resistive index, RI and pulsatility index, PI) are closely correlated with the severity of cirrhosis, hepatic encephalopathy and ascites. Aims: The aim of this study was to evaluate the effect of a short treatment with rifaximin on psychometric tests, cerebral hemodynamic parameters and blood ammonia levels in cirrhotic patients with MHE. Methods: Sixteen cirrhotic patients (10 male and 6 female) that resulted positive to at least one of the three psychometric tests performed in our Unit (TMT A, TMT B and DST) were enrolled in this study. All the patients enrolled were treated with rifaximin 1200 mg/die per os for 15 days. Transcranial Doppler (TCD) with measurement of RI and PI of both mean and posterior right cerebral arteries (MCA, PCA respectively), psichometric tests and blood ammonia levels measurement were performed at baseline and after 15 days of treatment. Data were analyzed with ANOVA test. Results: All patients completed the treatment with no side effects. The short treatment with rifaximin was associated with a significant improvement of psychometric tests and in particular of TMT-B (mean±SD, 111±74 vs 123±77 seconds; p<0,05) and DST (mean±SD, 31±12 vs 27±9 seconds; p<0,05) Among TCD parameters, we found a significant reduction of PCA-RI (mean±SD, 0,57±0,08 vs 0,61±0,07; p<0,05) and a trend toward reduction of PCA-PI (p=0,06). Blood ammonia levels after treatment were lower than before but the differences were no statistically significant. Conclusions: A short term treatment with rifaximin could be effective in improving psychometric tests and cerebral hemodynamic parameters in patients with MHE. These results indicate that the cerebral vascular resistance may reflect functional reversible changes rather than anatomical irreversible damage. We can hypothesize that rifaximin treatment and in particular the effects on intestinal microflora could be associated with a reduced production of toxins with consequent improvement of cerebral metabolism.

Disclosures:

The following people have nothing to disclose: Gianluigi Caracciolo, Maria Assunta Zocco, Andrea Lupascu, Bigida E. Annicchiarico, Matteo Garcovich, Maria Elena Ainora, Davide Roccarina, Francesca D'Aversa, Daniele D. Fer-rarese, Massimo Siciliano, Paolo Tondi, Antonio Gasbarrini

1342

Systemic and Hepatic hemodynamic dysfunction in patients with acute-on-chronic liver failure is significantly associated with dysregulated inflammation and marked sympathetic nervous system activation

Rajiv Jalan, Vikram Sharma, Rajeshwar Mookerjee; University College London, Institute of Liver and Digestive Health, London, United Kingdom

Background and Aim: Acute-on-chronic liver failure (ACLF) has recently been defined and is characterized by acute deterioration of cirrhosis with multi-organ failure, inflammation and high mortality. This study aims to define the systemic and hepatic hemodynamic characteristics of patients with ACLF. Methods: Sixty-patients with alcoholic cirrhosis were prospectively enrolled; stable cirrhosis [SC: n=27], decompensated cirrhosis but with no ACLF [DC: n=14] and ACLF ACLF: n=19]. Systemic (Swan-Ganz catheter measurement) and hepatic hemodynamic studies (HVPG and indocyanine green clearance) were performed and patients were followed for 3-months. Plasma samples were collected to measure norepinephrine (LC-MS) and inflammatory cytokines (ELISA: TNF-R1 and 2, IL-6; IL-8). Results: Three-month mortality was; SC: none; DC: 14%; ACLF: 47.2% (p<0.001). Mean arterial pressure was lowest in the ACLF group (p<0.001). Although the cardiac output (CO) was higher in the ACLF patients, the values were very variable and a lack of increase in CO was associated with higher mortality. The ACLF patients had significantly higher HVPG whilst the hepatic blood flow was markedly reduced with an increase in intrahepatic resistance, which predicted mortality (AUROC: 0.87, P<0.0001). In ACLF, the severity of intra-hepatic resistance correlated with markers of inflammatory response (IL-6, TNFR-1); norepinephrine levels, creatinine levels and severity of encephalopathy. Modeling data showed that the high norepinephrine levels in ACLF may contribute to a right shift of the HVPG-hepatic blood flow relationship and also correlate with severity of inflammation. Moreover, noradrenaline concentrations had a predictive utility in defining mortality (AUROC: 0.90; p<0.0001). Conclusions: There are clear disturbances in systemic and hepatic hemodynamics in ACLF, above and beyond that seen in decompensated cirrhosis and these are associated with dysregulated inflammation and severe activation of the sympathetic nervous system. A novel aspect of this study was the significant correlation between noradrenaline levels, increased intra-hepatic resistance and the development of multi-organ failure. Sympathetic activation also had predictive utility for high mortality rates in ACLF patients. Further study is warranted of the mechanism(s) by which sympathetic activation in ACLF primes organs, including the heart, increasing their susceptibility to injury, with the hope of identifying novel targets for therapy.

Disclosures:

Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus

The following people have nothing to disclose: Vikram Sharma, Rajeshwar Mookerjee

1343

Spontaneous Bacterial Peritonitis Mortality among Hospitalized Patients in the United States

Brian Kim1,2, Berkeley N. Limketkai1, Tinsay A. Woreta1, Po-Hung Chen1;

1Gastroenterology, Johns Hopkins University, Baltimore, MD; 2Hepatology, Mount Sinai Hospital, New York, NY

Background: Spontaneous bacterial peritonitis (SBP) is a common complication of portal hypertension from cirrhosis and is associated with significant morbidity and mortality. Using the

Nationwide Inpatient Sample (NIS), an all-payer inpatient database in the United States, we examined the clinical characteristics and risk factors associated with mortality in hospitalized SBP patients. Methods: The NIS was queried for all hospitalizations related to SBP from 2006 to 2010 using the International Classification of Disease-9-CM Code. Logistic regression was performed to evaluate the relationships between SBP mortality and factors such as age, gender, race/ethnicity, medical conditions at admission including variceal hemorrhage, hepatic encephalopathy (HE), acute renal injury (AKI), coagulopathy, and other infections. The lengths of stay (LOS) and total charges were also examined. Results: From 2006 to 2010, there were 77,738 SBP hospitalizations with 14,026 overall deaths (18.0% in-hospital mortality). The mean age of hospitalized patients was 55.6 years, and 36% of patients were females. The mean age of patients who died in the hospital was higher (57.8 vs. 55.1 years, p<0.001) than those who survived the admission. The group that died during hospitalization had longer LOS (11.6 vs. 9.4 days, p<0.001) and higher total charges ($119,507 vs. $65,261, p<0.001). In the multivariate analyses, older age, HE, variceal hemorrhage, coagulopathy, AKI, pneumonia (PNA), and sepsis were associated with increased in-hospital mortality. Hispanic ethnicity was associated with a lower risk of death as compared to white patients. No significant differences in mortality were noted with gender, HIV infection and concurrent UTI [Table]. Conclusion: SBP is associated with significant in-hospital mortality, especially in patients with concurrent risk factors. SBP remains a significant burden to the healthcare system with increased utilization seen in patients with in-hospital deaths.

Multivariate Logistic Regression Analysis of Risk Factors for In-Hospital SBP Mortality

VariableOdds Ratio95% CIP-value
Age1.021.01–1.02<0.001
Female Gender0.990.85–1.150.909
Hispanic ethnicity0.710.57–0.870.001
HE1.241.04–1.480.019
Variceal hemorrhage2.851.41–5.790.004
Coagulopathy1.311.06–1.620.012
AKI2.341.99–2.74<0.00l
PNA1.621.28–2.06<0.00l
UTI1.010.81–1.250.959
Sepsis6.275.24–7.49<0.001
HIV1.180.69–2.020.551

Disclosures:

The following people have nothing to disclose: Brian Kim, Berkeley N. Limketkai, Tinsay A. Woreta, Po-Hung Chen

1344

Impact of Liver Disease Status and Treatment with Rifax-imin on Complications of Cirrhosis in a Randomized, Placebo-Controlled Trial

Steven L. Flamm1, Arun J. Sanyal2, Guy W. Neff3, Robert L. Rol-leri4, Andrew C. Barrett4, Enoch Bortey4, Craig Paterson4, William P. Forbes4;

1Department of Medicine, Northwestern Feinberg School of Medicine, Chicago, IL; 2Virginia Commonwealth University, Richmond, VA; 3Tampa General Medical Group, Tampa, FL; 4Salix Pharmaceuticals, Inc., Raleigh, NC

Purpose: To evaluate baseline factors that may be predictive of imminent complications of cirrhosis, and to examine the effects of rifaximin (RFX) in reducing the risk of complications. Methods: Data from a 6-month, randomized, double-blind trial of RFX 550 mg BID vs. placebo (PBO) were evaluated in a post-hoc analysis which stratified patients according to: 1) baseline MELD score and INR (MELD≥12 and INR≥1.2 vs. MELD<12 and INR<1.2), and 2) presence vs. absence of ascites. Time to first complication (hepatic encephalopathy [HE], spontaneous bacterial peritonitis, variceal bleeding, and hepatorenal syndrome) was assessed. Patients (n=299) had a recent history of recurrent HE but were in remission at enrollment (Conn Score [CS], 0 or 1). Breakthrough overt HE was defined as an increase in CS to ≥2. Other complications were collected via adverse event reports. Results: Mean age was 56.2 years, 60.9% were male, and 91% took lactulose during the study. Mean MELD scores were higher in the 106 patients with ascites (RFX group: 14.1, PBO group: 14.0) vs. the 193 patients with no ascites (RFX group: 12.5, PBO group: 12.0). In patients with ascites, the hazard ratio for risk of any complication in the RFX group vs. PBO group was 0.58 (p=0.045, 42% relative risk reduction) (Figure). Patients without ascites experienced fewer overall complications; however, RFX relative to PBO was effective (p<0.001, 65% relative risk reduction). In patients with MELD≥12 and INR≥1.2 (n=153), the hazard ratio for the RFX vs. PBO was 0.40 (p<0.001, 60% relative risk reduction). Although fewer complications occurred in the MELD<12 and INR<1.2 group (n=54), RFX conferred a 76% reduction in relative risk. Conclusions: In patients with ascites, or with MELD≥12 and INR≥1.2, complications of cirrhosis were more likely, although rifaximin significantly reduced risk of complications in all subgroups. Future prospective studies are warranted to assess the ability of RFX to prevent complications of cirrhosis.

image

Disclosures:

Steven L. Flamm - Advisory Committees or Review Panels: Merck, Gilead, Vertex, Merck, Gilead, Vertex, Merck, Gilead, Vertex, Merck, Gilead, Vertex; Grant/Research Support: Merck, Vertex, Gilead, Pfizer, Anadys, Achillion, Abbott, Tibotec, Merck, Vertex, Gilead, Pfizer, Anadys, Achillion, Abbott, Tibotec, Merck, Vertex, Gilead, Pfizer, Anadys, Achillion, Abbott, Tibotec, Merck, Vertex, Gilead, Pfizer, Anadys, Achillion, Abbott, Tibotec; Speaking and Teaching: Merck, Gilead, Vertex, Merck, Gilead, Vertex, Merck, Gilead, Vertex, Merck, Gilead, Vertex

Arun J. Sanyal - Advisory Committees or Review Panels: Gore, Gilead, Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Bayer-Onyx, Genentech, Norgine, GalMed, Novartis, Echosens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept, Ikaria, Takeda, Gilead; Independent Contractor: UpToDate

Guy W. Neff - Consulting: Genentech, Vertex, Salix; Speaking and Teaching: Genentech, Vertex, Salix, BMS, Merck

Robert L. Rolleri - Employment: Salix Pharmaceuticals, Inc. Andrew C. Barrett - Employment: Salix; Stock Shareholder: Salix Enoch Bortey - Employment: Salix Pharmaceuticals, Inc. Craig Paterson - Employment: Salix Pharmaceuticals

William P. Forbes - Management Position: Salix Pharmaceuticals, Inc; Stock Shareholder: Salix Pharmaceuticals, Inc

1345

Vitamin D Deficiency is a Risk Factor for 30-day Mortality in Hospitalized Patients with Chronic Liver Disease

Raffi Karagozian1, Chinweike Ukomadu1, Kenneth B. Christopher2;

1 Gastroenterology, Hepatology & Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 2Division of Renal Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA

Background: Vitamin D deficiency has been linked to several chronic diseases, including cancer, diabetes, multiple sclerosis, Crohn's disease, cardiovascular diseases, rheumatoid arthritis, schizophrenia, and depression. Recent randomized controlled trials have shown reduced mortality risk in patients with vitamin D supplementation raising further attention to the role of vitamin D in prevention and risk reduction. In chronic liver disease (CLD), vitamin D deficiency may contribute to accelerated liver dysfunction and fibrosis by enhancing the inflammatory process. Vitamin D deficiency has also been shown to cause reduced antiviral response. A significantly high prevalence of vitamin D deficiency has been reported in CLD, however currently there is sparse information regarding how hypovita-minosis D effects the progression and natural history of liver disease. Previous data has shown a significant association of vitamin D levels with the degree of liver dysfunction, suggesting that vitamin D deficiency may predict hepatic decompensation and mortality in patients with CLD. Aim: The primary aim of this study is to determine if vitamin D deficiency in hospitalized patients with CLD is associated with poor clinical outcome and early mortality. Primary endpoint measured is 30-day mortality. Methods: Patients with CLD were identified from the Partners Healthcare system patient data repository (RPDR) using ICD-9-CM diagnoses. Inclusion criteria: hospitalized medical or surgical patients ≥18 years old, between 1993–2011. Diagnostic codes included all 571 .xx codes for chronic liver disease, 070.54 for chronic hepatitis C and 070.32 for chronic hepatitis B. When multiple liver disease diagnoses were present, the diagnosis identified as the first specific diagnosis within the observation period was assigned. Vitamin D levels were divided into four quartiles, lowest <10ng/ml and reference as >30ng/ml. Results: 4,562 hospitalized patients were identified. Mean age 55.3, 1,827 (40.1%) male, 3,593 (78.8%) white, and 2,377 (52.1%) were medical patients. Adjusting for age, race, Deyo-Charlson index, and medical/surgical patient, the adjusted OR for 30-day mortality was 2.32 (1.33–4.05) p=0.003 for 25(OH)D levels<10 ng/ml, 1.89 (1.16–3.08) p=0.01 for 25(OH)D levels 10–19.9ng/ml and 1.80 (1.08–3.02) p=0.025 for 25(OH)D levels 20–29.9ng/ml. Conclusion: Hospitalized chronic liver disease patients with vitamin D deficiency are at higher risk for 30-day mortality when controlled for Deyo-Charlson morbidity index. The 30-mortality risk is directly associated with the degree of vitamin D deficiency.

Disclosures:

Chinweike Ukomadu - Consulting: Gilead Sciences

The following people have nothing to disclose: Raffi Karagozian, Kenneth B. Christopher

1346

Moderate dietary sodium restriction in outpatients with cirrhosis and ascites iIn the real life: adherence and more

Filippo Morando1, Silvia Rosi1, Silvano Fasolato1, Salvatore Piano1, Mariateresa Nardi2, Marta Cavallin1, Francesca Cam-pagna1, Sara Montagnese1, Marialuisa Stanco1, Lorenza Care-garo1, Angelo Gatta1, Paolo Angeli1,3;

1 Department of Medicine DIMED, University of Padova, Padova, Italy; 2Istituto Oncologico Veneto, Padova, Italy; 3Department of Medicine DIMED, Unit of Medical Emergencies in Liver Transplantation, University of Padova, Padova, Italy

Background: regardless the controversial results of clinical trials, it is current opinion that in patients with cirrhosis and ascites, a moderate dietary sodium restriction (<90 mmol Na/day) should be indicated. Nevertheless, there is a lack of specific investigations on the correct adherence to a moderately dietary sodium restriction. In addition, some findings suggest that dietary sodium restriction may impair the total calories intake, favouring the occurrence of complications with a negative effect on survival. Aims: to evaluate the adherence of patients with cirrhosis and ascites to a moderately low salt diet and the impact of this on total intake of calories and on serum sodium concentration. Methods: 120 patients with cirrhosis and ascites followed as outpatients were interviewed by the same operator on the basis of a pre-established questionnaire including 14 questions related to the low-salt diet. A quantitative assessment of nutrient and salt intake was performed via computerized software program (Winfood software package-MediMatica, Italy). Results: among the 120 included patients, only 37 were found to follow a moderate dietary sodium restriction (Group A). Of the remaining 83 patients (group B), 54 (65.1%) were convinced to follow a low-salt diet whilst 29 (34.9%) stated that they did not follow it intentionally. The mean daily sodium intake in patients of Group A and Group B was 79.5±5.5 mmol/day and 205.9±14.1 mmol/day respectively (p<0.0001). The adherence to a moderate dietary sodium restriction was related to the severity of cirrhosis as expressed by the MELD score (18.4±1.1 vs 16.4±0.5, p< 0.05), serum level of urea (9.9±0.8 vs 7.6±0.5 μmol/l, p< 0.05), and presence of refractory ascites (67.6 vs 48.2, p<0.05). Adherence was higher among candidates to liver transplantation and among those who were followed as outpatients in a more strict way, by a new model of integrated specialized caregiving, the Care Management Program. Patients of Group A had a 18% reduction of the mean daily total intake of calories compared with Groups B patients (1382.5±43.6 vs 1658.7±45.5 kcal, p<0.0005) while there was no differences on the occurrence of hyponatremia (134.4±0.7vs 133.7±0.5, p=NS). Conclusions: Our data show a poor adherence of patients with cirrhosis and ascites to a moderate dietary sodium restriction. Adherence to diet seems to increase with the worsening of liver disease, probably due to the reduction of alternative therapeutic options. In addition, a deficiency in educational process to a moderate dietary sodium restriction can lead the patient to follow it through dangerous tools such as the reduction of the daily intake of food.

Disclosures:

The following people have nothing to disclose: Filippo Morando, Silvia Rosi, Silvano Fasolato, Salvatore Piano, Mariateresa Nardi, Marta Cavallin, Francesca Campagna, Sara Montagnese, Marialuisa Stanco, Lorenza Caregaro, Angelo Gatta, Paolo Angeli

1347

Liver cirrhosis is a risk for tuberculosis infection- a nationwide longitudinal study in Taiwan

Jee-Fu Huang1,2, Ming-Lung Yu2, Wan-Long Chuang2;

1Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

Tuberculosis (TB) and liver cirrhosis are both endemic in many regions of the world, and they contribute to major disease morbidity and mortality worldwide. TB disease is prevalent in patients with immune dysfunction, which is a common feature of cirrhosis. However, the risk of TB disease in cirrhotic patients has rarely been investigated. A nationwide cohort study was conducted aiming to elucidate and characterize the association between cirrhosis and TB disease by analyzing a large-scale database in Taiwan. The study pool consisted of 41,076 cirrhotic patients and 204,244 non-cirrhotic controls between January 1998 and December 2007. Cirrhotic and non-cirrhotic patients were 1:5 matched for age and sex. During the study period, 957 (2.32%) cirrhotic patients developed TB disease, yielding a rate that was significantly higher than that of non-cirrhotic patients (0.46%, 955/204,244; p < 0.001). Cox's regression model adjusted for age, sex, and underlying medical disorders, a significantly higher active TB disease rate was maintained for cirrhotic patients compared with their counterparts (adjusted hazard ratio [HR], 3.55; 95% confidence interval [CI], 3.08 - 4.09; p < 0.001). Alcoholism and hepatitis C virus (HCV) infection significantly increased TB disease risk with adjust hazard ratios of 2.18 (95% CI, 1.86 - 4.09; p < 0.001), and 1.18 (95% CI, 1.02 - 1.30; p < 0.001), respectively. Conclusion: Cirrhotic patients have a greater risk of TB disease than non-cirrhotic patients, particularly in patients with alcoholism and HCV infection.

Disclosures:

Wan-Long Chuang - Advisory Committees or Review Panels: Gilead, Roche, Norvatis; Speaking and Teaching: BMS

The following people have nothing to disclose: Jee-Fu Huang, Ming-Lung Yu

1348

The prediction of liver-related outcomes by renal biomarkers in cirrhotic patients

Sirirat Phuttasiriwat1, Somlak Vanavanan2, Sasivimol Rattanasiri3, Abhasnee Sobhonslidsuk1;

1Medicine, Ramathibodi hospital, Bangkok, Thailand; 2Pathology, Ramathibodi hospital, Bangkok, Thailand; 3Section for Clinical Epidemiology and Biostatistics, Ramathibodi hospital, Bangkok, Thailand

Background & Aims: Liver status affects survival in cirrhotic patients with one-year survival rate of about 50% in decompensated patients. Renal function was reported to be an important predictor of mortality. Serum creatinine level is not reliable in cirrhotic patients because it overestimates renal function. New renal biomarkers, such as urinary neutrophil gelatinase-associated lipocalin (uNGAL) and serum Cystacin C (sCys C), are proposed to be used for renal function assessment with more accuracy. We aimed to evaluate the role of uNGAL and sCys C for predicting death and liver-related outcomes in cirrhotic patients. Methods : A prospective cohort study was conducted in cirrhotic patients who attended liver clinics between 1 January 2012 and 30 June 2012. Informed consent was obtained prior to enrollment. Biochemical tests, which included sCys C and uNGAL performed by immunoassay, were carried out. All patients were followed up for 10 months. Data of death and liver-related outcomes defined as upper gastrointestinal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hospitalization were collected. Statistical analysis was performed with student-t test, non-parametric test and chi-square test as appropriate. The Receiver Operating Characteristic (ROC) curve analysis was used to assess the performance of sCys C and uNGAL in predicting death and liver-related outcomes. The Cox proportional hazard model was used to determine prognostic factors of death and liver-related outcomes. Results: Eighty-six cirrhotic patients with 41 (47.67%) compensated and 45 (52.33%) decompensated patients were enrolled. All patients except 5 patients (5.81%) were followed up until the end of the study. Mean follow up was 9.0±2 months. Death and liver-related outcomes occurred in 9 patients (12.5%) and 13 patients (19.7%). The area under curve of sCys C in predicting liver-related outcomes was 0.75 (95% CI: 0.70, 0.88). The appropriate cutoff of sCys C was 1.03 mg/L with a sensitivity of 83.33%, a specificity of 67.65% and a positive likelihood ratio of 2.58. From univariate analysis, hemoglobin, sCys C, MELD score, Child-Pugh score and decompensated status were significantly associated with liver-related outcomes. Only sCys C was an independent predictor of liver-related outcomes with hazard ratio of 36.13 (95% CI: 1.77, 739.80).(p-value=0.02) Conclusions: Serum Cystacin C level, but not urine NGAL level, predicts liver-related outcomes in cirrhotic patients who have serum creatinine level less than 1.5 mg/dl. Further studies are required to confirm the result of our study.

Disclosures:

The following people have nothing to disclose: Sirirat Phuttasiriwat, Somlak Vanavanan, Sasivimol Rattanasiri, Abhasnee Sobhonslidsuk

1349

Is acute kidney injury stage 1 (AKI1) according to modified AKIN criteria associated with higher mortality in cirrhotic patients with ascites?

Theresa Bucsics, Philipp Schwabl, Kathrin Soucek, Mattias Man-dorfer, Arnulf Ferlitsch, Markus Peck-Radosavljevic, Thomas Reiberger; Internal Medicine III, Div. of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

Background: Renal dysfunction is associated with increased morbidity and mortality in cirrhotic patients with ascites. Recent studies suggest that a modified acute kidney injury (AKI) classification, based on the definition of the AKI network (AKIN), may be more sensitive in predicting mortality in patients with acute kidney injury than classic AKIN or HRS criteria. Aims: To evaluate the outcome of cirrhotic patients with ascites developing AKI, staged according to the modified AKIN criteria. Methods: Retrospective, single-center cohort study. Clinical and laboratory data of 689 adult cirrhotic patients with ascites undergoing paracentesis were collected at the day of paracen-tesis and for 7 days afterwards. Patients with non-portalhypertensive ascites (n=56), baseline creatinine levels >1.5 mg/dL (n=105), secondary bacterial infections (n=19) or incomplete data (n=102) were excluded. In the remaining 407 patients, AKI development was staged according to AKIN criteria and classified as follows: stage A: AKI1 with follow-up serum creatinine level (CREA) <1.5 mg/dL, stage B: AKI1 with follow-up CREA >1.5 mg/dL, stage C: AKI2 and AKI3, control group: no development of AKI. Three-months survival was assessed by Kaplan Meier curves and compared using log-rank test. Results: Among 407 patients, 74 (18%) developed AKI after paracentesis (AKI1 n=51, AKI2 n=18, AKI3 n=5; stage A n=20, stage B n=31, stage C n=23). MELD scores, Child-Pugh stages, as well as a diagnosis of SBP at paracentesis were equally distributed among AKI groups. Male sex was more prevalent across all AKI groups (n=46; 62%), except for stage A, which included more women (65%). Patients with AKI1 had increased mortality compared to patients without AKI (median survival 89 vs. 414 days, p=0.014). However, subdividing AKI1 into stage A and stage B revealed a significant increase in mortality in patients with stage B, though not in patients with stage A, compared to the control (survival: stage A: 515 days, p=n.s. vs. control; stage B: 64days, p=0.001 vs. control). Only 5 patients developed AKI3 and their survival was similar to AKI2. Combining AKI3 with AKI2 (stage C) revealed the highest mortality compared to the control group (median survival 35 vs. 414 days, p<0.001). Conclusions: AKIN criteria provide prognostic information for cirrhotic patients with ascites undergoing paracentesis. Both AKI1 and AKI2/3 were associated with a step-wise increase in mortality. However, patients developing AKI1 without a rise in CREA above 1.5 mg/dL are at relatively low risk for 3-months mortality.

Disclosures:

Mattias Mandorfer - Advisory Committees or Review Panels: Janssen

Markus Peck-Radosavljevic - Advisory Committees or Review Panels: Bayer, Gilead, Janssen, BMS; Consulting: Bayer, Boehringer-Ingelheim, Jennerex, Eli Lilly; Grant/Research Support: Bayer, Roche, Gilead, MSD; Speaking and Teaching: Bayer, Roche, Gilead, MSD, Eli Lilly

Thomas Reiberger - Grant/Research Support: Gilead, Gilead, Phenex; Speaking and Teaching: Roche, MSD, Roche, MSD

The following people have nothing to disclose: Theresa Bucsics, Philipp Schwabl, Kathrin Soucek, Arnulf Ferlitsch

1350

Obstructive Sleep Apnea Can Strongly Influence Cognition and Driving in Cirrhosis

Jasmohan S. Bajaj1, Leroy Thacker2, David Leszczyszyn3, Samuel Taylor3, Pamela Monteith1, Nicole Noble1, Melanie White1, Michael Fuchs1, Douglas M. Heuman1;

1Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA; 2Biostatistics, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA; 3Neurology, Sleep Division, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA

Cirrhosis is associated with altered cognition, sleep-wake cycle and driving impairment, which are also found in obstructive sleep apnea (OSA). OSA and cirrhosis(cirr) often coexist but the relative contribution of either on cognition, sleep quality &driving is unclear. Aim: To evaluate the effect of OSA on cognition and driving performance in cirrhotics with/without OSA compared to non-cirrhotic OSA patients and controls. Hypothesis: OSA & cirrhosis would affect cognition differently & OSA pts (with/without cirrhosis) would have greater difficulties with centercrossings (CC) & road-edge excursions(REE) not speeding in the 2nd than the 1st half of the simulation since speeding requires wakefulness while CC & REE worsen with sleepiness.Methods: 4 age-matched groups (cirr+OSA, cirr only, OSA alone & controls) were recruited. OSA was diagnosed using Berlin questionnaire (BQ) &prior polysomnography. All cirrhotics were Child A & not on HE treatment. A standard cognitive battery for minimal HE diagnosis (impairment=cognitive battery >2SD beyond controls), sleep questionnaires [Epworth(ESS), Pittsburgh Quality of Sleep Index(PQSI) high score worse] were performed. Subjects then underwent an hour-long monotonous driving simulation without distractors(divided for analysis into six epochs) .Speeding, CC & REE were noted during each epoch. Cognition, sleep questionnaires and driving outcomes were studied between groups using mixed linear model & analysis of driving outcomes in 2nd minus 1st half(Δ) of driving simulation. Results: 99 age-matched subjects (20 ctrls, 25 OSA, 31 Cirr & 23 Cirr+OSA) were included. A significantly higher % of cirrhotics (54%:cirr+OSA 45%, cirr 58%) were cognitively impaired(MHE) compared to OSA (36%) & ctrls (0%,p=0.003) indicating that cirrhosis, not OSA is associated with it.Sleep evaluation:OSA pts had higher BQ positivity(ctrl 0%, OSA 100%, cirr45%,cirr+OSA 77% p<0.0001),PQSI (ctrl 4 OSA 10, cirr 8, cirr+OSA 10,p<0.0001) & ESS (ctrl 6, OSA 12, cirr 9,cirr+OSA 14,p<0.0001). BQ+ status did not differ between cognitively impaired(MHE)/unimpaired pts.Driving simulation: BQ+ pts had significantly higher ΔCC(26 vs 4,p=0.002) & ΔREE (24 vs 6, p=0.001) but similar Δspeed (2 vs 2) compared to negative pts. 'in the mixed model, CC & REE had a significant (p=0.03 &0.001) group by epoch interaction but not speeding. Cirrhosis did not have any additive effect on driving simulation over& above OSA. Conclusion: OSA and cirrhosis affect cognition & driving simulation differently and the BQ can differentiate these patients. Awareness of OSA as a differential of cognitive &driving issues in cirrhosis is important to ensure proper management.

Disclosures:

Jasmohan S. Bajaj - Advisory Committees or Review Panels: Salix, Merz, otsuka, ocera, grifols, american college of gastroenterology; Grant/Research Support: salix, otsuka, grifols

Douglas M. Heuman - Consulting: Bayer, Grifols, Genzyme; Grant/Research Support: Exilixis, Novartis, Bayer, Bristol Myers Squibb, Scynexis, Ocera, Mannkind, Salix, Globeimmune, Roche, SciClone, Wyeth, Otsuka, Ikaria, UCB, Celgene, Centocor, Millenium, Osiris; Speaking and Teaching: Otsuka, Astellas

The following people have nothing to disclose: Leroy Thacker, David Leszczyszyn, Samuel Taylor, Pamela Monteith, Nicole Noble, Melanie White, Michael Fuchs

1351

Sarcopenic Obesity and Muscle Fat Infiltration are Associated with Higher Mortality in Patients with Cirrhosis

Aldo J. Montano-Loza1, Judith Meza-Junco2, Carla M. Prado3, Michael Sawyer2, Mang M. Ma1, Crystal Beaumont2, Nina Esfan-diari2, Norman Kneteman4, Vickie Baracos2;

1 Division of Gastroenterology & Liver Unit, University of Alberta, Edmonton, AB, Canada;2Department of Oncology, Cross Cancer Institute, Edmonton, AB, Canada; 3Department of Nutrition, Food and Exercise Sciences, The Florida State University, Tallahassee, FL; 4Department of Surgery, University of Alberta, Edmonton, AB, Canada

Background/Aims: Overweight and obesity are now endemic in Western countries. Patients with cirrhosis may develop simultaneous loss of skeletal muscle and gain of adipose tissue, culminating in the condition of sarcopenic obesity. Moreover, muscle depletion is characterized by both a reduction in muscle size and increased proportion of inter-and intra-muscular fat. In this study we aimed to establish if sarcopenia, sarcopenic obesity and muscle fat infiltration predict increased mortality in cirrhotic patients. Methods: We analyzed 606 cirrhotic patients who were consecutively evaluated for liver transplant and had a computed tomography (CT) scan at the 3rd lumbar vertebrae. Data were recovered from medical charts. The 3rd. lumbar skeletal muscle index (L3 SMI) and the muscle attenuation (MA) were measured by CT. Sarcopenia and muscle fat infiltration (characterized as low MA) were described using previously published gender and BMI-specific cutoffs. Sarcopenic obesity was defined as those patients with concurrent overweight or obesity (BMI>25 kg/m2). Patients were followed until death, liver transplant or the last visit. Results: Four hundred-and five patients were males (67%), and cirrhosis etiology was HCV in 227 patients (38%), alcohol in 125 (21%), cryptogenic/NASH in 161 (27%), autoimmune liver disease in 50 (8%), HBV in 38 (6%) and others in 5 patients (1%). Two hundred and fifty-eight patients had concomitant HCC (43%). During mean follow-up of 20±2 months, 237 patients received a liver transplant (39%), 231 died (38%), and 138 (23%) were alive. Two hundred and seventy-two patients had sarcopenia (45%), 122 patients had sarcopenic obesity (20%) and 312 patients had low MA (52%). By Cox regression analysis both, L3 SMI (HR 0.97, 95% CI 0.96–0.99, P<0.001), and MA (HR 0.97, 95% CI 0.96–0.98, P<0.001) were associated with mortality, whereas BMI was not (HR 0.99, 95% CI 0.98–1.01, P=0.5). Patients with sarcopenia (20±3 vs. 58±22 months, Log Rank <0.001), sarcopenic obesity (19±5 vs. 41±11 months, Log Rank <0.001), and low MA (27±5 vs. 55±15 months, Log Rank =0.004) had worse median survival than patients without sarcopenia, sarcopenic obesity and normal MA. Lastly, patients with sarcopenia and low MA had significantly worse survival than patients with none of these two defects (20±3 vs. 58±22 months, Log Rank <0.001). Conclusions: Body composition assessment with CT images helps to disclose otherwise occult muscle depletion and muscle fat infiltration (MA) in patients with cirrhosis. Cirrhotic patients with muscle depletion and with low MA have a poor prognosis, regardless of overall body weight or BMI.

Disclosures:

The following people have nothing to disclose: Aldo J. Montano-Loza, Judith Meza-Junco, Carla M. Prado, Michael Sawyer, Mang M. Ma, Crystal Beaumont, Nina Esfandiari, Norman Kneteman, Vickie Baracos

1352

Functional, Anthropometric and Prognostic Associations of Muscle Wasting Assessed by Computed-Tomography in Patients with Cirrhosis

Ziva Mrevlje1, Ounali Jaffer3, Matthew Maddocks2, Natasha Vidas4, Shabnah Ratnarajah1, Michael A. Heneghan1, John B. Karani3, Julia Wendon1, Nigel Heaton1, William Bernal1;

1Institute of Liver Studies, Kings College Hospital, London, United Kingdom; 2Palliative Care and Policy, Kings College Hospital, London, United Kingdom; 3Radiology, Kings College Hospital, London, United Kingdom; 4Nutrition and Dietetics, Kings College Hospital, London, United Kingdom

Background. Skeletal muscle wasting in patients with chronic liver disease (CLD) is increasingly recognised as being both common and prognostically important. Recent reports suggest that muscle wasting on Computed Tomography (CT) based assessment of skeletal muscle cross-sectional area is an independent predictor of mortality. However, the clinical and functional associations of this wasting are poorly characterised. In a large cohort of patients with CLD assessed for liver transplant (LT) we therefore determined skeletal muscle area at the 3rd lumbar (L3) level using CT, and examined its relation to survival, and for the first time to concurrent anthropometric, functional and cardiopulmonary exercise test (CPET) assessments. Patients and Methods. 216 patients with CLD assessed for first LT at a single centre were studied; L3 Skeletal Muscle Index (L3SMI) normalised for stature was determined from analysis of CT images using the SliceOmatic Software. Anthropometry was performed by trained dietetic staff and CPET using upright cycle-ergometer. Non-transplanted survival was compared at one year after assessment. Results. Median age of the cohort was 56 years (IQR 49–61) and 55 (25%) were female. MELD at assessment was 14 (11–19) and follow up 726 days (432–1045); 159 patients were waitlisted of whom 123 (77%) underwent LT. Median L3SMI in males was 47.4 (40.7–53.7) cm2/M2 and in females 38.3 (35.1–43.5). L3SMI correlated closely with Hand Grip Strength (r=0.437, p<0.0001) and with Mid-arm Muscle Circumference (r=0.581, p<0.0001). There was no correlation with MELD score (r=-0.001 p=0.93) but L3SMI was closely related to the presence of ascites. L3SMI correlated weakly with CPET measures of aerobic capacity (Anaerobic Threshold (r=0.152, p<0.05), MV02 (r=0.160, p<0.03) but closely with the peak workload (Watts) achieved (r=0.395, p<0.0001). L3SMI was significantly lower in non-survivors; 38.7 (32.4–48.6) vs. 45.1 (39.1–55) (p<0.02) and on multivariate analysis with adjustment for age, gender and MELD score, was an independent predictor of mortality: for lowest tertile of L3SMI, adjusted Hazard Ratio was 3.5 (95% CI 1.7–7.4), (p<0.001). Conclusion. In patients with CLD, muscle wasting as assessed by CT using the L3SMI is strongly and independently related to survival. L3SMI correlates with anthro-pometrically determined measures of muscle bulk and function but not with MELD. It did not relate closely to CPET measures of cardio-respiratory aerobic capacity but rather to those indicative of skeletal muscle deconditioning and fatigue. Our data confirm its prognostic importance and potential as a modifiable risk factor for survival in CLD.

Disclosures:

Julia Wendon - Advisory Committees or Review Panels: Excalenz, Pulsion

Nigel Heaton - Advisory Committees or Review Panels: Novartis, Roche; Speaking and Teaching: Astellas

The following people have nothing to disclose: Ziva Mrevlje, Ounali Jaffer, Matthew Maddocks, Natasha Vidas, Shabnah Ratnarajah, Michael A. Heneghan, John B. Karani, William Bernal

1353

Bacterial DNA detection in ascites fluid in cirrhotic patients: molecular characterisation and clinical impact

Cornelius Engelmann1, Delia Prywerek1, Sandra Krohn1,2, Albrecht Boehlig1, Adam Herber1, Antonis Chatzinotas2, Ingo Fetzer3,2, Stephan Boehm1, Thomas Berg1;

1Gastroenterology/Hepatology, University Hospital Leipzig, Leipzig, Germany; 2Environmental Microbiology, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany; 3Stockholm Resilience Centre, Stockholm University, Stockholm, Sweden

Introduction: Spontaneous bacterial peritonitis (SBP) is a serious complication in cirrhotic patients. Due to the limitations of culture-dependent bacterial identification methods, diagnosis is established on the basis of an elevated leukocyte count (>0,5/nL). We applied culture-independent PCR-based methods for the detection and differentiation of bacterial DNA (bactDNA) in order to characterize the bacterial spectrum in both leukocytic and non-leukocytic ascites fluid (AF). Moreover, the clinical impact of this marker in cirrhotic patients was evaluated. Methods: 339 AF samples from 162 cirrhotic patients (2,09 ± 2,036 per patient) were collected between February 2011 and December 2012. BactDNA was detected using realtime PCR with broad range primers targeting the V3 and V4 variable regions of the 16S rRNA-gene. PCR-products of positive ascites fluid samples were subsequently sequenced and polymicrobial chromatograms were analysed using the web tool Ripseq. Results: We present a method that allows us to rapidly detect bactDNA in AF samples and to subsequently identify the most abundant sequence types, even in mixed samples. Whereas SBP was diagnosed according to a leukocyte count >0,5/nL in 12,4%, bactDNA could be detected in 35,7% of all AF samples. The percentage of bactDNA detection was 33.3% in non-leukocytic AF as compared to 47,6% in leukocytic AF (p=0,072). Direct sequencing of purified PCR products revealed a significant amount of mixed chromatograms (50%) and showed a dominance of sequence types from gram-positive bacteria (mainly Staphylococci, Streptococci). During follow-up (4–27 months), 24 patients were transplanted and 34 patients died. A main reason for death was sepsis (50%). Mean transplant-free survival was 365 days (CI 260–471) in patients with bactDNA positive AF after index paracentesis (n=62) as compared to 424 days (CI 346–502) in those with undetectable bactDNA (n=100) (p=0,209). The presence of bactDNA was associated with lower platelet counts and thromboplastin time as well as lower ascites fluid protein content but higher CRP levels. Conclusion: Detection and differentiation of bacterial DNA using culture-independent PCR-methods are suitable tools to further characterize ascites samples from cirrhotic patients. The clinical impact of bactDNA detection, however, remains controversial and further prospective studies are needed for a broader evaluation of the predictive value of positive bactDNA results and to assess possible correlations to other clinical parameters and outcome.

Disclosures:

Thomas Berg - Advisory Committees or Review Panels: Gilead, BMS, Roche, Tibotec, Vertex, Jannsen, Novartis, Abbott, Merck; Consulting: Gilead, BMS, Roche, Tibotec; Vertex, Janssen; Grant/Research Support: Gilead, BMS, Roche, Tibotec; Vertex, Jannssen, Schering Plough, Boehringer Ingelheim, Novartis; Speaking and Teaching: Gilead, BMS, Roche, Tibotec; Vertex, Janssen, Schering Plough, Novartis, Merck, Bayer

The following people have nothing to disclose: Cornelius Engelmann, Delia Prywerek, Sandra Krohn, Albrecht Boehlig, Adam Herber, Antonis Chatzinotas, Ingo Fetzer, Stephan Boehm

1354

The Association between Baseline Quantitative Liver-spleen Scan (QLSS) tests and Time to First Clinical Event: A Secondary Analysis of the HALT-C Trial

John C. Hoefs1, Wen-Pin Chen2, Daniel Gillen3;

1Medicine, University of California Irvine, Orange, CA; 2BioStatistics, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA; 3Statistics, University of California Irvine, Irvine, CA

Data on N=223 HALT-C trial participants (Hepat;55:1019) were analyzed to assess the association between baseline QLSS tests and the time to first clinical event (CE). METHOD: CE defined as any of two consecutive CTP score 7, variceal bleeding, ascites, hepatic encephalopathy, and liver-related death. Liver transplantation (LT) (and listing), HCC, presumed HCC, and non-hepatic deaths were not CE. Patients were at risk for a CE from the time of entry to the first CE, loss-to follow-up, listing for LT, HCC, non-hepatic death, or study end. Patients were evaluated for CE every 3 months with maximal follow-up of 8 years (median follow-up time 5.5 years). 53 patients had a CE. RESULTS: In univariate analyses, baseline perfused hepatic mass (PHM), spleen volume corrected for ideal weight (SV/IBW), T50 TCR-L (ratio of liver counts in 3D ROI of surface voxels 50 % of maximal voxel count to total liver counts), the ratio of liver to liver plus spleen pixel counts ((L/L+S)p), and estimated peritonoscopy score average {EPSA=(4.342–2.008RR-.0209PHM+18.15/RL)+sqrt[313/(R+.5L) - log RR -9.6])/2:RR=pixel ratio, RL=R lobe length, L=L lobe length} (Hep22:1113) were significantly (p<.0001) associated with risk of a CE by unadjusted analysis. After adjustment for other baseline QLSS measures and potential confounding demographic factors including age, gender, BMI, cirrhosis and lifetime number of drinks, SV/IBW (hazard ratio 1.29 (95% CI 0.66, 2.46) P = .043) and EPSA (hazard ratio 4.34 (95% CI 1.01, 1.65) P = .034) remained significantly associated with the risk of a clinical outcome. While SV/IBW has previously been reported as a longterm correlate of CE in the HALT-C trial (Hepat;55:1019), EPSA has not. Figure depicts Kaplan-Meier estimates of survival curves for time to first CE stratified by tertiles of baseline EPSA. Our findings indicate that baseline QLSS measures are univariately associated with time to first CE. Further, these results suggest that in addition to SV/IBW, EPSA is an important predictor of long-term CEin this patient population.

Disclosures:

image

The following people have nothing to disclose: John C. Hoefs, Wen-Pin Chen, Daniel Gillen

1355

Restless Leg Syndrome (RLS) is associated with Hepatic Encephalopathy (HE) in decompensated cirrhosis. A clinical pilot study

Patrick Basu1,2, Niraj J. Shah3, Md A. Rahman2, Ravi Siriki2, Sak-ina Farhat1;

1Columbia University School of Physicians and Surgeons, Forest hills, NY; 2NSLIJHS/ Hofstra North Shore LIJ School of Medicine, NY, New York, NY; 3JamesJ. Peters VA Medical Center, Icahn School of Medicine at Mount Sinai, NY, New York, NY

Objective: The prevalence of RLS is close to 10% in the general population; which adversely affects the quality of life (QOL). Exact etiology of RLS is still unknown. Iron deficiency, small intestinal bacterial overgrowth (SIBO) and inflammatory bowel disease (IBD) have clear associations with RLS. Decompensated cirrhosis with portal hypertension has multi-organ involvement causing minimal and overt encephalopathy, sleep disturbances ( dysnomia, parasomnia) and stupor; all of which has a clear association with sub acute bacterial peritonitis ( SBP ) which has a precipitating clinical state along with SIBO. This clinical study evaluates the association of RLS in HE amongst decompensated cirrhotics. Methods: One hundred and eight (n=108) patients were recruited and subdivided into three sub-groups. Group A (n=36) - decompensated cirrhotic (mean MELD of 16, OHE 20/36 (55%), MHE 16/36 (44%), esophageal varices grade II 24/36 (67%). Group B (n=36) - chronic liver disease without cirrhosis with mean MELD 6: Alcohol related 9/36 (25%), NASH 12/36 (33%), HCV 12/36 (33%), HBV 1/36 (3%) and AIH 2/36 (6%). Group C (n=36) healthy controls. Initially all received Xifaxan 550mg orally twice daily for 10 days to eradicate co-existing SIBO. All underwent Methane breath test for SIBO. Baseline labs: Serum levels for renal function, ferritin, iron studies, hemoglobin and hematocrit, ammonia, Celiac and IBD serology, stool lactoferrin & calprotectin and urine for toxicology screening were collected. Groups A and B underwent neuro-psychometric and flicker testing for MHE and OHE and sleep testing for RLS (with Mayo RLS questionnaire). Exclusion: Chronic iron deficiency, Celiac disease, IBD, major depression, IBS, benzodiazepines, narcotics, alcohol, anti-psychotics and use of illicit drugs. Results: Group A 24/36 (67%) had RLS: [ OHE 16/20 (80%), MHE 8/16 (50%), esophageal varices 8/10 (80%), alcoholic cirrhotic 10/14 (71%), CHC 3/6 (50%), NASH 3/6 (50%) and SIBO 14/36 (39%) ]. Group B 1/36 (3%) RLS and SIBO 7/36 (19%). Group C : 2/36 (6%) RLS and SIBO 3/36 (8%). All individuals were confirmed by sleep study and RLS questionnaire. Serum ammonia has no impact on RLS. Conclusion: This clinical trial postulates that decompensated cirrhotics with Hepatic encephalopathy have high incidence of RLS with portal hypertension. Larger trials will validate this finding.

Disclosures:

Md A. Rahman - Employment: NSLIJ FOREST HILLS HOSPITAL

The following people have nothing to disclose: Patrick Basu, Niraj J. Shah, Ravi Siriki, Sakina Farhat

1356

Randomized clinical trial: Effects of multi-species probiotics on small intestinal bacterial overgrowth in patients with chronic liver disease- a placebo controlled study

Dae Won Jun1, Ho Hyun Nam1, Jin-Hwa Moon2, Tae Yeob Kim1, Joo Hyun Sohn1, Dong Hee Koh3;

1Internal Medicine, Hanyang University, Seoul, Republic of Korea; 2Pediatrics, Hanyang University, Seoul, Republic of Korea; 3Internal Medicine, Hallym University, Seoul, Republic of Korea

Background: This study was conducted to investigate the efficacy of probiotics administration in alleviating SIBO and intestinal permeability in chronic liver disease. Methods: Fifty three patients with chronic liver disease were randomized to receive either probiotics or placebo. After 4 weeks, the changes in SIBO, intestinal permeability and clinical symptoms were examined and compared. The lactulose-based hydrogen breath test was conducted to identify SIBO. The intestinal permeability was assessed by comparing the absorbability of lactulose and mannitol. The changes in digestive symptoms, composition of fecal bacteria, and liver function were also compared after four weeks of administration. Results: The positive rate of SIBO was 26% in chronic liver disease patients. After four weeks later, in the probiotics group, 24% of patients showed improvement of SIBO, but in placebo group, there was no patient whose SIBO was improved and 16% showed aggravation of SIBO (p<0.05). The treatment group showed significant increase in the level of fecal B. lactis, L. rhamnosus, and L. acidophilus (p<0.05). Although probiotics also contained B. bifidum, B. longum, and S. thermophiles, the changes in the levels of B. bifidum, B. longum, and S. thermophilus were not significant. By contrast, there were no significant changes in the levels of the ingested bacteria in the placebo group. About half of treatment and 31.3% of placebo group reported improvement in intestinal permeability, the difference between two groups was statistically insignificant (p=0.248). Improvement in abdominal pain of the probiotics and placebo group was 3.17±1.6 and 1.95±2.4 respectively (p=0.056) while improvement in gastrointestinal symptoms of the probiotics and placebo group was 3.35±1.7and 2.05±2.3 respectively, suggesting that digestive symptoms of the probiotics group improved compared to placebo (p=0.047). Conclusions: 4 weeks probiotics administration in chronic liver disease patients was effective in alleviating SIBO and clinical symptoms but ineffective in improving intestinal permeability and liver function.

Disclosures:

The following people have nothing to disclose: Dae Won Jun, Ho Hyun Nam, Jin-Hwa Moon, Tae Yeob Kim, Joo Hyun Sohn, Dong Hee Koh

1357

Anticoagulant therapy with sulodexidum for portal vein thrombosis in patients with liver cirrhosis

Ionel Copaci, Gener Ismail, Laurentiu Micu, Simona Ioanitescu, Grethi Chiriac; Center of Internal Medicine, Fundeni Clinical Institute, Bucharest, Romania

Background. Treatment of portal vein thrombosis (PVT) in patients with liver cirrhosis is not well established. Aim of the study. We intended to assess the safety and efficacy of sulodexidum to treat PVT in cirrhotic patients. Patients and methods. From June 2010 to March 2011, 350 patients with liver cirrhosis admitted to our clinic received Doppler ultrasound examination as a part of routine workup. In the presence of PVT, spiral CT or magnetic resonance was performed to exclude concomitant hepatocellular carcinoma and to evaluate the extension of thrombosis in the portal-splenic-mesenteric axis. 36 pts diagnosed with non-neoplastic PVT and cirrhosis were prospectively enrolled (21 in the treatment group with sulodexidum 2 tb/day and 15 in the control group). In 58.3% of patients PVT was an occasional finding, 11.1% presented with acute abdominal pain, while in 30.6% with bleeding from gastro-esophageal varices. In this last group treatment was started after endoscopic eradication of varices by band ligation. In the treatment group 28.6% had complete PVT and 71.4% had partial PVT. The mean MELD score was 15.4. Therapy was administered for a median period of 12 months and individuals were followed for a medium time of 19 months. Results. Complete recanalization of the portal vein occurred in 23.8% of subjects, partial recanalization in 38% and no response in 38.2%. No significant side effects, particularly bleeding complications, were observed during therapy. The median value of platelets was 58,000/mm3 and 55,000/mm3 at the end of treatment. 3 of 21 pts who stopped treatment showed rethrombosis of the portal vein at 1, 4 and 6 months. In univariate analysis, previous bleeding caused by portal hypertension and time between diagnosis and initiation of treatment < 14 days were positively associated with PV recanalization. Decompensation occurred during the study period significantly more in placebo than in sulodexidum treated patients [placebo 7/15 (46.6%) vs 6/21 (28.5%); p=0.01]. Conclusions. Sulodexidum demonstrated to be safe and effective in the treatment of PVT in patients with liver cirrhosis.

Disclosures:

The following people have nothing to disclose: Ionel Copaci, Gener Ismail, Lau-rentiu Micu, Simona Ioanitescu, Grethi Chiriac

1358

Metformin reduces plasmatic ammonia in portacaval shunted rats

Ana Isabel Gomez-Sotelo1, Isidora Ranchal1, Javier Ampuero1, Jose Antonio Del Campo1, Jose Manuel Lázaro de la Osa3, Antonio Galindo Galindo1, Juan Bautista2, Manuel Romero-Gomez1;

1UCM Digestive Diseases and ciberehd, Valme University Hospital, Sevilla, Spain; 2Molecular Biology Department, Seville University, Seville, Spain; 3Department of Biochemistry, Valme University Hospital, Sevilla, Spain

Background&Aims: Metformin has been found associated with reduced risk of overt hepatic encephalopathy and it showed a partial inhibitory effect on glutaminase type K in cultured Caco2 cells (Ampuero et al. PLoS 2012). The aim of this study was to assess the effect of metformin on levels of plasma ammonia in rats with portacaval shunts. Material and Methods: Twenty four adult male Wistar rats were included. Portacaval shunt was constructed according to modified Numata technique (Numata. Microsurgery 1983). Rats were randomized in two groups: Group 0 (n=12) did not receive any medication; Group 1 received metformin at 30mg/kg orally q.d. for two weeks (n=12). Three groups of 4 rats were included in each group: Portacaval shunted rats (PC), sham-operated(S) rats and control rats(C). Rats were sacrificed 4 weeks after surgery and blood ammonia levels were quickly measured (Roche Diagnostic, Mannheim, Germany). Enzymatic activity and gene expression will be measured. Statistical analysis was carried out using U-Mann Whitney test, ANOVA and Spearman's coefficient. Results: Ammonia levels at week four were lower in the group treated with metformin in comparison with non-treated rats (73+41 μg/dl vs. 142+115 μg/dl;p<0.05). In PC rats ammonia level at week 4 was 238±166 μg/dL in non-treated PC rats and 110±49 μg/dL in PC rats treated with metformin. Indeed, PC rats treated with metformin showed similar ammonia levels than sham-operated rats (110+49 μg/dL vs. 110+32 μg/dL;p=1). Conclusions: Metformin therapy reduced plasma ammonia levels at week four and avoided hiperammoniemia in portocaval shunted rats. Metformin could reduce inflammatory response associated with hyperinsulinaemia but also could modulate glutaminase activity. Metformin could be a promising therapeutic approach on hepatic encephalopathy in cirrhotic patients.

Plasma ammonia levels in portacaval shunt (PC), sham-operated and control rats with (red) and without (blue) metfomin treatment.

image

Disclosures:

Manuel Romero-Gomez - Advisory Committees or Review Panels: Roche Farma,SA., MSD, S.A., Janssen, S.A., Abbott, S.A.; Grant/Research Support: Ferrer, S.A.

The following people have nothing to disclose: Ana Isabel Gomez-Sotelo, Isidora Ranchal, Javier Ampuero, Jose Antonio Del Campo, Jose Manuel Lάzaro de la Osa, Antonio Galindo Galindo, Juan Bautista

1359

Validation of the CLIF- SOFA and other prognostic scores for patients with cirrhosis admitted to intensive care unit (ICU)

Eleni Theocharidou1, Giulia Pieri1, Evangelos Cholongitas1, Ban-wari Agarwal2, Andrew K. Burroughs1;

1The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital, Royal Free Hampstead NHS Trust and Institute of Liver and Digestive Health, University College London, London, United Kingdom; 2Intensive Care Unit, Royal Free Hospital, Royal Free Hampstead NHS Trust, University College London, London, United Kingdom

Aims: There are no validated prognostic models derived from patients with cirrhosis admitted to ICU, a population with high mortality. General prognostic models -Acute Physiology and Chronic Health Evaluation (APACHE), Sequential Organ Failure Assessment (SOFA)- have proven more accurate at predicting mortality than current liver-specific models -Child-Pugh, Model for End-stage Liver Disease (MELD). A modification of SOFA, the Chronic Liver Failure (CLIF)-SOFA, has been proposed for patients with acute decompensation, based on which patients can be classified in 4 groups (acute on chronic liver failure (ACLF) 0–3). The aim of this study was to validate all current prognostic scores, as well as the Royal Free Hospital (RFH) score, which was developed from a large cohort of patients admitted to RFH ICU and incorporates bilirubin, INR, lactate, A-a gradient, urea and indication of admission to ICU. Methods: Between 2005–2012306 consecutive patients with cirrhosis were admitted to our ICU. The following scores were assessed using parameters at admission: Child-Pugh, MELD, MELD-sodium, APACHE II, SOFA, CLIF-SOFA and RFH score. The number of failing organ systems (FOS) was assessed using both the SOFA criteria (SOFA≥3 for each organ system) (FOS-SOFA) and the CLIF-SOFA criteria (FOS-CLIF). Patients were classified in ACLF 0–3 groups. Predictive accuracy and calibration were evaluated using AUROC and the goodness-of-fit χ2, respectively. Results: The mean age was 51.6±11.9 years; there were 67% men; main aetiology of liver disease was alcohol in 55%, and main indication for admission to ICU was variceal bleeding in 55.4%. In-hospital mortality was 39.2%. The AUROC for the different scores was: Child-Pugh 0.68, MELD 0.73, MELD-sodium 0.71, APACHE II 0.73, SOFA 0.74, FOS-SOFA 0.66, CLIF-SOFA 0.75, FOS-CLIF 0.73, ACLF 0.72, RFH 0.78. The goodness-of-fit χ2 was: Child-Pugh 4.89 (p=0.43), MELD 2.81 (p=0.95), MELD-sodium 6.91 (p=0.55), APACHE II 11.26 (p=0.13), SOFA 6.21 (p=0.63), FOS-SOFA 3.33 (p=0.19), CLIF-SOFA 9.18 (p=0.33), FOS-CLIF 3.72 (p=0.29), ACLF 2.99 (p=0.22), RFH 2.91 (p=0.94). Parameters associated with mortality in multivariate logistic regression were age (OR 1.04, p=0.005), admission for non-variceal bleeding (OR 2.17, p=0.014), bilirubin (OR 1.004, p=0.001), INR (OR 1.46, p=0.011), and lactate (OR 1.12, p=0.024). Conclusions: Although the CLIF-SOFA and the ACLF classification were developed from a large cohort of patients with acute deterioration, they do not seem to perform better than the original SOFA and the commonly used MELD score. The simpler RFH score showed the best predictive accuracy and excellent calibration.

Disclosures:

The following people have nothing to disclose: Eleni Theocharidou, Giulia Pieri, Evangelos Cholongitas, Banwari Agarwal, Andrew K. Burroughs

1360

Cost Effectiveness of Rifaximin in the Treatment of Hepatic Encephalopathy

Stephen E. Congly, Michael D. Leise, W. Ray Kim; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN

BACKGROUND: Hepatic encephalopathy (HE) in patients with cirrhosis has a broad impact both on patients and on their families as a result of impaired quality of life and loss of economic productivity as well as increased risk of death. Although contemporary treatment for hepatic encephalopathy consisting predominantly of lactulose and rifaximin is helpful in most patients, their cost-effectiveness remains uncertain. AIM: We conduct a cost utility analysis of three strategies: (1) lactulose alone, (2) lactulose followed by rifaximin salvage in patients in whom lactulose is ineffective, and (3) rifaximin therapy in combination with lactulose upfront. METHODS: The base case scenario of our model mirrors the phase three registration trial data (RFHE-3001) in which rifaximin was compared to placebo in conjunction with lactulose in maintaining remission in patients with a prior history of HE. Thus, a Markov model was constructed to compare the three prophylaxis strategies. A five year time horizon was used with three month cycles. Model estimates were derived from the RFHE-3001 data as well as other published literature, with costs being based on a third party payer's perspective. RESULTS: The model predicted that 24.5% of patients on lactulose alone would be alive at the end of the five year study period, compared to 30% for rifaximin salvage and 31.8% for rifaximin upfront. The mean total healthcare cost would be $67009 for lactulose, $73551 for rifaximin salvage and $91647 for rifaximin upfront, with 6.1%, 30.4% and 49.6% of the total cost being attributable to the medication (lactulose and/or rifaximin) respectively. Overall, lactulose alone was the least effective and least costly strategy, whereas the addition of rifaximin either initially or after a second recurrence both led to improved outcomes and increased costs. In the calculation presented in the table, the incremental cost effectiveness ratio (ICER), as compared to lactulose alone, was $38833 per QALY for rifaximin salvage and $94680 per QALY for rifaximin upfront. One-way sensitivity analysis showed that costs of hospitalization and costs of rifaximin were the biggest drivers of the model. CONCLUSIONS: Based on this model, the addition of rifaximin as part of the management strategy for hepatic encephalopathy may be cost effective depending on the payer's willingness to pay.

Results of Base-Case Model

StrategyCost [$]Incremental Cost [$]Effectiveness [QALY]Incremental Effectiveness [QALY]ICER [$/QALY]
Lactulose67009-1.99--
Salvage7355165422.160.1738833
Rifaximin91647246382.250.2694680

Disclosures:

W. Ray Kim - Advisory Committees or Review Panels: Salix; Consulting: Bristol Myers Squibb, Gilead

The following people have nothing to disclose: Stephen E. Congly, Michael D. Leise

1361

A Randomized Control Trial Demonstrates that Cirrhosis Causes Selenium Deficiency

Raymond F. Burk1, Kristina E. Hill1, Amy K. Motley1, Daniel W. Byrne2, Brooke K. Norsworthy1;

1Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; 2Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN

Selenium is an essential micronutrient that expresses its biological functions through selenoproteins. The liver metabolizes selenomethionine, the principal dietary form of selenium, to selenide, which is used for synthesis of selenoproteins. It then synthesizes selenium-rich selenoprotein P (SEPP1) and secretes it into the plasma to supply extra-hepatic tissues with selenium via receptor-mediated endocytosis. Plasma SEPP1 is depressed in patients with cirrhosis. We carried out a placebo-controlled double-blind study to determine whether selenate, which does not require hepatic processing, would raise selenoprotein levels in the plasma of patients with cirrhosis. Patients in Childs-Pugh (C-P) classes A, B, and C were supplemented with placebo or supra-nutritional amounts of selenium as selenate (200 μg/d, 400 μg/d) or selenomethionine (200 μg/d) for 4 weeks. Plasma SEPP1 concentration and glutathione peroxidase activity (GPX), the latter due to GPX3 secreted by the kidneys, were measured before and after supplementation. SEPP1 and GPX were significantly increased (19–24%) in C-P class C patients by both doses of selenate but not by selenomethionine or placebo. In addition, GPX was significantly increased 16–21% by both doses of selenate but not by selenomethionine or placebo in C-P class B patients. Within the groups that responded to selenate there was considerable variation in response, suggesting that selenium deficiency varied in severity among the patients. These results indicate that severe cirrhosis causes mild to moderate selenium deficiency by impairing metabolism of selenomethionine to selenide and that supplementation with inorganic selenium, but not with selenomethionine, is effective in treating the deficiency. Additional clinical trials are needed to determine the dose of inorganic selenium needed to correct the selenium deficiency and to determine whether correcting the deficiency will improve patient health. This trial was registered at clinicaltrials.gov as NCT00271245. Supported by NIH DK58763 and ULI RR024975.

Disclosures:

The following people have nothing to disclose: Raymond F. Burk, Kristina E. Hill, Amy K. Motley, Daniel W. Byrne, Brooke K. Norsworthy

1362

Single-center validation of the EASL-CLIF Consortium definition of acute-on-chronic liver failure (ACLF) and CLIF-SOFA for the prediction of mortality in cirrhosis

Pedro E. Soares e Silva1, Leonardo Fayad1, César Lazzarotto1, Marcelo F. Ronsoni1, Maria Luiza Bazzo2, Esther B. Dantas-Cor-rea1, Janaína L. Narciso-Schiavon1, Leonardo L. Schiavon1;

1Internal Medicine, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Brazil; 2Department of Clinical Analysis, Federal University of Santa Catarina, Florianópolis, Brazil

Introduction: Over the last few years, the idea of ACLF has emerged to identify those subjects with organ failure and high mortality rates. However, the absence of a precise definition has limited the clinical application and research related to the ACLF concept. We sought to validate the ACLF definition and the Chronic Liver Failure (CLIF)-Sequential Organ Failure Assessment (SOFA) Score recently proposed by the EASL-CLIF Consortium in a cohort of patients admitted for acute decompensation (AD) of cirrhosis. Methods: The diagnosis of cirrhosis was established either histologically (when available) or by the combination of clinical, imaging, and laboratory findings in patients with evidence of portal hypertension. Patients were clinically assessed within 24 hours of admission and at days 3, 7, 30 and 90 post enrollment. All subjects underwent laboratory evaluation at admission. The CLIF-SOFA score and the ACLF criteria were applied according to the EASL-CLIF Consortium definition. Results: Between December 2010 and November 2012, 144 cirrhotic patients were included, with a mean age of 52.8 ± 10.9 years, and a male predominance (75.7%). Hepatitis C was the cause of cirrhosis in 41.0% of the patients, alcohol abuse in 39.6% and hepatitis B in 3.5%. Previous history of cirrhosis decompensation was observed in 63.2% of the sample. The mean MELD score was 16.4 ± 7.0 and 51.4% of the individuals were Child-Pugh C. At enrollment, 40 patients (27.8%) met the new criteria for ACLF (Grades 1, 2 and 3 in 19.4%, 5.6% and 2.8%, respectively). The mean CLIF-SOFA was higher in those with ACLF (9.8 ±3.3 vs. 5.4 ±2.1, P< 0.001). ACLF patients also showed a higher prevalence of ascites, alcoholic etiology of cirrhosis, infection at admission, Child-Pugh Class C and a lower proportion of patients admitted for gastrointestinal bleeding. Concerning laboratory data, ACLF was related to higher white-cell count, Creactive protein, bilirubin, INR, AST, creatinine and lower sodium levels. The 30-day mortality was 57.5% in ACLF group and 12.5% in the remaining subjects (P < 0.001). When evaluated according to ACLF severity, the 30-day mortality was 42.9%, 87.5% and 100% in grades 1, 2 and 3, respectively. CLIF-SOFA was significantly higher among non-survivors (9.7 ± 3.5 vs. 5.7 ± 2.3, P < 0.001). The AUROC of CLIF-SOFA in predicting 30-day mortality was 0.838 ± 0.038, with sensitivity of 94% and specificity of 54% for values > of 5. Conclusion: In our single-center experience the CLIF-SOFA and the EASL-CLIF Consortium definition of ACLF proved to be strong predictors of short-term mortality in cirrhotic patients admitted for AD.

Disclosures:

The following people have nothing to disclose: Pedro E. Soares e Silva, Leonardo Fayad, César Lazzarotto, Marcelo F. Ronsoni, Maria Luiza Bazzo, Esther B. Dan-tas-Correa, Janaína L. Narciso-Schiavon, Leonardo L. Schiavon

1363

The therapeutic efficacy of splenectomy was attenuated by necroinflammation of the liver in patients with liver cirrhosis

Reiichiro Kondo1,2, Toshiro Ogata4, Hirohisa Yano1, Osamu Nakashima5, Jun Akiba1, Yoriko Nomura1,3, Masamichi Nakayama1, Masayoshi Kage2,3;

1Department of Pathology, Kurume University School of Medicine, Kurume-shi, Fukuoka-ken, Japan; 2Cancer Center, Kurume University Hospital, Kurume, Japan; 3Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan; 4Department of Surgery, Kurume University School of Medicine, Kurume, Japan; 5Department of Clinical Laboratory Medicine, Kurume University Hospital, Kurume, Japan

Aim: Splenectomy is a therapy for thrombocytopenia caused by hypersplenism with liver cirrhosis. Hypersplenism is of great relevance in the management of liver cirrhosis because of the widespread use of myelodepressant drugs such as interferon. As no standard therapy exists for this complication, we evaluated the efficacy and determinant of therapeutic outcomes of splenectomy in the treatment of hypersplenism in patients with liver cirrhosis. Methods: We studied the laboratory findings of 56 patients who underwent splenectomy for hypersplenism with liver cirrhosis. The mean age was 60 ± 8 years. Serum of 51 and 5 patients were positive for hepatitis C and B virus, respectively. In addition, we examined the histopathological findings of hepatosplenic tissues of 12 patients who underwent hepate-ctomy for hepatocellular carcinoma and splenectomy for hypersplenism with liver cirrhosis on one stage surgery. The histologic liver damage of these specimens was evaluated for fibrosis (stage 0 to 4) and inflammation (grade 0 to 4). The locations of platelets in hepatosplenic tissues were identified by immuno-histochemistry. We used monoclonal antibodies against CD41. The platelet areas in hepatosplenic tissues were measured using WinROOF software. Results: Among 56 patients, 38 patients had high serum alanine aminotransferase (ALT) levels (≦38 IU/l). Blood platelet counts 3 months after splenectomy in patients with high serum ALT levels were significantly lower than those with normal serum ALT levels (P < 0.01, high ALT patients 4 ± 2 × 104 /mm3 to 16 ± 6 × 104 /mm3; normal ALT patients 4 ± 1 × 104 /mm3 to 21 ± 8 × 104 /mm3). Histologically, liver tissues of high ALT patients showed a significantly higher degree of inflammation than those of normal ALT patients (P = 0.01, grade; 2 ± 1 vs. 1 ± 1). Immunohistochemically, in liver tissues, platelets were observed along the destructed limiting plate of the expanded fibrous portal area with inflammation and in the sinusoidal space of the periportal area. Morphome-try revealed that platelet areas in liver tissues of high ALT patients were larger than those of normal ALT patients (15217 ± 8058 μm2 vs. 8745 ± 5970 μm2). In splenic tissues, the platelet areas of high ALT patients were about as large as those of normal ALT patients (50652 ± 22250 μm2 vs. 69203 ± 16033 μm2). Conclusions: In liver cirrhosis, hepatic necroinflammation contribute to the accumulation of platelets in liver; therefore, the elimination of hypersplenism by splenectomy does not efficiently improve thrombocytopenia. Serum ALT level in cirrhotic patients may be a useful surrogate marker to predict the outcome of splenectomy.

Disclosures:

The following people have nothing to disclose: Reiichiro Kondo, Toshiro Ogata, Hirohisa Yano, Osamu Nakashima, Jun Akiba, Yoriko Nomura, Masamichi Nakayama, Masayoshi Kage

1364

Diabetes mellitus is an independent risk factor for decompensation, death or liver transplantation in patients with HCV related cirrhosis

Laure Elkrief1, Pascale Chouinard1, Noelle Bendersky2, Beatrice Larroque3, Gérard Babany1, Francois Durand1, Pierre-Emmanuel Rautou1, Dominique Valla1;

1Service d'Hépatologie, Hôpital Beaujon, Clichy, France; 2Département d'information médicale, Hôpital Beaujon, Clichy, France; 3Unité d'épidémiologie et de recherche clinique, Hôpital Beaujon, Clichy, France

Introduction: In patients with chronic hepatitis C virus (HCV) infection, progression to cirrhosis is related to age, co-infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV), associated diabetes, and alcohol intake. In patients with HCV-related cirrhosis, the impact of these factors on the development of complications and on the outcome is unclear. Patients and methods: All consecutive patients hospitalized in the liver unit between January 1st 2006 and December 31st 2008 were included. The identification of patients was based on ICD 10th edition codes for chronic HCV infection and cirrhosis. Medical records and hospital discharge diagnostic codes (obtained from the French medical program PMSI) of all hospital stays from inclusion (date of the first hospitalization) to March 2013 were retrospectively analyzed. Variables collected at inclusion were age, sex, MELD score, diabetes, alcohol intake, HIV and HBV co-infection. Events collected during follow-up were ascites, encephalopathy, bacterial infections, renal dysfunction, gastrointestinal bleeding, hepatocellular carcinoma (HCC), and death or liver transplantation (LT). Cox uni-variate and multivariate analysis were performed. Results: 348 patients (68 % men, median age 59 years) were included. Median MELD score at inclusion was 10. Forty, 29, and 6% and 6% of patients had diabetes, alcohol intake, and HIV or HBV infection, respectively. Median follow-up was 40 months. HCC, ascites, renal dysfunction, encephalopathy, bacterial infections, and gastrointestinal bleeding occurred in 58%, 48%, 21%, 19%, 19%, and 14% of the patients, respectively. Death or LT occurred in 70% of the patients. Multivariate analyses showed that diabetes at inclusion was an independent predictor of the development of ascites [odds ratio (OR) (95% confidence interval) 1.4 (1.1–1.9), p=0.03], encephalopathy [2.4 (1.5–4), p<0.0001], infection [2.2 (1.5–3.4), p<0.0001], renal dysfunction [1.8 (1.1–2.8), p=0.02], but not of gastrointestinal bleeding. Diabetes also independently predicted HCC development in patients with MELD <10 at inclusion [1.5 (1–2.1), p=0.04]. Alcohol intake was an independent predictor of infections [1.6 (1–2.4), p=0.04]. Inclusion MELD score ≥10 [1.9 (1.5–2.6, p<0.0001], diabetes [1.3 (1–1.7), p=0.03] and HBV infection [2.2 (1.4–3.6), p=0.001] were the only factors independently predicting death or LT. Conclusion: In hospitalized patients with HCV related cirrhosis, diabetes is an independent risk factor for the major complications of cirrhosis and for death or LT. Thus, diabetes should be taken into account in the pathophysiology of complications of HCV related cirrhosis.

Disclosures:

Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis; Speaking and Teaching: Gilead

Dominique Valla - Board Membership: Sequana Medical; Independent Contractor: IRIS; Speaking and Teaching: Mayoly Spindler, MSD, Janssen Pharmaceuticals

The following people have nothing to disclose: Laure Elkrief, Pascale Chouinard, Noelle Bendersky, Beatrice Larroque, Gérard Babany, Pierre-Emmanuel Rautou

1365

Child Pugh scoring is as good as MELD and MELD-Na for short and long-term prognosis in cirrhosis: Results from a multicentre study

Christos K. Triantos1, Konstantinos Zisimopoulos1, Cristina Riga-monti2, Ioannis Goulis3, Spilios Manolakopoulos4,6, Emanuel K. Manesis5, Maria Kalafateli1, Emmanuel Tsochatzis2, Fenia Papalexi3, Katerina Georgiou6, Konstatinos Thomopoulos1, Vasiliki Nikolopoulou1, Evangelos Akriviadis3, Chrisoula Labropoulou-Karatza C7, Andrew K. Burroughs2;

1 Department of Gastroenterol-ogy, University Hospital of Patras, Patra, Greece; 2The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital, London, United Kingdom; 3Fourth Department of Internal Medicine, Aristotle University Medical School, Hippokration General Hospital of Thessa-loniki, Thessaloníki, Greece; 42nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, Athens, Greece;5Academic Department of Medicine, Hippokration General Hospital, Athens, Greece; 6Department of Gastroenterology, Polyclinic General Hospital, Athens, Greece; 7Department of Internal Medicine, University Hospital of Patras, Patras, Greece

Background: The Model for end-stage liver disease (MELD) is used for prioritisation of patients waiting for liver transplantation and models 3-month mortality. However, the prognostic accuracy in other settings of cirrhosis is not clear (Aliment Pharmacol Ther 2005;22:1079–89). We evaluated MELD, Child-Pugh score (CPS), CPS-creatinine and MELD-Na for prognosis in cirrhosis. Patients/Methods: Five liver centres: 1135 consecutive outpatient cirrhotics: 65 lost to follow-up and 69 with baseline hepatocellular carcinoma excluded-1001 analysed. Men: 580 (57.9%), age: 58 (18–92) years, follow-up: 35 (1–256) months, CP(A/B/C): 48/37/15%, CPS:7 (5–14), MELD: 12 (6–39), CPS-creatinine:8 (6–16), MELD-Na: 13 (7–41), HBV 18%, HCV 17%, alcohol 32%, PBC 15%, autoimmune 6%, other 12%. CPS/MELD components, CP-creatinine (CP score+1,2,3 (if creatinine<1.3, 1.3–1.5 (4.2%) and >1.5 (5.4%) mg/dl, respectively), MELD/CPS scores and MELD-Na were evaluated in different models for prognosis, using logistic regression analysis. Results: 354 (35.4%) patients died (120<1 year, 58<3 months). MELD and CPS were independently associated with 3-month, 1-year and overall survival when separately evaluated multivariately. However, when MELD (or MELD-Na) and CPS (or CPS-creatinine) were entered in the model, then only CPS (or CPS-creatinine) was independently associated with survival (Table). Using ROC curves the survival predictive value of each score was: 3-month AUC: CPS 0.7, CPS-creatinine 0.7, MELD 0.68, MELD-Na 0.68 (p=0.421); 1-year AUC: CPS 0.68, CPS-creatinine 0.7, MELD 0.67, MELD-Na 0.66 (p=0.504); overall AUC: CPS 0.61, CPS-creatinine 0.62, MELD 0.59, MELD-Na 0.59 (p=0.655). Conclusions: CPS has better prognostic significance compared to MELD in outpatients with cirrhosis, for both short and long-term survival and thus should not, and need not, be abandoned in clinical practice.

Multivariate analysis of factors predictive of short- and long-term survival in patients with cirrhosis.

3-month survival
 HR95% CIP value
Age1.0651.031–1.1<0.001
Sex2.4191.135–5.1580.022
CPS1.3531.146–1.597<0.001
Diabetes mellitus2.971.415–6.2360.004
1-year survval
Age1.0431.019–1.067<0.001
CPS1.1991.01–1.4360.046
Sex1.9491.168–3.250.011
Overall sunival
Age1.0461.034–1.059<0.001
Sex1.4191.086–1.8550.01
CPS1.1761.07–1.2940.001

Disclosures:

Spilios Manolakopoulos - Advisory Committees or Review Panels: NOVARTIS, ROCHE, MSD, BMS, GILEAD; Consulting: ROCHE, GILEAD, BMS; Speaking and Teaching: MSD, GILEAD, BMS

The following people have nothing to disclose: Christos K. Triantos, Konstantinos Zisimopoulos, Cristina Rigamonti, Ioannis Goulis, Emanuel K. Manesis, Maria Kalafateli, Emmanuel Tsochatzis, Fenia Papalexi, Katerina Georgiou, Konstatinos Thomopoulos, Vasiliki Nikolopoulou, Evangelos Akriviadis, Chrisoula Labropoulou-Karatza C, Andrew K. Burroughs

1366

Standardized Neurological Assessment In Cirrhotic Patients : Even Patients without Overt HE No Longer Have a Normal Examination

Sarah Mouri1, Marika Rudler1, Géraldine Rousseau1, Hedi Benos-man1, Nicolas Weiss2,3, Dominique Thabut1;

1Hepatology ICU, AP-HP, hôpital Pitié-Salpêtrière, Paris, France; 2Unité de réanima-tion neurologique, pôle des maladies du système nerveux, AP-HP, hôpital Pitié-Salpêtrière, Paris, France; 3Institut Hospitalo-Universitaire de Neurosciences, IHU-A, AP-HP, hôpital Pitié-Salpêtrière, Paris, France

Background and aims : Overt Hepatic Encephalopathy (HE) is a severe complication of cirrhosis. Its definition is unclear, but includes several neurological manifestations ranging from asterixis and/or shortened attention span to coma. There is no gold standard for the diagnosis of overt HE. Clinical diagnosis of HE is crucial, as its presence influences prognosis, and clinical management of cirrhotic patients. However, there is an important interobserver variability in neurological examination. The aim of this study was, to assess the prevalence of neurological abnormalities assessed by a senior neurologist expert in the setting of metabolic encephalopathy in patients with and without overt HE. Methods : All consecutive patients admitted for a complication of cirrhosis between June 2012 and April 2013 in our Hepatology ICU were examined by a senior neurologist, using a standardized neurological examination. Patients with medical history of neurological disease were excluded. Presence of overt HE was assessed by a senior hepatologist unaware of neurologist's findings. If unusual clinical findings, EEG, CT scan and/or MRI were performed in order to rule out any other neurological disorders. HESA and CHESS score were assessed the day of clinical examination. Results : 68 patients were included (Male gender=75% ; age=58 ±11; aetiology of cirrhosis : alcohol=68%, viral=26%, other=6% ; Child-Pugh score : A=13%/B=15%/C=72% ; MELD score=18 ± 7 ; presence of HCC=16%). Thirty-six patients (53%) had overt EH (CHESS : 3.13 ± 3.10 and HESA : 1.94 ± 1.24) and 32 (47%) no overt HE (CHESS : 1.00 ± 2.13 and HESA : 0.32 ± 0.48). Overt HE patients presented with motor deficit in 7 patients (20%), Babinski's sign in 8 patients (22%), pyramidal syndrome in 9 patients (25%), abolished tendon reflexes in 5 patients (14%), sensitive deficit in 1 patients (3%), frontal syndrome in 14 patients (39%), apraxia in 18 patients (50%) and psycho-motor slowering in 26 patients (72%). Surprisingly, patients without overt HE presented with motor deficit in 1 patients (3%), Babinski's sign in 1 patients (3%), pyramidal syndrome in 2 patients (6%), abolished tendon reflexes in 4 patients (13%), absent corneal reflexe in 1 patient (3%), frontal syndrome in 14 patients (44%) and apraxia in 10 patients (32%). No other cause than HE was retrieved to explain clinical abormalities in those patients. Conclusion : Standardized neurological examination is able to improve the detection of neurological abnormalities even in patients without overt HE. Overt HE is probably underdiagnosed. Standardized neurological examination should be directly performed by hepatologists after minimal training.

Disclosures:

Marika Rudler - Speaking and Teaching: Gilead Sciences, BMS, Gore, Eumedica

The following people have nothing to disclose: Sarah Mouri, Géraldine Rousseau, Hedi Benosman, Nicolas Weiss, Dominique Thabut

1367

Renal effects of different doses of α-2 adrenergic agonists alone or in combination with traditional diuretics in rats with experimental cirrhosis and ascites

Giovanni Sansoe1, Manuela Aragno2, Raffaella Mastrocola2, Giulio Mengozzi3, Rhys Whomsley4, Maurizio Parola2;

1Gastroenterology Unit, Gradenigo Hospital, Torino, Italy; 2Department of Clinical and Biological Sciences, University of Torino, Torino, Italy; 3Clinical Biochemistry Laboratory, San Giovanni Battista Hospital, Torino, Italy; 4Division of Exploratory Projects, Shire Pharmaceutical Development Ltd., Basingstoke, United Kingdom

Background. In refractory ascites, sympathetic nervous system activation leads to reduced sodium delivery to the Henle's loop and to negligible responses to traditional diuretics. α2-adrenergic receptor agonists are sympatholytic drugs and, when associated with diuretics, may improve natriuresis in advanced cirrhosis. Aims & Methods. Mechanism of action and efficacy of different doses of two α2 agonists (clonidine and SSP-002021R, an oral guanfacine prodrug), alone or associated with diuretics, were assessed in eight groups of 10 rats with ascitic cirrhosis due to 13-week CCl4 administration (groups G1-G8, see later) and compared, through complete evaluation of renal function and hormonal status, to ten rats with ascitic cirrhosis (G9) and ten ascitic cirrhotic rats receiving daily traditional diuretics (i.e. 0.5 mg/kg furosemide plus 2 mg/kg K+-canrenoate during the 11 th-13th weeks of CCl4) (G10).The groups of cirrhotic rats treated with α2-agonists received daily, during the 11 th-13th weeks of CCl4: clonidine 0.3 mcg (G1), SSP-002021R 5 mg/kg (G2), traditional diuretics + clonidine 0.2 (G3), 0.5 (G4), or 1 mcg (G5), traditional diuretics + SSP-002021R 2 (G6), 7 (G7), or 10 mg/kg (G8). Results. The best performances, in terms of drug-induced increase in urinary sodium excretion rate, were found in group G1 (clonidine alone), G3 (diuretics + clonidine 0.2 mcg) and G7 (diuretics + guanfacine prodrug 7 mg/kg). Sodium excretions in these three groups were significantly better than in the cirrhotic group treated with diuretics alone (G10) (all P<0.03). Glomerular filtration rate and renal plasma flow were significantly higher in cirrhotic rats treated with clonidine alone (G1) or guanfacine prodrug alone (G2) than in cirrhotic rats undergoing traditional diuretic treatment (G10) (all P<0.03). The addition of guanfacine prodrug (2 mg/kg) in G6 to diuretics (G10) reduced tubular free-water reabsorption from 45 ± 12 to 20 ± 8 microL/min (aquaretic effect of α2-agonists) (P<0.01) and reduced serum norepinephrine levels from 423 ± 122 to 211 ± 111 ng/L (P<0.01) and plasma renin activity from 25 ± 12 to 9 ± 7 ng/mL/h (P<0.03). Conclusions. α2 agonists reduce adrenergic function and secondary aldosteronism and improve natriuresis in cirrhotic ascites, even when associated with loop diuretics and anti-adosterone drugs. The aquaretic effects of α2 agonists underline beneficial effects exerted on hemody-namics, glomerular filtration rate and renal perfusion pressure.

Disclosures:

Giovanni Sansoe - Consulting: Shire Pharmaceuticals Ltd., Basingstoke, Hampshire, UK.

Rhys Whomsley - Employment: Shire Pharmaceutical Development; Patent Held/Filed: Shire Pharmaceutical Development; Stock Shareholder: Shire Pharmaceutical Development

Maurizio Parola - Independent Contractor: Shire Pharmaceutical Ltd, Basingstoke, UK

The following people have nothing to disclose: Manuela Aragno, Raffaella Mas-trocola, Giulio Mengozzi

1368

Child-Na score: a new predictive model for 1-year survival in 555 cirrhotic patients with symptomatic portal hypertension treated by transjugular intrahepatic portosystemic shunt

Hui Chen1, Ming Bai1, Xingshun Qi1, Lei Liu1, Chuangye He1, Zhanxin Yin1, Kaichun Wu2, Daiming Fan2, Guohong Han1;

1Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China; 2State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China

Background/aims: A number of models and factors have been developed to predict survival following transjugular intrahepatic portosystemic shunt (TIPS) in patients with cirrhosis but rare have gained wide acceptance, especially in the era of covered stents. The aim of the present study was to establish an evidence-based and validated model for 1-year survival after TIPS. Patients and methods: A total of 555 consecutive patients with cirrhosis and symptomatic portal hypertension treated with TIPS from March 2001 to June 2012 were included. We comprehensively investigated the prognostic factors for 1-year survival and developed a new model in the covered stent training cohort (July 2010-December 2011) by using the Cox proportional regression hazards model. Then, this new model was validated in the bare stent validation cohort (March 2001-July 2010) and covered stent validation cohort (January 2012-June 2012). Results:The independent predictors of 1-year survival included Child-Pugh score and serum sodium in the multivariate analysis and a new score to incorporate serum sodium into Child-Pugh score was developed: “Child-Na score”. This new score differentiated two groups (6–8 points; ≥9 points) with distinct prognosis (1-year cumulative survival rate: 96.7% versus 64.1%; P < 0.001). These results were confirmed in the two validation cohorts and remained significant in the subgroup analysis according to different indications. Conclusion: A Child-Na score ≤8 identifies patients with a good 1-year cumulative survival following TIPS, especially for those with variceal bleeding. Refractory ascitic patients with 9 or more points in the Child-Na score have a high mortality rate and should rather receive other evidence-based treatments to avoid useless expensive procedures.

Cumulative survival rate of the two Child-Na score groups (6–8 points; ≥9 points) in the training and the two validation cohorts

image

Disclosures:

The following people have nothing to disclose: Hui Chen, Ming Bai, Xingshun Qi, Lei Liu, Chuangye He, Zhanxin Yin, Kaichun Wu, Daiming Fan, Guohong Han

1369

Slower cortical auditory processing in patients with liver cirrhosis without clinical symptoms of hepatic encephalopathy

Jin-Hwa Moon2, Dae Won Jun1, Tae Yeob Kim1, Joo Hyun Sohn1, Jung Don Chae3;

1Internal Medicine, Hanyang University, Seoul, Republic of Korea; 2Pediatrics, Hanyang University, Seoul, Republic of Korea; 3Clinical pathology, Eulji University, Seoul, Republic of Korea

Background: Cerebral function in patients with liver cirrhosis (LC) ranges from normal to severe encephalopathy, and an arbitrary classification of hepatic encephalopathy (HE) does not aid in evaluating the mechanism of patients' neurocognitive impairment. The aim of this study was to detect early changes of cognitive processing in cirrhotic patients without clinical symptoms of encephalopathy by studying event related potentials (ERPs). Methods: The subjects were 21 adult LC patients without clinical encephalopathy and 29 normal controls. For neuropsychological testing, NCT-A, NCT-B, the line tracing test (LTT), serial dotting test (SDT) and digit symbolic test (DST) were performed. For ERP testing, auditory oddball paradigms were used. The N100, P200, N200 and P300 parameters measured from the Cz electrode were analyzed. Results: LC patients had longer performance times on NCT-A (P=0.002), SDT (P=0.005), DST (P=0.000) than the control group. LC patients showed longer latencies for N100 (113.9±11.6 ms vs 111.67±10.2 ms, P=0.038), P200 (194.2±28.9 ms vs 185.9±18.8 ms, P=0.034), N200 (261.2±46.1 ms vs 242.4±31.1 ms, P=0.004), and P300 (366.1±98.7 ms vs 325.4±43.8 ms, P=0.001) than control group. The amplitudes of the ERP components in the two groups were not significantly different. The N200 latency of the patients without minimal hepatic encephalopathy (MHE) was significantly longer than that of the controls (P=0.006). Conclusions: Prolonged early ERP parameter latencies in clinically normal LC patients with or without MHE suggest that slower auditory cortical processing is the first sign of cerebral deterioration. They were found even in clinically normal LC patients without MHE.

Disclosures:

The following people have nothing to disclose: Jin-Hwa Moon, Dae Won Jun, Tae Yeob Kim, Joo Hyun Sohn, Jung Don Chae

1370

Cirrhotic decompensated patients in ICU requiring mechanical ventilation: Early prognosis and long-term survival

Faouzi Saliba1,2, Eric Levesque1, Philippe Ichai1,3, Didier Samuel1,3;

1Centre Hepato-Biliaire, AP-HP Hopital Paul Brousse, Villejuif, France; 2UMR-S785, Univ Paris-Sud, Villejuif, France; 3Unit 785, Inserm, Villejuif, France

Mortality of cirrhotic patients admitted to the ICU and who required mechanical ventilation varies between 60 and 91%. The aim of our study is to assess the prognosis of these patients, their outcome at 1-year and analyze predictive factors of long-term mortality and liver transplant perspectives. Patients and methods: from May 2005 to May 2011, 583 decompensated cirrhotic patients were admitted to our 15-beds liver unit. We studied retrospectively then prospectively the 246 consecutive decompensated cirrhotic patients who required mechanical ventilation either at admission or during ICU stay. Results: Alcohol was the most common etiology (69%) and bleeding related to portal hypertension (30%) and severe sepsis (33%) were the most common reason for admission in ICU. 119 patients (48.5%) were intubated at admission and 127 other patients required mechanical ventilation during their stay with an overall mean length of mechanical ventilation of 10.9 ± 13.2 days. ICU and hospital mortality were respectively 65.8 % and 70.3%. Prognostic severity scores (SOFA, SAPS II, MELD, MELD Na and Child-Pugh), the need for other organ support therapy (Continuous Renal Replacement therapy and/or vasopressors), infection and total bilirubin value at ICU admission were significantly associated with ICU mortality. Seventy-three patients (29%) were discharged from the hospital after a mean stay of 34.5 ± 30.7 days. Among these patients alive at ICU discharge, the one year transplant free survival was only 23%. Logistic regression analysis using transplant free survival at one year as the endpoint, identified two independent risk factors: the length of ventilation during the ICU stay (odds ratio [OR] = 1.3; 95% confidence interval [CI], 1.03–1.7; p=0.02) and total bilirubin at ICU discharge (OR=1.04; 95% CI, 1.01–1.07; p=0.0013). The MELD score determined the day of the ICU discharge was significantly higher in the sub-group of patients who have died at 1-year or who have been transplanted (n=56) than those who have survived without liver transplantation (n=17) (24.4 ± 6.7 vs. 17.2 ± 3.1, p<0.0001). Conclusion: Cirrhotic patients admitted to the liver ICU secondary to an acute decompensation and who required mechanical ventilation have a poor prognosis without liver transplantation with a 1-year mortality of 93%. A renewed burst of management interest for these patients after ICU discharge is necessary in order to improve their outcome. At ICU discharge, a MELD score higher 21.5 can help the hepatologists to identify patients who may benefit from liver transplantation program.

Disclosures:

Faouzi Saliba - Advisory Committees or Review Panels: Novartis, Roche, Genzyme; Grant/Research Support: Astellas; Speaking and Teaching: Schering Plough, Gambro, MSD

Didier Samuel - Consulting: Astellas, BMS, Gilead, Janssen-Cilag, LFB, MSD, Novartis, Roche, Biotest

The following people have nothing to disclose: Eric Levesque, Philippe Ichai

1371

Modulation of the innate immune response in bile duct ligated rats by oral administration of carbons of controlled porosity results in a reduction in liver and kidney injury and severity of portal hypertension

Jane Macnaughtan, Junpei Soeda, Vikram Sharma, Abeba Habte-sion, Jude A. Oben, Nathan Davies, Mookerjee P. Rajeshwar, Rajiv Jalan; UCL Institute of Hepatology, University College London, London, United Kingdom

Introduction A dysregulated inflammatory response consequent on increased bacterial translocation is central to the pathogen-esis of many complications of cirrhosis. We describe the biological effects of a non-absorbable, orally administered carbon of controlled porosity, which has been shown to bind endotoxin, on innate immune function in bile duct ligated rats and thus demonstrate the importance of the gut-liver immunological axis on disease pathogenesis. Methods Male Sprague-Dawley rats were randomised to bile duct ligation (BDL) or sham biliary surgery and studied after 4 weeks. They were randomised to receive standard chow+/− carbons of controlled porosity (Mast-carbon, UK) at a dose of 0.4g/100g body weight per day for 14 days until completion of the experiment. Animals then underwent haemodynamic assessment followed by collection of portal venous (PV) and arterial (A) blood. Flow cytometric analysis was conducted evaluating CD11 b, CD43 and His48 expression and ROS production using BD LSR II. Results Administration of the carbons resulted in a significant reduction in ALT in BDL rats (74.8 +5.2 vs 49.0 +6.5IU/ml p<0.05). This was associated with a significant reduction in portal pressure (12.5+/−0.3 vs 10.3+/−0.6 mm Hg, p<0.05) and plasma creatinine (37.2 + 1.5 vs 30.1 +0.8 μmol/l, p<0.05). The PV and arterial total WCC, neutrophil and monocyte populations in BDL rats were significantly increased compared to sham animals (Fig 1). Total WCC and neutrophil counts were significantly reduced in carbon-treated BDL rats (p<0.05). We also observed a significant increase in PV monocyte ROS production between sham and BDL rats (p<0.05). Carbon therapy resulted in a significant decrease in monocyte ROS production in response to LPS stimulation suggestive of a diminished primed state (p<0.05). This was particularly marked within the CD43lo subpopulation. Conclusions Orally administered carbons of controlled porosity modulate the dysregulated innate immune response in cirrhosis, which is associated with a reduction in liver injury, renal failure and severity of portal hypertension. These effects were associated with modulation of population and phenotype of trafficking innate immune cells from the gut and reflected in the systemic innate immune response.

Figure 1 Cell populations(×10*7)/ml

 Total WCC (A)Total WCC (PV)Neutrophilcount (A)Neutrophilcount(PV)Monocytecount (A)Monocytecount (PV)
  1. * p<0.05 Sham vs BDL

  2. # p<0.05 BDLvs BDL+carbon

Sham1.2+/−0.11.5+/−0.040.3+/−0.1O.3+/−0.50.1+/−0.030.1+/−0.02
BDL8.9+/−1.5*11.1+/−1.4*2.6+/−0.4*3.3+/−0.5*2.9+/−0.9*3.6+/−1.3*
BDL+ Gambro,4.5+/−0.3#6.5+/−1.61.4+/−0.1#l.6+/−0.4#1.4+/−0.32.2+/−0.6

Disclosures:

Nathan Davies - Patent Held/Filed: UCL

Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus

The following people have nothing to disclose: Jane Macnaughtan, Junpei Soeda, Vikram Sharma, Abeba Habtesion, Jude A. Oben, Mookerjee P. Rajeshwar

1372

Leucine reverses anabolic resistance of hyperammonemia in cirrhosis: a prospective controlled study

Cynthia Tsien3, Samjhana Thapaliya1, Gabriella A. TenHave2, Arthur J. McCullough1, Nicolaas E. Deutz2, Srinivasan Dasarathy1;

1 Gastroenterology and hepatology, Cleveland Clinic Foundation, Cleveland, OH; 2Kinesiology, Texas A&M University, College Station, TX; 3Gastroenterology, University of Toronto, Toronto, ON, Canada

Background. Cirrhosis is a state of anabolic resistance with failure of sarcopenia to reverse with nutrient supplementation. There are no direct studies on the rate of muscle protein synthesis in cirrhosis. We have shown that hyperammonemia results in impaired protein synthesis by a myostatin dependent, AMPK dependent inhibition of mTOR, a critical stimulator of protein synthesis. We now determined whether a high dose of leucine reverses anabolic resistance in cirrhosis. Methods. A prospective study was performed to quantify the muscle fractional protein synthesis rate (FSR) in well compensated cirrhotics (n=6; 54±5y) and matched controls (n=7; 46±16y) using incorporation of a primed constant iv infused L-[ring-2H5]-pheny-lalanine ([2H5]PHE) for 7 h. Serial vastus lateralis muscle biopsies were obtained before and at the end of the study. Plasma enrichment of (L-[2H5]-phenylalanine) was determined by LC-MS/MS. FSR and plasma amino acid changes in response to leucine enriched branched chain amino acid mixture (LEBCAA; 7.5g leucine, 3.75g each isoleucine and valine) was determined. 3-methylhistidine (3MH) as a measure of myofibrillar protein breakdown and plasma ammonia quantified at 0, 60, 180 and 420 min. Results. In cirrhotics, FSR of muscle protein was 2.33±0.2%/d in controls and 2.10±0.43%/d in cirrhotics (p=0.14). The rate of decline of the branched chain amino acid concentration was similar up to 8 hr after the oral administration of the LEBCAA mixture. Plasma glutamine was higher in cirrhotics. Plasma phenylalanine and tyrosine were significantly higher in cirrhotics at baseline and subsequent to LEBCAA, were no longer different in the 2 groups. 3MH was not significantly different (p>0.1) throughout the 8 h of the study between cirrhotics and controls. Conclusions. LEBCAA induce a comparable FSR increase in the skeletal muscle in cirrhotics providing compelling rationale for this intervention to prevent and reverse sarcopenia of cirrhosis. There is indirect evidence of lowering of ammonia by glutamine synthesis in the skeletal muscle in response to the high dose of leucine administered. High dose leucine can potentially increase skeletal muscle mass and lower ammonia through a non ureagenic, skeletal muscle glutamine synthetic mechanism.

Disclosures:

The following people have nothing to disclose: Cynthia Tsien, Samjhana Thapaliya, Gabriella A. TenHave, Arthur J. McCullough, Nicolaas E. Deutz, Srinivasan Dasarathy

1373

Aquaporin-1 associated to arterial capillary proliferation and sinusoidal transformation are related with portal hypertension in primary biliary cirrhosis

Hiroaki Yokomori1, Masaya Oda2,3;

1Internal Medicine, Kitasato University Medical Center, Saitama, Japan; 2Organized Center of Clinical Medicine, International University of Health and Welfare, Tokyo, Japan; 3Internal Medicine, Sanno Medical Center, Tokyo, Japan

Backgrounds and Aims: The pathophysiology of hepatic arterial capillary proliferation and sinusoidal capillalization accompanying liver fibrosis remains unclear. From a clinical perspective, variceal bleeding attributable to portal hypertension is a major problem among patients with primary biliary cirrhosis (PBC), even in the precirrhotic stage. Recently, evidence related to participating molecules and pathophysiological information has been accumulating. Although aquaporins (AQP)s in normal hepatobiliary system have been investigated, AQP localizations and changes in the hepatic microvascular systems including hepatic sinusoids are little understood. This study was conducted to clarify the localization of AQP-1 and their alterations in microvessels in normal human liver and in PBC stage I–IV. Materials and Methods: Human control and PBC liver specimens were obtained. Immunohistochemical (IHC) and Western blot analyses were conducted for AQP-1. For in situ hybridization, AQP1 peptide nucleic acid probes were used with a catalyzed signal amplification system. Immunoelectron microscopy (IEM) was conducted using immunoglobulin-gold-silver staining. Results: In control liver and stage I–II PBC liver, AQP–1 immunoreactivity was localized mainly in portal venules, hepatic arterioles and bile ducts in the portal tract, but was detected only slightly in the sinusoids. In IEM, electron dense products, indicating the localizations of AQP1, were only slightly evident on sinusoidal endothelial cells in control and PBC stage I–II. AQP–1 expressions were not only enhanced in the proliferated arterial capillaries opening into the sinusoids at the peripheral edge of the fibrotic septa, but also aberrantly expressed in the sinusoids in the vicinity of fibrous septum in stage III- IV PBC liver tissues. Moreover, proliferative capillary endothelial cells are in conjunction with hepatic sinusoidal cells in hepatic sinusoids. By IEM, the electron dense products indicating the localizations of AQP-1 were hardly evident on the sinusoidal endothelial cell (SEC)s in control and PBC stage I–II PBC liver, but were densely deposited on the periportal SECs, and proliferative capillary endothelial cells associated with the sinusoids at the peripheral edge of fibrotic septa in stage III PBC as well as at the edge of regenerative nodules in stage IV PBC. Overexpressions of AQP-1 at protein and mRNA levels were demonstrated, respectively, using Western blot and ISH. Conclusion:Angiogenetic and fibrotic responses are probably induced by AQP-1, leading to enhanced flow of arterial blood into the sinusoids, thereby contributing to the progression of portal hypertension in PBC.

Disclosures:

The following people have nothing to disclose: Hiroaki Yokomori, Masaya Oda

1374

Prevelance of fragmented QRS in patients with cirrhosis and relationship between the presence of fragmented QRS and systolic dysfunction and diastolic dysfunction

Mehmet Demir2,1, Adnan Burak Akcay1,2;

1Gastroenterology, Mustafa Kemal University, Hatay, Turkey; 2Cardiology, Mustafa Kemal University, Hatay, Turkey

Backgraund; Left ventricular systolic dysfunction and diastolic dysfunction have been considered as a component of cirrhotic cardiomyopathy. The aim of this study was to determine the frequency of fragmented QRS (fQRS) in patients with cirrhosis and relationship between the presence of fQRS and systolic dysfunction and diastolic dysfunction Methods: The study included 89 patients with cirrhosis (age: 56±12 years; 64% male; Child A/B/C: 14/39/36; etiologies: viral: 52%, alcohol: 22%, cryp-togenic: 16%, others: 10%) and 80 healthy volunteers. fQRS pattern was described as presence of RSR' manifested as existence of additional R wave and notching in either R or S waves in ECG recordings. Conventional echocardiography and tissue Dopplerechocardiography were performed in patient and control groups. Results: When compared to those in healthy volunteers, fQRS was more frequent in patients with cirrhosis (54% vs 10%, p <0.01).The patients with cirrhosis with fQRS had worse systolic and diastolic functions in comparison to the patients with cirrhosis without fQRS (Table 1). Higher age (p=0.04), serum levels of sodium (p<0.001),albumin (p=0.03),Child-Pugh Stage (p=0.012) and MELD score (p=0.013) were risk factors for the presence of fQRS in the patients with cirrhosis. Conclusions: In this study, fQRS was found more frequent in patients with cirrhosis in comparison to healthy volunteers. In addition, the patients with cirrhosis with fQRS had worse systolic functions and diastolic functions. These data suggest that fQRS may represent a novel noninvasive marker for cirrhotic cardiomyopathy in patients with cirrhosis.

Table 1. Conventional and tissue doppler related characteristics of the patients with cirrhosis with fragmented QRS
VariablePatients with cirrhosis with fQRS n=48Patients with cirrhosis without fQRS n=41P
  1. fQRS; fragmented QRS, LAD: left atrial diameter, LVDD:left ventricular diastolic diameter, LVEF; left ventricular ejection fraction, PAB;pulmonary artery pressure, IVRT; Isovolumetric relaxation time, DT;deceleration time

Conventional Doppler   
LAD (cm)2.9 ±0.72.8 ±0.30.45
LVDD(cm)4.2 ±2.14.4 ±3.20.49
LVEF (%)60.2 ± 3.959.8 ±6.10.56
PAB (mm Hg)18±721 ±80.43
IVRT (msec)75 ±2495 ±28P< 0.001
DT (msec)187 ± 67230 ±69P< 0.001
E/A0.87 ± 0.341.37 ±0.86P< 0.001
Tissue Doppler   
Sm (cm/s)8.2 ±1.710.2 ±2.1p < 0.01
Em (cm/s)8.9 ± 3.411.4 ± 4.1p < 0.01
Am (cm/s)7.3 ±1.37.9 ±2.20.16
E/Em10 ±438±48p < 0.05

Disclosures:

The following people have nothing to disclose: Mehmet Demir, Adnan Burak Akcay

1375

Correction of Hyponatremia with Tolvaptan therapy is associated with Improved Cognition, Quality of Life, Reduced Caregiver Burden and Brain Edema on MRI in Cirrhosis

Jasmohan S. Bajaj1, Vishwadeep Ahluwalia2, Edith A. Gavis1, George Feldman3, Ariel Unser1, Nicole Noble1, Melanie White1, Pamela Monteith1, HoChong Gilles1, Leroy Thacker4, Douglas M. Heuman1;

1Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA; 2Radiology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA; 3Nephrology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA; 4Biostatistics, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA

Hyponatremia can adversely impact cognition &quality of life(QOL) in cirrhosis but the effect of Na correction using the aquaretic tolvaptan on these is unclear. Aim : to evaluate the effect of tolvaptan on sodium, cognition, QOL and brain MR spectroscopy(MRS) in cirrhosis. Methods : Cirrhotics with Na<130meq/l were included for a 4 wk trial. At wk 0, pts underwent cognitive testing (table), QOL using Chronic Liver Disease Questionnaire(CLDQ) &Perceived Caregiver Burden from their caregivers(PCB). Pts then underwent fluid restriction &diuretic withdrawal. At wk 2 if Na was still<130, above procedures were repeated, brain MRS done & tolvaptan started at 15mg titrated upto 30mg/day for 2 wks with regular clinic and lab monitoring 3/wk. After 2 wks of tolvaptan(wk4), all procedures included MRI were repeated. Comparisons were made between wk 0 & 2(drug-free) and wk 2& 4(drug period) for Na, MELD, cognition, CLDQ & PCB. Brain MRS analysis centered on parietal white & occipital gray matter;creatine ratios of glutamate, myoinositol and choline (cho) were studied. Results : 26 cirrhotics were enrolled; 9 normalized Na without drug between wk0 &2. The remaining 17 got tolvaptan; 2 dropped out (1 transplant, 1 withdrew consent). 15 pts (age 58 yrs MELD 17,80% on lactulose) who received median 26mg/day tolvaptan over 13±2 days were analyzed. Mental status remained normal on drug. A significant improvement in Na, ammonia & selected cognitive tests was seen only on drug not in the pre-drug period (Table). QOL & caregiver burden were also improved only on tolvaptan. On MRS, a significantly reduced brain swelling indicated by increased Cho/Cr post-drug was seen in white (0.24 to 0.29,p=0.01) & gray matter (0.18 to 0.22, p<0.001) on tolvaptan. Conclusions : Tolvaptan-induced aquaresis &serum Na increase was associated with enhanced cognition and QOL,lowered caregiver burden &decreased brain swelling on MRI in cirrhosis.

 Week 0 (screen)Week 2 (drug initiation)Week 4 (drug end)
Na (meq/L)124±3126±2133±4*
Ammonia63.3±26.863.5±24.744±14*
Number connection test-A (low score=good)59±4164±5848±22*
Number connection test-B (low score=good)166±73174±117130±50*
Digit Symbol (low score=bad)37±1539±1544±I8
Block design (low score=bad)18±1119±1122±9
Line tracing time (low score=good)151±61165±127I48±1O2
Line tracing errors (low score=good)54±5255±4745±40*
Serial dotting(low score=good)111±58100±4692±49
Inibitory control lures(low score=good)15±919±1313±8*
Inibitory control targets(low score=bad)84±2188±1187±17
Chronic Liver Disease Questionnaire(low score=bad)3.4±l.23.4±1.13.8±1.2*
Perceived Caregiver Burden (low score=good)78±2280±l570±12*
* p<0.05 week 2 compared to 4; none of the comparisons between week 0 and 2 were significant

Disclosures:

Jasmohan S. Bajaj - Advisory Committees or Review Panels: Salix, Merz, otsuka, ocera, grifols, american college of gastroenterology; Grant/Research Support: salix, otsuka, grifols

HoChong Gilles - Speaking and Teaching: Bayer/Onyx

Douglas M. Heuman - Consulting: Bayer, Grifols, Genzyme; Grant/Research Support: Exilixis, Novartis, Bayer, Bristol Myers Squibb, Scynexis, Ocera, Mannkind, Salix, Globeimmune, Roche, SciClone, Wyeth, Otsuka, Ikaria, UCB, Celgene, Centocor, Millenium, Osiris; Speaking and Teaching: Otsuka, Astellas

The following people have nothing to disclose: Vishwadeep Ahluwalia, Edith A. Gavis, George Feldman, Ariel Unser, Nicole Noble, Melanie White, Pamela Monteith, Leroy Thacker

1376

Sleep and Neuropsychological Abnormalities in HCV Veterans with Active Mental Illness (MI) and/or Active Substance Use (SU)

Nicole Loo1,2, Khurram Bari1,2, Carol A. Eggers1,2, Yanhong Deng3, Maria Ciarleglio3, Guadalupe Garcia-Tsao1,2;

1Digestive Diseases, VA-CT Healthcare System, West Haven, CT; 2Digestive Diseases, Yale School of Medicine, New Haven, CT; 3Biostatistics, Yale Center for Analytical Sciences, New Haven, CT

Background Abnormalities in sleep and neuropsychological testing (NPT) are present in cirrhosis. Patients (pts) with MI and/or SU have been excluded from these studies. These comorbidities are quite prevalent in veterans with HCV infection. Objective To assess, in veterans with HCV infection and MI/SU, whether differences in sleep and NPT are present between pts with and without cirrhosis. Methods From 2003–2008, 247 pts with HCV infection and MI/SU were prospectively included in a study to assess adherence/response to antiviral therapy. Pts with decompensated cirrhosis were excluded. Different NPT, surveys and rating scales were obtained at baseline. Sleep questions from the Chronic Liver Disease Questionnaire and NPT were evaluated. The presence of cirrhosis was based on biopsy or a combination of clinical, laboratory and imaging criteria. Results Shown in Table. Cirrhosis (all compensated) was present in 34/247 pts (14%). Groups were similar in age, gender, BMI and Wide Range Achievement Test (indicating similar educational and intellectual coefficient). Pts with cirrhosis had more difficulty sleeping and falling asleep at night and did worse on trailmaking B, pegboard, and coding. These tests relate to concentration, visuomotor, and psychomotor speed. Tendencies for worsened sleep and NPT persisted when patients were analyzed by subgroup (MI only or SU only). Conclusion Despite the presence of active MI and/or SU, abnormalities in sleep symptoms and NPT are more prominent in pts wtih compensated HCV cirrhosis compared to those without cirrhosis.

Table 2. Demographics and test result comparisons between patients with and wtihout cirrhosis.
 Total nNo Cirrhosis (n-213)Cirrhosis (n = 34)P value
Age, median y24751510.96
Male gender, n (%) Female Male2476(2.8) 207(97.2)0(0) 34(100)0.99
Race, n (%) Caucasian African American Other247113(53.1) 86(40.4) 14(6.6)26(76.4) 5(14.7) 3(8.8)0.009
BMI, median24528.429.00.87
Mental Illness/Substance Abuse, n (%) Mental Illness Only [No Substance Abuse] Substance Abuse Only [No Mental Illness] Both Mental Illness/Substance Abuse24775(35.2) 40(18.8) 98(46.0)13(38.2) 10(29.4) 11(32.4)0.23
Platelet, median245213113<0.0001
Albumin (g/dL), median2374.33.8<0.0001
Total Bilirubin (mg/dL), median2410.61.03<0.0001
INR, median2401.11.2<0.0001
Creatinine (mg/dL), median2421.00.850.0005
MELD score, median2357.479.12<0.0001
Normalized by Age Wide Range Achievement Test, median24694980.23
CLDQ Question #4 - Sleepy during the day, n (%) Not sleepy [Scale 6–7] Sleepy [Scale 1–5]24731(14.6) 182(85.5)4(11.8) 30(88.2)0.67
CLDQ Question #16 - Difficulty sleeping at night, n (%) No difficulty [Scale 6–7] Difficulty [Scale 1–5]24765(30.5) 148(69.5)4(11.8) 30(88.2)0.024
CLDQ Question #20 - Difficulty falling asleep at night, n (%) No difficulty [Scale 6–7] Difficulty [Scale 1–5]24778(36.6) 135(63.4)5(14.7) 29(85.3)0.012
Trailmaking B test, median seconds2471071150.036
Grooved Pegboard, median seconds2467991.50.015
Word Fluency Test, median words24625220.23
Coding in 90 seconds, median correct codes2474036.50.032

Disclosures:

The following people have nothing to disclose: Nicole Loo, Khurram Bari, Carol

A. Eggers, Yanhong Deng, Maria Ciarleglio, Guadalupe Garcia-Tsao

1377

Urinary Tract Infections are Associated with Similar Poor Outcomes Compared to Other Infections in a Multi-Center Hospitalized Cirrhosis Cohort (NACSELD)

Heather M. Patton1, Jacqueline G. O'Leary2, Rajender Reddy3, PatrickS. Kamath4, Florence Wong5, BenedictMaliakkal6, Michael B. Fallon7, Guadalupe Garcia-Tsao8, Ram M. Subramanian9, Raza Malik10, Leroy Thacker11, Jasmohan S. Bajaj11;

1Department of Gastroenterology, UC San Diego Health System, San Diego, CA; 2Baylor University Medical Center, Houston, TX; 3University of Pennsylvania School of Medicine, Philadelphia, PA; 4Mayo Clinic School of Medicine, Rochester, MN; 5University of Toronto, Toronto, ON, Canada; 6University of Rochester Medical Center, Rochester, NY; 7University of Texas Medical School at Houston, Houston, TX; 8Yale University Medical Center and Connecticut VA Healthcare System, New Haven, CT; 9Emory University Medical Center, Atlanta, GA; 10Beth Israel Deaconess Medical Center, Boston, MA; 11 Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA

Urinary tract infections (UTI) are prevalent among hospitalized patients and are an important preventable nosocomial infection. Prospective multi-center data on UTI in cirrhosis and their effect on outcomes compared to other infections are lacking. Aim: To evaluate the outcomes of hospitalized cirrhotics with UTI versus non-UTI infections in the NACSELD cohort. Methods: NACSELD is a 15-center database of infected cirrhotic inpatients in which demographics, infection/cirrhosis details, and outcomes are prospectively collected. Outcomes recorded include death, length-of-stay (LOS), organ failures (hepatic encephalopathy, dialysis, ventilation or shock), and acute-on-chronic liver failure (ACLF) defined as ≥2 organ failures. UTI was defined as urine WBC >15/hpf with either positive urine gram stain or culture. Admitted patients with a UTI were compared to those admitted with non-UTI infections. Results: 445 cirrhotics (57% male, MELD 20.5, 29% alcoholic) were enrolled, 28% with UTI vs. 72% with non-UTI infection. Patients with UTI were less likely to be male (43 vs. 64%, p<0.001) and had a lower admission WBC count (6718 ± 4875 vs. 8908 ± 7451, p=0.003) vs. non-UTI infections. Patients with UTI were more likely to require dialysis (41 vs. 22%, p<0.001) and to have a nosocomial infection (25 vs. 12%, p<0.001) compared to non-UTI infections but did not differ in rates of other organ failures, ACLF, or second infections. Risk of mortality was not significantly different with UTI vs. non-UTI infections (13 vs. 21%, p=NS). UTI were more likely to yield positive cultures and had higher rates of gram+ (45 vs. 30%, p=0.009), gram-(47 vs. 23%, p<0.001), fungi (7 vs. 1%, p=0.034) and resistant organisms (Vancomycin-resistant Enterococcus 11 vs. 4%, p=0.011 and fluoroquinolone resistance 20 vs. 7%, p<0.001). LOS did not vary between the 2 groups. Conclusions: UTI is a morbid infection among hospitalized cirrhotics. UTIs were associated with inpatient dialysis, but remaining outcomes were similar to the non-UTI infections in this multi-center study. Nosocomial and antibiotic resistant infections are prevalent among hospitalized cirrhotics with UTI, both of which are potentially modifiable variables with infection control measures.

Disclosures:

Jacqueline G. O'Leary- Consulting: Vertex, Gilead

Florence Wong - Consulting: Gore Inc; Grant/Research Support: Grifols

Michael B. Fallon - Advisory Committees or Review Panels: Bayer/Onyx; Grant/Research Support: Ikaria Therapeutics, Gilead, ANADYS, Mochida, Eaisi, Research Triangle Institute

Jasmohan S. Bajaj - Advisory Committees or Review Panels: Salix, Merz, otsuka, ocera, grifols, american college of gastroenterology; Grant/Research Support: salix, otsuka, grifols

The following people have nothing to disclose: Heather M. Patton, Rajender Reddy, Patrick S. Kamath, Benedict Maliakkal, Guadalupe Garcia-Tsao, Ram M. Subramanian, Raza Malik, Leroy Thacker

1378

Treatment of Hepatic Encephalopathy: Comparing the Effects of Adding Rifaximin to Lactulose on Patient Outcomes

Alesa Courson, Jennifer D. Twilla, Jayme Hara, G Morgan Jones; Pharmacy, Methodist University Hospital, Memphis, TN

Background: Hepatic encephalopathy (HE) is a mix of neuropsychiatric signs and symptoms that occurs in chronic liver disease (CLD). Without transplantation, patients with HE have 1 and 3 year mortality rates of 58% and 77%, respectively. Rifaximin is approved for the reduction of HE recurrence in CLD patients; however, few studies have evaluated the benefit of adding rifaximin to lactulose for treatment of acute HE. Our primary objective was to assess the effect of adding rifaximin to lactulose on hospital length of stay (LOS) and hospital readmission in patients with acute HE. Methods: We conducted a retrospective review of patients admitted with HE between 2007 and 2012. Patients were assigned to one of three groups based on treatment type and response: lactulose monotherapy, lactulose plus rifaximin combination therapy, or therapy escalation. Therapy escalation was defined as the addition of rifaximin after 24 hours of lactulose monotherapy. Adult patients diagnosed with hepatic cirrhosis were included. Those with neurologic diseases, severe comorbid conditions, acute liver failure, prior antibiotic treatment of current HE episode, history or possibility of transplant within 1 month, and transjugular intrahepatic portosystemic shunt placement were excluded. Results: We included 87 patients in monotherapy, 62 in combination, and 24 in therapy escalation groups. Median LOS was 6 days in monotherapy and 8 days in combination group (p=0.9). At 180 days, patients receiving combination therapy had fewer readmissions than those receiving monotherapy (2.4% vs. 16.2%; p=0.02). Mortality rates were higher in patients who had ≥4 negative prognostic factors for HE resolution (30.6%) than those with ≤3 (1.6%), regardless of therapy. Patients on monotherapy and those who had therapy escalation were evaluated to determine appropriateness of initial therapy based on predictors of nonresponse to lactulose. Eighty-five percent of monotherapy patients and 87.5% of the therapy escalation group had at least 1 predictor of nonresponse, classifying their initial treatment as inappropriate. Conclusion: Addition of rifaximin to lactulose for treatment of acute HE did not reduce hospital LOS; however, it did result in lower readmission rates at 180 days. In-hospital mortality was increased in patients with >4 negative prognostic factors for poor recovery from HE. Based on the predictors of nonresponse to lactulose, the majority of patients received inappropriate initial therapy for HE. In the future, we plan to create an algorithm based on the predictors of nonresponse that stratifies patients to receive initial combination therapy or monotherapy for acute HE treatment.

Disclosures:

The following people have nothing to disclose: Alesa Courson, Jennifer D. Twilla, Jayme Hara, G Morgan Jones

1379

TIMP-1 in patients with cirrhosis: Relation to liver dysfunction, portal hypertension, and hemodynamic changes

Troels M. Busk1, Flemming Bendtsen2, Hansen Jørgen Nielsen3, Nils Brünner4, Vibeke Jensen4, Søren Møller1;

1Centre of Functional Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; 2Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; 3Department of Surgical Gastroenterology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; 4Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Background and aim: Patients with cirrhosis and portal hypertension often develop complications relating to hemodynamic changes. The diagnosis and consequences hereof are often based on invasive procedures, such as liver biopsy and measurements of the hepatic venous pressure gradient. Thus, there is obviously a need to identify non-invasive markers of the severity of liver cirrhosis. Matrix metalloproteinases and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs) play a pivotal role in hepatic fibrogenesis and fibrolysis. The aim of the study was to investigate plasma TIMP-1 in liver cirrhosis patients undergoing catheterization and relate the findings to the degree of liver dysfunction, portal hypertension and hemodynamic changes. Methods: We included 96 patients with verified cirrhosis (Child A/B/C: 31/33/32) and 15 matched controls without liver disease. All individuals underwent a liver vein catheterisation with hemodynamic assessment. TIMP-1 was determined in arterial and hepatic venous plasma using the in-house MAC-15 TIMP-1 ELISA, which measures total (complexed and uncomplexed) TIMP-1 with high analytical performance. Results: There was no significant difference between arterial and hepatic venous concentrations of TIMP-1 in either patients or controls. Hepatic venous concentrations of TIMP-1 was significantly increased in patients with liver cirrhosis 317(193) ng/ml versus 153(104) (median/IQ range) (p < 0.001) with a progressive increase throughout the Child classes with the highest levels in Child class C patients (p < 0.001). Circulating TIMP-1 correlated significantly with ICG-clearance (r = - 0.62, p < 0.0001), GEC (r = - 0.40, p < 0.0001), the hepatic venous pressure gradient (r = 0.59, p < 0.0001), mean arterial pressure (r = - 0.40, p < 0.0001), and systemic vascular resistance (r = - 0.36, p < 0.0001). Conclusions: TIMP-1 is significantly increased in patients with liver cirrhosis. TIMP-1 correlates significantly with the severity of the liver disease, degree of portal hypertension, and the vasodilatory state. TIMP-1 may represent a promising non-invasive marker to predict development of hemodynamic-related complications in patients with cirrhosis.

Disclosures:

The following people have nothing to disclose: Troels M. Busk, Flemming Bendtsen, Hansen Jørgen Nielsen, Nils Brünner, Vibeke Jensen, Søren Møller

1380

Development of a formula for estimating the daily average plasma glucose concentration in patients with liver cirrhosis and its clinical application

Yasushi Ide1, Toshihiko Mizuta1, Hiroshi Isoda2, Taiga Otsuka1, Shunya Nakashita1, Saori Kamachi1, Chika Tsuji1, Keizo Anzai1, Iwata Ozaki1;

1 Internal Medicine, Saga University, Saga, Japan; 2National Hospital Organization Ureshino Medical Center, Ure-shino, Japan

Background/Aim: Liver cirrhosis (LC) often causes abnormal glucose fluctuations, leading to oxidative stress or hepatocar-cinogenesis. Because their hemoglobin (Hb) and albumin (ALB) metabolism is altered, there is no reliable average plasma glucose (AG) marker for LC patients. Therefore, we examined correlations between daily AG measured by a continuous glucose monitoring system (CGMS) and conventional markers of glucose metabolism and hepatic function and devised a formula for estimating AG (eAG) and “true” HbA1c (estimated HbA1c; eHbA1c) in LC patients. We also assessed whether eHbA1c values correlate with recurrence of hepatocellular carcinoma (HCC). Methods: Hospitalized LC patients (n = 30; 20 men) wore a CGMS-Gold (Medtronic Mini-Med) for 3 days (24 h/day) to measure interstitial glucose concentrations. We defined the resultant 3-day mean glucose concentration as AG. Fasting plasma glucose (FPG), insulin (FPI), and C-peptide; HbA1c; glycated ALB (GA); and 1, 5-anhydrogluctitol were used as glucose metabolism markers and BMI, Child-Pugh score, Hb, platelet count, alanine aminotransferase, γ-glutamyltransferase, ALB, prothrombin time, total bilirubin, and hyaluronic acid as hepatic function markers and other relevant variables. We divided the data set into 20 item development and 10 item validation sets. We used the development set to examine correlations between AG and each patient variable assessed. We then used these variables in a stepwise regression model to devise an estimated regression equation for AG. We verified a correlation between eHbA1c and HbA1c. Results: AG correlated significantly with HbA1c, GA, FPI, and ALB. HbA1c levels were lower in patients with anemia. Stepwise regression analysis (adopted P value) selected three factors (HbA1c, Hb, and ALB) for estimating AG and eHbA1c by the following regression formulas: eAG = 163.76 +28.028 ×HbAlc(%) -9.132 ×Hb (g/dL) -21.124 ×ALB (g/dL) eHbA1c = 7.333 +0.977 ×HbAlc(%) -0.318 ×Hb (g/dL) -0.736 ×ALB (g/dL) We used these formulas to examine correlations between eHbA1c and recurrence free survival rate in 78 HCV-positive LC patients treated with local ablation or hepatic resection for first HCC. Patients with eHbA1c ≥6.2 had significantly higher recurrence rates than those with <6.2. (HR 2.34, P = 0.006). Conclusion: Although conventional glucose metabolism markers correlate significantly with true AG measured by CGMS in LC patients, it is necessary to correct for Hb values and hepatic function. As calculated by our formula, eHbA1c may be useful for evaluating or managing glucose metabolism in patients with LC. Moreover, managing glucose concentrations may decrease hepatocarcinogenesis.

Disclosures:

The following people have nothing to disclose: Yasushi Ide, Toshihiko Mizuta, Hiroshi Isoda, Taiga Otsuka, Shunya Nakashita, Saori Kamachi, Chika Tsuji, Keizo Anzai, Iwata Ozaki

1381

Transjugular Intrahepatic Porto-Systemic Shunt (TIPS) in Patients with Liver Cirrhosis and MELD >15

Mohamad A. Hanouneh1, Ibrahim A. Hanouneh1, Bradley Confer1, Rocio Lopez2, Maggie H. Samaan1, Nizar N. Zein1;

1Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH; 2Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH

Background: It remains to be determined whether TIPS procedure is safe in patients with advanced liver cirrhosis. The aim of the study is to evaluate the impact of TIPS on transplant-free survival in patients with liver cirrhosis and MELD score >15. Methods: We identified all adult patients who underwent TIPS procedure at our institution between 2004 and 2011 (N=470). A total of 144 patients had MELD greater than 15 at the time of TIPS procedure. These 144 TIPS patients were matched 1:1 to patients with liver cirrhosis who did not undergo TIPS based on age and MELD score using the greedy algorithm. Patients were followed to the time of death or liver transplantation. Kaplan-Meier curves were generated and log-rank tests were used to test for differences in survival outcome between the two groups. Results: A total of 288 patients with liver cirrhosis were included in the study, of whom 144 underwent TIPS and 144 did not. The two groups were matched based on age and MELD score, and were comparable with regards to gender and ethnicity. The mean MELD and Child's Pugh Scores in the entire study population were 20.9±6.5 and 10.5±1.8 respectively. The most common indication for the TIPS procedure was varices (49%), followed by refractory ascities (42%). In the first 2 months following the insertion of TIPS, there was a trend towards increased mortality or need for liver transplantation in patients who had TIPS compared to those who did not, but this did not reach statistical significance value (p=0.07). On the other hand, after the 2 month mark, TIPS becomes significantly beneficial with a 56% lower risk of dying or needing liver transplantation (p<0.01) than cirrhotic patients who did not undergo TIPS. Conclusion: In patients with liver cirrhosis and MELD >15, TIPS might improve transplant-free survival beyond 2 months of the procedure.

image

Disclosures:

The following people have nothing to disclose: Mohamad A. Hanouneh, Ibrahim A. Hanouneh, Bradley Confer, Rocio Lopez, Maggie H. Samaan, Nizar N. Zein

1382

Dynamics of renal function and the renin angiotensin aldosterone system in patients with stable liver cirrhosis: effects of posture and volume- and sodiumloading

Annette D. Fialla1, Helle C. Thiesson2, Peter Bie3, Ove B. Schaffal-itzky de Muckadell1, Aleksander Krag1;

1Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark; 2Department of Nephrology, Odense University Hospital, Odense, Denmark; 3Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark

Introduction: In cirrhosis the key sodium retaining mechanisms relates to the renin angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS). However, early changes in the interplay of the systems and the magnitude of the responses to postural change and sodium/volume loading may provide new insights in the fragility of the kidneys in cirrhosis with normal creatinine. We aimed to characterize the neurohumoral and dynamics of renal function in response to postural change, sodium- and volume loading in patients with cirrhosis compared to healthy controls. Method : In 18 patients with stable cirrhosis and normal creatinine (mean 86 μmol/l) and 6 healthy controls, the RAAS, SNS as well as renal function and sodium excretion was examined during postural change and sodium/volume load. Results: The plasma renin concentration (PRC) was at rest increased nearly 5-fold; 120±47 mlU/l vs. 25±3 mlU/l, in patient compared to healthy controls. During standing this activation was enhanced (144 %, p<0.001) and reduced by changing to sitting position (118%, p<0.001) and during volume/sodium loading (42%, p=0.3) compared to baseline. Plasma angiotensin II (ANGII) in the supine position was at the same level in patients and controls despite the very high PRC in that position (13.8 ±1.9 pg/ml vs. 8.8 ±2.4 pg/ml, p>0.05). The expected responses to the renin stimulation were seen during erect and sitting position as well as after saline infusion. The calculated rise in pg/ml of aldosterone pr unit plasma ANGII was for patients; 3.6 (95% CI 2.4–4.7) pg/ml and for controls; 14.5 (95% CI 9.3–19.8) pg/ml, p<0.05.The SNS was highly activated during all postural positions in cirrhotics compared to controls and at rest (noradrena-lin; 3.66±0.35 vs. 1.92±0.13 pg/ml, p<0.001). The effective renal plasma flow and glomerular filtration rate were at the same level in the two groups at rest whereas the renal function deteriorated during standing in the patients (decreased by 42% vs. 15%, p=0.035). The sodium excretion was markedly reduced in the cirrhotic patients during all postural positions. Conclusion: Renal function in stable cirrhosis with normal creatinine is fragile and challenges with posture and volume- and sodium loading unmask impaired renal function and a dissociation of the response in the RAAS.

Disclosures:

The following people have nothing to disclose: Annette D. Fialla, Helle C. Thiesson, Peter Bie, Ove B. Schaffalitzky de Muckadell, Aleksander Krag

1383

Need to Better Target Empirical Antibiotic Therapy Due to the Increasing Rate of ‘Extensively’- and ‘Pan- Drug Resistant’ Infections in Chirrosis

Manuela Merli1, Cristina Lucidi1, Vincenza Di Gregorio1, Valerio Giannelli1, Gianna Iacovone1, Michela Giusto1, Kameliya Koryukova1, Oliviero Riggio1, Mario Venditti2;

1Gastroenterology, Sapienza Università di Roma, Roma, Italy; 2Department of Infectious Disease, Sapienza Università di Roma, Roma, Italy

Emergence of antibiotic resistance is becoming a severe healthcare-related burden, particularly relevant in cirrhosis. Our study was aimed at analyzing the prevalence and the characteristics of bacterial resistances to antimicrobial therapies and the rate of failure of first-line treatment in hospitalized cirrhotics. We included all consecutive patients hospitalized in the last 5 years, with an infection microbiologically documented. Infections were classified as community acquired(CA), hospitalacquired(HA)and healthcare-associated(HCA). Any bacteria resistant to at least 3 antibiotic classes but sensible to more than 2 classes, was defined as “multidrug resistant”(MDR), those resistant to all antibiotics but sensible to 1 or 2 classes were classified as “Extensively Drug Resistant”(XDR) and those resistant to all classes as “Pan-drug Resistant”(PDR). MELD and Child-Pugh scores, the history of hospitalizations in the last 6 months or of infections in the last year, the use of any antibiotics during the last month, the crhonic use of non-absorbable antibiotics and the use of quinolone prophylaxis were investigated as possible risk factors. A total of 87 patients were enrolled: 16% had CA, 47% HA and 37% HCA infections. Bacteria were MDR in 48 patients. MDR bacteria more frequently isolated were: Enterobacteriaceae ESBL(42%), Vancomycin-Resistant-Enterococci(21%), Methicillin-Resistant Staphylococcus Aureus(12%). Prevalence of MDR, XDR and PDR is shown in the figure 1. The rate of failure of empirical antibiotic therapy was 42% in MDR, 61% in XDR and 83% in PDR (p=0.05). The multivariate analysis confirms the number of hospitalizations in the last 6 months (p=0.035;OR=1 .2;95%CI: 1.15–1.45) and the number of infections in the last year (p=0.045;OR=1 .1 ;95%CI:1.05–1.5) as independent predictors of infections due to XDR/PDR bacteria. Our study showed a high prevalence of resistances to multiple antibiotic therapies and a consequent lack of the efficacy of currently recommended empirical therapy. The history of recurrent hospitalizations and previous infections would be take into account in the decision of the better antibiotic strategy.

image

Disclosures:

The following people have nothing to disclose: Manuela Merli, Cristina Lucidi, Vincenza Di Gregorio, Valerio Giannelli, Gianna Iacovone, Michela Giusto, Kameliya Koryukova, Oliviero Riggio, Mario Venditti

1384

Role of Transcranial Doppler (TCD) in the evaluation of cerebral hemodynamic in cirrhotic patients: correlation with severity of the disease and Minimal Hepatic Encephalopathy (MHE) development

Gianluigi Caracciolo1, Maria Assunta Zocco1, Andrea Lupascu2, Bigida E. Annicchiarico1, Matteo Garcovich1, Maria Elena Ain-ora1, Davide Roccarina1, Francesca D'Aversa1, Daniele D. Fer-rarese1, Massimo Siciliano1, Paolo Tondi2, Antonio Gasbarrini1;

1Internal Medicine and Gastroenterology, UCSC, Rome, Italy; 2Internal Medicine and Angiology, UCSC, Rome, Italy

Background: Several studies showed that cerebral blood flow is decreased in patients with chronic liver disease, especially in the presence of hepatic encephalopathy. Recently, it has been suggested that, in cirrhotic patients, cerebral vascular resistance indices (resistivity index, RI and pulsatility index, PI) are good indicators of cerebral hemodynamic abnormalities and are closely correlated with the severity of cirrhosis, hepatic encephalopathy and ascites. However there are still poor data about cerebral vascular indices and MHE. Aims: The aim of this study was to correlate cerebral arteries resistance indices with the severity of liver disease and the development of MHE. Methods: 19 consecutive cirrhotic patients (13 male and 6 female) were enrolled in this study. Exclusion criteria were overt hepatic encephalopathy (West Haven >0), age <18 years, active alcohol consumption, sepsis, cerebrovascular diseases, cerebral neoplasms, cardiac diseases, peripheral vascular diseases, treatment with rifaximin and lactulose in the previous 30 days. All patients underwent TCD with the detection of right mean and posterior cerebral artery (MCA and PCA) and measurement of RI and PI. Blood samples were collectd for detection of ammonia, bilirubin, creatinine, INR and albumin levels and the Child-Pugh score was calculated. Psychometric tests (TMT-A, TMT-B and DST) were performed in order to assess the presence of MHE. Results: Among the patients enrolled 12 had MHE (63%). When we compared patients with and without MHE we found a statistically significant difference in MCA-RI (mean±SD: 0,58±0,05 vs 0,65±0,08; p<0,05), MCA-PI (mean±SD: 0,96±0,1 vs 1,18±0,2; p<0,05) and blood ammonia levels (mean±SD: 107±54 vs 58±16; p<0,05). Differences in PCA-RI and PCA-PI between the two groups showed a trend toward sig-nificancy (p=0,06). MCA-RI and MCA-PI were also correlated with Child-Pugh score (MCA-RI: 0.58±0.05, 0.68±0.07, 0.68±0.8 in Child A, B and C respectively; p<0,05) (MCA-PI: 0.96±0.13, 1.3±0.28, 1,27±0.19 in Child A, B and C respectively; p<0,05). Conclusions: Cerebral vascular resistance indices assessed by TCD seem to be related with the severity of liver disease and could be useful for the diagnosis of MHE in cirrhotic patients.

Disclosures:

The following people have nothing to disclose: Gianluigi Caracciolo, Maria Assunta Zocco, Andrea Lupascu, Bigida E. Annicchiarico, Matteo Garcovich, Maria Elena Ainora, Davide Roccarina, Francesca D'Aversa, Daniele D. Ferrarese, Massimo Siciliano, Paolo Tondi, Antonio Gasbarrini

1385

Long term outcomes of patients with portal biliopathy and significant biliary obstruction with non-surgical management

Akash Shukla, Amit A. Gupte, Vedant H. Karvir, Prashant Dhore, Shobna Bhatia; Gastroenterology, Seth GS Medical College & KEM Hospital, Mumbai, India

Introduction Portal biliopathy (PB) is reported in up to 80% of patients with extra hepatic portal venous obstruction (EHPVO) on MRCP. 5–14% of these are symptomatic. There are no data about natural history of PB. We therefore, analyzed our data of patients with EHPVO, who had significant biliary obstruction (dilated common bile duct [CBD]/intrahepatic biliary radicals [IHBR]) due to PB, but did not undergo surgery due to lack of shuntable vessels. Methods Consecutive records of all patients of EHPVO who attended the liver clinic between were reviewed. We analyzed data of patients with PB with significant biliary obstruction on ultrasound with or without secondary biliary cirrhosis (SBC). Patients with liver disease due other causes were excluded. The clinical course of patients till May 2013 was recorded at last follow up or by phone call interview. Baseline characteristics of patients with PB who developed decompensated liver disease were compared to those who did not,using SPSS 16.0. Institutional ethics committee approved the protocol. Results Of 620 patients with EHPVO, 57 (9.2%; 33 [56.9%] men) had PB. Their median follow-up from onset of symptoms of EHPVO was 11 (4–39) years. Patients with PB had later onset of symptoms as compared to patients with EHPVO without PB (21.9 [15.6] vs 16.6 [12.2] y, p= 0.045). Ten of 57 (17.5%) patients with PB had jaundice, 38 (65.5%) patients had gastro intestinal bleed, 6 had ascites at presentation; 3 of them had transient ascites after variceal bleed. Seven patients had CBD stones. Decompensation due to SBC was seen in five patients; three at presentation whereas two developed after 23 and 24 years after onset of symptoms, respectively. Elevated AST, ALT and ALP were present in 26 (44.8%), 14 (24.1 %) and 34 (58.6%) patients, respectively. 13 patients underwent ERCP because of symptoms or presence of CBD stones. Proportion of patients with jaundice, elevated AST, elevated ALT, elevated ALP at presentation was similar in patients who developed hepatic decompensation as compared to patients with PB who did have hepatic dysfunction (p =ns for all). Of patients with PB who had variceal bleed at presentation (n=38), none developed hepatic decompensation as against 5 of 19 (26.3%) patients who did not have GI bleed at presentation (p=0.003). Conclusion Portal biliopathy with significant biliary obstruction occurs in about 9.2% of patients with EHPVO. Patients with EHPVO with PB have a later onset of the symptoms as compared those without PB. Patients with PB who do not present with variceal bleed have a higher chance of hepatic decompensation.

Disclosures:

The following people have nothing to disclose: Akash Shukla, Amit A. Gupte, Vedant H. Karvir, Prashant Dhore, Shobna Bhatia

1386

Quantitation and location of the severity of brain edema in patients with acute on chronic liver failure and hepatic encephalopathy

Nicolas Weiss2, Matteo Rosselli3, Sarah Mouri1, Dominic Yu4, Damien Galanaud6, Banwari Agarwal5, Dominique Thabut1, Rajiv Jalan3;

1Hepatology ICU, AP-HP, hôpital Pitié-Salpêtrière, Paris, France; 2Neurological ICU, AP-HP, hôpital Pitié-Salpêtrière, Paris, France; 3Hepatology, Royal Free Hospital, London, United Kingdom; 4Radiology, Royal Free Hospital, London, United Kingdom; 5ICU, Royal Free Hospital, London, United Kingdom; 6Radiology, AP-HP Pitié-Salpêtrière hospital, Paris, France

Introduction: Hepatic encephalopathy (HE) is associated with brain swelling. However, in patients with varying severity of HE and those with acute on chronic liver failure (ACLF), the site and severity of brain swelling is unknown. In animal models, brain water in the different regions is measured using gravimetry. Using specific techniques of analysis, CT scan is able to measure a radiological gravity that correlates with physical gravity. It is possible to determine the weight, the volume and the specific gravity (SG) of the different brain regions in patients. The aims were to assess the importance, localization and characteristics of brain edema in cirrhotic patients with ACLF and HE. Methods: Patients admitted for HE in 2 Hepatology ICUs, that underwent a CT-scan were recruited. HE grade was assessed using the West-Haven criteria and ACLF was diagnosed using the CLIF Consortium criteria. Quantitative brain CT analysis was performed using the Brainview software to determine the volume, the weight and the SG of the different brain regions. Results were compared to patients that underwent a CT in the work-up for hepatic transplantation (cirrhotic controls) and to healthy controls. Results: Thirty-seven HE patients, 20 cirrhotic controls and 61 healthy controls were included. Characteristics of HE patients: male:64%, age: 56±11, etiology: alcohol: 61%, MELD: 20±11, Grade 3–4 HE: 21 (57%), ACLF: 16 (43%). Neither the weight, the volume nor the SG of brain, differed between the 3 groups of patients. Cirrhotic patients had increased brainstem SG compared to healthy control [1.02448 (1.0240–1.0250) vs 1.02167 (1.0213–1.0221) respectively, p<0.0001 ], whereas cerebellum SG was decreased [1.03234 (1.0317–1.0329) vs 1.03494 (1.0344–1.0355) respectively, p<0.0001]. Intraventricular CSF SG was different between cirrhotic patients and controls [1.01153 (1.0108–1.0122) vs 1.00865 (1.0080–1.0093) respectively, p<0.0001]. In cirrhotic patients with HE, intraventricular CSF SG was correlated to MELD score (p=0.05). In ACLF patients, brainstem SG was higher in patients with Grade 3–4 HE compared with patients with no/mild HE [1.025 ± 0.0019 vs 1.023 ± 0.0017, p=0.056]. However, in patients without ACLF, HE did not influence brainstem SG. Conclusion : The severity and site of brain swelling, measured using SG suggests that the edema is het-erogenous in the different brain regions in cirrhotic patients. Pathophysiologically, HE in ACLF patients appears distinct and is associated with increased brain stem SG and indicates a possibility of blood-brain barrier permeability dysfunction.

Disclosures:

Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus

The following people have nothing to disclose: Nicolas Weiss, Matteo Rosselli, Sarah Mouri, Dominic Yu, Damien Galanaud, Banwari Agarwal, Dominique Thabut

1387

Treatment of refractory portal systemic encephalopathy with balloon-occluded retrograde transvenous obliteration (BRTO) - a new approach

Amar Mukund1, S. Rajesh1, Ankur Arora1, Shiv K. Sarin2;

1Inter-ventional Radiology, Institute of liver and biliary sciences, New Delhi, India; 2Hepatology, Institute of liver and biliary sciences, New Delhi, India

Introduction and aim: Hepatic encephalopathy (HE) is an important cause of morbidity in patients with cirrhosis. Shunt induced HE has limited treatment options and is often refractory to medical therapy. We evaluated the efficacy of BRTO in the management of recurrent HE due to spontaneous large porto-systemic shunts in patients with cirrhosis. Materials & Method: We performed 29 sessions of BRTO in 26 patients using sodium tetradecyl sulphate foam since April 2011 to March 2013. Recurrent HE, refractory to ammonia lowering measures including gut sterilization (rifaxamine and lactuole combination therapy) and dietary restrictions was the main indication for BRTO in 21 patients. In 5 patients the procedure was indicated for obliteration of tumorous gastric fundal varices and was excluded from the analysis. The patients in the study group had cirrhosis along with history of recurrent HE (grade 2 to 4) requiring multiple hospital admissions. Porto-systemic communication in the form of gastro/lieno-renal shunt was present in all cases. Technical success was defined as complete obliteration of shunt as well as the varices. Clinical and lab parameters including arterial ammonia level were evaluated before and after the procedure. Results: Technical success was achieved in 21 of 23 sessions (91%). Complete obliteration of gastro/lieno-renal shunt was seen in 18 of 21 patients (86%) and partial obliteration in remaining on follow-up imaging. All patients were male [mean age - 58 years (Range 47 - 69 years)] and 15 of them had child's A and rest had child's B cirrhosis. Immediate clinical improvement (within 24–48 hours of procedure) of HE was observed in 19 of 21 patients (90%) with post procedure decrease in serum ammonia levels from 220 + 81 to 108 + 35 μg/dl. Two patients had delayed improvement. Post-procedure complication consisting of ascites, septicemia with acute kidney injury or deranged liver function tests was encountered in 5 patients. All the patients were clinically and symptomati-cally better on discharge and up to a follow up of 18 months (one month and thereafter 3, 6, 12, 18 months). These patients were able to resume normal work and did not require any further hospitalization. Two patients required bowel decontamination for next three months. Four (19%) patients showed worsening of esophageal varices at 3–12 month and underwent endoscopic variceal ligation. 30 days post procedure mortality was observed in one patient who succumbed to sepsis and multi-organ failure at 4 weeks of procedure. Conclusion: Portal systemic HE, refractory to medical management can be effectively treated by BRTO with no significant procedure related complications.

Disclosures:

The following people have nothing to disclose: Amar Mukund, S. Rajesh, Ankur Arora, Shiv K. Sarin

1388

Hypercoagulability in portal vein thrombosis is related to the presence of liver cirrhosis

Rupesh Rajani1, Roza Chaireti2,3, Annika Bergquist1, Tor Melin4, Ingalill Friis-Liby5, Marjo Kapraali6, Stergios Kechagias7, Tomas L. Lindahl3, Sven Almer1;

1Dept. of Gastroenterology and Hepatol-ogy, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; 2Dept. of Acute Internal Medicine and Coagulation Unit, Linköping University Hospital, Linköping, Sweden; 3Dept. of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; 4Division of Gastroenterology & Hepatology, Lund University Hospital, Lund, Sweden; 5Dept. of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden; 6Department of Clinical Sciences Danderyd Hospital, Division of Medicine, Karolinska Institute, Stockholm, Sweden; 7Department of Gastroenterology and Hepatology, Linköping University Hospital, Linköping, Sweden

Introduction The concept of bleeding complications in chronic liver disease has been challenged in recent years, as increasing evidence associating liver diseases with hypercoagulability has been reported. Methods We measured thrombin generation in the presence of thrombomodulin in patients with PVT (n=47 ), cirrhosis (n=24) and compared the results with those obtained from healthy controls (n=21). Hypercoagulability was expressed as thrombin generation (total and maximum, i.e. Endogenous Thrombin Potential, ETP and peak, respectively) measured in the presence of thrombomodulin (TM), by means of the Calibrated Automated Method (CAT®). We assessed resistance to TM by using ratios (marker measured in the presence/absence of thrombomodulin). Results Patients with cirrhosis generated more thrombin compared to healthy controls (p=0.006 for ETP and p<0.001 for peak) and patients with non cirrhotic PVT (p=0.003 and p=0.006 for ETP and peak) (Figure 1). They also exhibited resistance to thrombomodulin (ratios for ETP and peak; p=0.006 respectively p<0.001 compared to controls and p=0.003 and p=0.013 compared to non cirrhotic PVT). Among patients with PVT, only those with cirrhotic PVT exhibited higher thrombin generation (p=0.017 and p=0.019 for ETP and peak) and thrombomodulin resistance (p=0.001 for both ratios ETP and peak) compared to controls. Conclusion Our results indicate that hypercoagulability and thrombomodulin resistance in patients with portal vein thrombosis (PVT) is mainly caused by the presence of cirrhosis. Patients with cirrhotic PVT may therefore benefit from longer treatment with anticoagulants than non-cirrhotic patients.Randomized clinical trials are needed to test this hypothesis.

Figure 1.

Endogenous Thrombin Potential (ETP) measured in the presence of thrombomodulin (TM)

Disclosures:

Tomas L. Lindahl - Advisory Committees or Review Panels: Boehringer-Ingelheim, Bristol-Meyer Squibb; Board Membership: Medirox, Nordic Haemostasis; Management Position: Diapensia; Speaking and Teaching: Roche Diagnostics, Octapharma, Leo-Pharma

The following people have nothing to disclose: Rupesh Rajani, Roza Chaireti, Annika Bergquist, Tor Melin, Ingalill Friis-Liby, Marjo Kapraali, Stergios Kechagias, Sven Almer

1389

Liver Disease in X-Linked Agammaglobulinemia: A Predominance of Nodular Regenerative Hyperplasia?

Christopher Koh1, Gulbu Uzel2, Sergio Rosenzweig3, Xiongce Zhao4, David E. Kleiner5, T. Jake Liang1, Steven M. Holland2, Theo Heller1;

1 Liver Diseases Branch, NIDDK, NIH, Bethesda, MD;2Lab-oratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD; 3Laboratory of Host Defenses, NIAID, NIH, Bethesda, MD;4Office of the Director, NIDDK, NIH, Bethesda, MD;5Laboratory of Pathology, NCI, NIH, Bethesda, MD

Introduction: X-linked agammaglobulinemia (XLA), or Bruton's disease, is a rare genetic disorder affecting 1:350,000 persons, where individuals fail to produce mature B-cells. Common clinical manifestations include recurrent bacterial infections, enteroviral infections, arthritis, malignancies and growth hormone deficiencies. To date, only 46 cases of liver disease have been described in XLA patients, of which 44 are from viral hepatitis and 2 from nodular regenerative hyperplasia (NRH). Aims: To assess and characterize the biochemical, radiological and histological markers of liver disease in patients with XLA along with hepatic hemodynamics and endoscopic follow-up. Methods: Patients with genetically confirmed XLA were evaluated for continued management from January 1990 to May 2013. Patients were followed with biomarkers of hepatic inflammation, synthetic function, portal hypertension and radiologic imaging. When clinically indicated liver biopsies, HVPG measurements, and endoscopies were performed. Results: Seven patients with XLA were evaluated (7 males, 5 Caucasian, 1 Asian, 1 African American) with a mean age of 29 years (range 23 to 49), mean BMI 26.8 (range 18.9 to 36.4) and a mean age of diagnosis of 5 years (range 1.4 to 9). No patients tested positive for viral hepatitis by DNA or RNA quantitation. On liver histopathology, 5 patients had NRH, 2 of whom had NRH and NASH, 1 patient had steatosis and 1 had no significant pathology. Compared to those without NRH, patients with NRH had elevated HVPG (9.8 vs. 2.0 mm Hg, p=0.005), hepatomegaly (20.3 vs. 14.8 cm, p=0.02) and splenomegaly (mean 16.1 vs. 10.7 cm, p=0.01). All patients with NRH also had evidence of portal hypertension (5 portal hypertensive gastropathy, 3 dilated gastrointestinal tract collateral vessels, 2 with ascites). Patients with NRH had lower platelet counts (63K vs. 176 K/uL, p<0.001), lower albumin (3.0 vs. 4.0 g/dL, P=0.008), lower total protein (5.3 vs. 7.6 g/dL, p=0.016), higher alkaline phosphatase (307 vs. 65 U/L, p=0.02) and higher direct bilirubin (0.32 vs. 0.1 mg/dL, p=0.047). On mixed model repeated measure regression, patients with NRH demonstrated a significant platelet decline over time as compared with patients without NRH (p=0.0056). Conclusions: Liver enzyme abnormalities are seen in XLA and are often attributed to drug hepatotoxicity or infection. However, these patients are also susceptible to other liver diseases such as NASH or NRH, a noncirrhotic portal hypertensive liver disease. As patients with XLA continue to live longer, understanding their evolving hepatic pathology is critical both for their care and may help model the biology of NRH.

Disclosures:

The following people have nothing to disclose: Christopher Koh, Gulbu Uzel, Sergio Rosenzweig, Xiongce Zhao, David E. Kleiner, T. Jake Liang, Steven M. Holland, Theo Heller

1390

Acute Kidney Injury Network (AKIN) criteria in the detection of renal failure in patients with cirrhosis, ascites and a serum creatinine < 1.5 mg/dl

Silvia Rosi1, Salvatore Piano1, Filippo Morando1, Silvano Faso-lato1, Marta Cavallin1, Elisabetta Gola1, Sara Montagnese1, Antonietta Sticca1, Angelo Gatta1, Paolo Angeli1,2;

1Department of Medicine DIMED, University of Padova, Padova, Italy; 2Depart-ment of Medicine DIMED, Unit of Medical Emergencies in Liver Transplantation, University of Padova, Padova, Italy

Background and aims: The assessment of renal function is critical in the management of patients with cirrhosis and ascites. Renal failure was defined as a serum creatinine (sCr) ≥ 1.5 mg/dl in these patients. Unfortunately sCr is not an accurate marker of glomerular filtration rate (GFR) in patients with cirrhosis, as a result some of them could have a reduced GFR despite a sCr < 1.5 mg/dl Recently it has been proposed the adoption of AKIN criteria, becouse they could detect promptly an impairment of renal function in these patients. When a baseline value for sCr is not available, AKIN network proposed to estimate it using the Modification of Diet in Renal Disease (MDRD) study equation assuming baseline eGFR is 75 ml/min per 1.73 m2 However this strategy has never been evaluated in patients with cirrhosis. The aims of our study were: a) to evaluate GFR in patients with cirrhosis, ascites and sCr < 1.5 ml/min, b) to evaluate the ability of AKIN criteria as a predictor of GFR ≤ 60 ml/min in these patients. Methods: we analyzed prospectively the data of 216 consecutive cirrhotic patients (150 males, 66 females; mean age 58 ± 9.6 years) with ascites and serum creatinine < 1.5 mg/dl. For each patient, blood and urine samples were evaluated on the fifth day after the withdrawal of diuretics and the beginning of a 90 mmol/day Na diet. GFR was calculated using inulin clearance (INU). Estimated GFR (eGFR) was evaluated using CKD-EPI and MDRD7 equations. Baseline sCr was estimated using the MDRD equation assuming baseline eGFR was 75 ml/min per 1.73 m2. Plasma renin activity (PRA) was assessed by RIA. Results: Mean GFR was 86 ± 30.9, 84.5 ± 19.7 and 83.4 ±25.3 ml/min using INU, CKD-EPI, MDRD7 respectively. 43 patients (19.9%) had a GFR ≤ 60 ml/min. Patients with GFR ≤ 60 ml/min showed an higher three month mortality rate with respect to patients with GFR < 60 ml/min (11.6 vs 2.9% p= 0.029). When baseline sCr was estimated using the MDRD equation, 19 patients met AKIN criteria for AKI (8.8%), but only 9 of them (47.4%) showed a GFR ≤ 60 ml/min. As a result AKIN criteria indentified only 20.1% of patients with GFR ≤ 60 ml/min. Three month mortality was not significantly different in patients with AKI vs no AKI (0 vs 5%). At multivariate analysis PRA was the only independent predictor of GFR ≤ 60 ml/min (OR= 1.072, CI= 1.021–1.124; p<0.01). Conclusions: creatinine based formulas are inaccurate in the estimation of GFR in patients with cirrhosis, ascites and sCr < 1.5 mg/dl. As a consequence, AKIN criteria with the MDRD-based estimation of baseline sCr are not useful in the identification of patients with a GFR ≤ 60 ml/min.

Disclosures:

The following people have nothing to disclose: Silvia Rosi, Salvatore Piano, Filippo Morando, Silvano Fasolato, Marta Cavallin, Elisabetta Gola, Sara Montagnese, Antonietta Sticca, Angelo Gatta, Paolo Angeli

1391

Can computerized brain training games be used to identify early cognitive impairment in cirrhosis?

Erica Tartaglione1, Mark Derleth2, Lei Yu2, George N. Ioannou1,2;

1Veterans Affairs Puget Sound Health Care System, Seattle, WA; 2University of Washington, Seattle, WA

Objectives We evaluated whether commercially available, computerized “brain-training” games can be used to identify subtle cognitive impairments in patients with cirrhosis. Methods We compared patients with cirrhosis who did not have overt encephalopathy (n=31), patients with pre-cirrhotic chronic liver disease (n=28) and normal controls without liver disease (n=16) with respect to their scores on the number connection test-A (NCT-A), the Inhibitory Control Test (ICT) and five, short (~2 minutes), brain-training games that were administered on an Apple iPad and tested different cognitive domains. Results Patients with cirrhosis had similar scores to patients with pre-cirrhotic liver disease and slightly worse scores than normal controls in the NCT-A and the ICT, although these differences were not statistically significant. In contrast, patients with cirrhosis had significantly worse scores than patients with precirrhotic liver disease and even more so than normal controls in all five of the brain training games. After adjustment for age and educational attainment, these differences remained significant for two of the tests, “Color Match” which is a version of the Stroop test and measures attention, and “Memory Matrix”, which measures visuospatial memory. The area under the ROC curve discriminating cirrhosis from pre-cirrhotic liver disease was 0.56 (95% CI 0.41–0.72) for the ICT and 0.58 (95% CI 0.43–0.73) for the NCT-A indicating no discrimination, while it was 0.75 (95% CI 0.63–0.87) for “Color Match” and 0.77 (95% CI 0.64–0.90) for “Memory Matrix”, indicating good discrimination. Conclusions Short, brain-training games administered on an iPad can be used as psychometric tests to detect subtle cognitive impairments in patients with cirrhosis without overt encephalopathy that could not be detected by the NCT-A or the ICT.

Disclosures:

The following people have nothing to disclose: Erica Tartaglione, Mark Derleth, Lei Yu, George N. Ioannou

1392

Procalcitonin is a valid marker of infection in cirrhosis patients with hepatocellular carcinoma after transarterial chemoembolization

Seo Young Yang1, Wonhyeong Park1, Moon Hyung Lee1, Bokyong Choi1, Chi Woon Cha1, Tae Gyoon Kim1, Tae Kyu Lim2;

1Gastroenterology, Internal Medicine, Veterans Health Service Medical Center, Seoul, Republic of Korea; 2Oncology, Internal Medicine, Veterans Health Service Medical Center, Seoul, Republic of Korea

Background/Aims: Bacterial infections are life-threatening complications in patients with cirrhosis. But it is rather difficult who patients with hepatocellular carcinoma after transarterial chemoembolization. The goal of this study was to determine the ability of serum procalcitonin in the diagnosis of bacterial infection in cirrhosis patients with hepatocellular carcinoma after chemoembolization. Methods: 118 patients with HCC after TACE were analysed and stratified into three groups according bacteriological and cirrhotic finding; cirrohotic wih (group A = 24) and without (group B =73) infection, and non-cirrhotic and non-infected (grouop C = 21). This retrospective cohort study which was conducted from June 2010 to May 2012. Measurement of serum procalcitonin and CRP level was performed on during admission after transarterial chemoembolization. Results: Serum procalcitonin levels were significantly higher in cirrhotic patients with bacterial infection (Group A; 3.6 ng/ml [0.5–23.4]) rather than without infection (Group B; 0.7 ng/ml [0.1–6.7]) and non-cirrhotic and non-infected (Group C; 0.4 ng/ml [0.1–1.4]), respectively. Using a cut-off level of 0.64 ng/ml, provided the most accurate in identifying patients with infection (AUC:0.93, Sensitivity: 95 %, Specificity: 77 %). However, serum CRP level was less sensitive and specific for the diagnosis of infection (AUC:0.81, Sensitivity: 91 %, Specificity: 65 %). Conclusions: Serum procalcitonin is a useful marker to predict the clinically significant bacterial infection in patients with hepatocellular carcinoma after transarterial chemoembolization.

Disclosures:

The following people have nothing to disclose: Seo Young Yang, Wonhyeong Park, Moon Hyung Lee, Bokyong Choi, Chi Woon Cha, Tae Gyoon Kim, Tae Kyu Lim

1393

Frequency of Liver Disease in HIV-infected Patients with Thrombocytopenia in the Post HAART Era

Andrew Zimmerman, Valerie Martel-Laferriere, Douglas T. Dieterich; Mount Sinai School of Medicine, New York, NY

Introduction: HIV providers often overlook thrombocytopenia, considering it a normal complication of HIV infection. In the pre-HAART era, idiopathic thrombocytopenic purpura secondary to HIV was a common cause of thrombocytopenia. However, the continued prevalence of thrombocytopenia in the post HAART era should prompt us to look elsewhere for causes of this condition. We know that liver disease is strongly correlated with thrombocytopenia. The prevalence of liver disease is increased among HIV-infected patients. The aim of this study is to describe the association between liver disease and thrombocytopenia in HIV-infected patients. Methods: This is a cross-sectional study of de-identified data done at Mount Sinai Hospital. The data warehouse was queried to identify all HIV-infected patients seen between February 1 st and July 31 st 2012. Demographic data, concomitant diagnosis, and laboratory values were extracted. A FIB-4 score ≥ 3.25 was used to identify patients with advanced fibrosis/cirrhosis. Data were analysed in SPSS. Results: During the study period, 3,130 HIV-infected patients were seen. The prevalence of platelet counts (PLT) ≤150, ≤100, and ≤50 ×10Λ9/L were 25.2%, 5.8%, and 1.5% respectively. The prevalence of liver disease and abnormal FIB-4 scores are presented in the table. Compared to the 2,341 patients with normal PLT, the 789 patients with PLT ≤150 ×10Λ9/L were more likely to be male (597 (75.7%) vs. 1624 (64.9%); p=0.001) and older (median: 52.6 (IQR: 45–59) vs. 47.2 (37–54) years; p<0.001). Patients with PLT ≤150 ×l0Λ9/L were also significantly more likely to have been diagnosed with liver disease (51.1% vs. 21.9%; p<0.001), had an abnormal FIB-4 score (27.4% vs. 1.4%; p<0.001), and had higher AST (30.9 (19.5–50.0) vs. 25.7 (20.0–33.0) U/L; p<0.001) and ALT (36.0 (25.0–58.0) vs. 23.9 (17.0–35.0) U/L; p<0.001). Among those not known to have liver disease, patients with PLT ≤150 ×l0Λ9/L were more likely to have an abnormal FIB-4 score (12.4% vs. 0.5%; p<0.001). Conclusions: We found that thrombocytopenia in HIV-infected patients is associated with a very significant increase in the likelihood of liver disease. An elevated FIB-4 score was found in 12.4% of the patients with PLT ≤150 ×10Λ9/L without a diagnosis of liver disease, suggesting an under diagnosis of liver disease in HIV-infected patients.

 PLT ≤ 150 ×l0Λ9/L (n=789)PLT ≤ 100 ×l0Λ9/L (n=181)PLT ≤ 50 ×l0Λ9/L (n=46)
Prevalence of patients with a liver condition403/789 (51.1%)145/181 (80.1%)41/46 (89.1%)
Prevalence of patients with an abnormal FIB-4 score216/789 (27.4%)126/181 (69.6%)46/46 (100%)
Prevalence of patients without a liver condition but with an abnormal FIB-4 score48/338 (12.4%)15/36 (41.7%)5/5 (100%)

Disclosures:

Douglas T. Dieterich -Advisory Committees or Review Panels: Gilead, Genentech, Janssen, achillion, idenix, Merck, Tobira, Boehringer Ingelheim, TIbotec, Inhibitex, Roche, Vertex

The following people have nothing to disclose: Andrew Zimmerman, Valerie Martel-Laferriere

1394

Low Levels of 25 Hydroxy Vitamin D Are Independently Associated With the Risk of Infection in Cirrhotic Patients

Rodolphe Anty1,2, Marie Tonohouan1, Patricia Panaia-Ferrari1, Thierry Piche1, Alexandre Pariente3, Philippe Gual1,2, Albert Tran1,2;

1 Centre Hospitalier universitaire de Nice, Nice, France; 2INSERM 1065, Nice, France; 3CH de Pau, Pau, France

Low levels of vitamin D are associated with a higher mortality in patients with cirrhosis . Reasons are not known. Active metabolite of vitamin D is implicated in innate and acquired immunity. The purpose of this study was to assess the levels of vitamin D in cirrhotic patients with and without bacterial infection. Patients and methods: 25 OH vitamin D was assessed in consecutive cirrhotic patients hospitalized in our hepatology unit from 11/2010 to 11/2012 using an immuno-assay (Diasorin, Inc, Stillwater, USA). Infected cirrhotic patients diagnosed according to clinico-biological and bacteriological exams were compared to non infected patients. Results: Eighty-eight Patients mainly men (66%), aged of 59[51–69] years with BMI 24.4 [20.8–28.8] kg/m2 were included. Thirty-eight infected were compared to fifty non infected patients. Causes of cirrhosis were mainly alcohol (70%), hepatitis C (10%) or both (9%) and were similar in both groups. Infections were characterized by bacteriemia (21%), urinary tract infections (24%), spontaneous bacterial peritonitis (29%), pneumonia (8%), cutaneous infections (5%), and others (13%). Compared to non infected patients, infected cirrhotic patients had lower level of 25 OH vitamin D (6.6[4.8–11.9] vs 11.2 [6.0–17.0] ng/mL, P=0.01), higher level of Child-Pugh score (11 [9–13] vs 7 [5–9], P<0.0000001), pulse rate (80 [70–100] vs 75 [60–80], P=0.004), body temperature (37.5 [37–38.2] vs 37[36.8–37.3] °c, P=0.002), Aspartate amino transferase (92.5 [55–143] vs 53.5 [36–87.3] IU/L, P=0.013), Alanine Amino transferase (54.5[28–80] vs 34.5 [23–55] IU/L, P=0.04), leucocytes count (7700[5525–10175] vs 5400 [4000–7850] /mm3, P=0.008) and C reactive protein (27.3 [12.7–52] vs 8.4 [2.1–14.1] ng/mL, P=0.00002. A higher Child-Pugh score (OR=2.2395%CI[1.45–3.4], P=0.002) and a lower level of 25 OH vitamin D (OR=0.85 [0.74–0.98], P=0.039) were the only independent parameters associated with infections in cirrhotic patients in a logistic regression analysis including all the parameters significantly associated with infection in univariate analysis. Conclusion: Low level of 25 OH vitamin D was independently associated with bacterial infections in cirrhotic patients. The impact of 25 OH vitamin D supplementation on infection rate and death in deficient cirrhotic patients should be assessed in randomized trials.

Disclosures:

The following people have nothing to disclose: Rodolphe Anty, Marie Tonohouan, Patricia Panaia-Ferrari, Thierry Piche, Alexandre Pariente, Philippe Gual, Albert Tran

1395

Prevalence and outcomes of infections amongst hospitalized patients with cirrhosis (1998 to 2007): A population based study

Habeeb Salameh1, PatrickS. Kamath2, Whitney Jennings3, KirkB. Russ4, Ashwani K. Singal3;

1Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX; 2Department of internal Medicine, Division of Gastroenterology, Mayo Clinic, Rochester, MN; 3Department of internal Medicine, Division of Gastroenterology, University of Alabama, Birmingham, AL; 4Department of Internal Medicine, University of Alabama, Birmingham, AL

Background and aims: Bacterial infection is an important determinant of mortality in patients with cirrhosis. We analyzed frequency of infections and impact on mortality in hospitalized cirrhotics. Methods: Nationwide Inpatient Sample (1998–2007) was queried for admissions with cirrhosis and examined for a) community acquired infections (CAI): spontaneous bacterial peritonitis (SBP), urinary tract infection (UTI), cellulitis, pneumonia, and C. difficile associated colitis (CDAC) and b) hospital acquired infections (HAI): catheter associated UTI (CAUTI), central line associated blood stream infection (CLABSI) and ventilator associated pneumonia (VAP). In-hospital mortality (IHM), length of stay (LOS), and total charges were analyzed. Results: Of 742,391 admissions with cirrhosis (47% alcoholic), 186,635 (23%) and 6322 (1%) had CAI and HAI respectively. Between 1998 and 2007, there was trend of increasing prevalence for CAI (20–25%) and HAI (0.6–0.9%). Of CAI, UTI was most prevalent (9–12%) followed by cellulitis (5–6%), sepsis (6%), SBP (2–3%), and pneumonia (1–2%). About 6% of patients were discharged with sepsis diagnosis, 56% of which without an identified source. CAI was most prevalent amongst cirrhotics with ascites or with renal insufficiency (RI): 20–25% and 38–43% respectively. Prevalence increased in all subgroups except for patients with variceal hemorrhage (12% in 1998 to 10% in 2007). Of HAI, CLABSI was most prevalent (0.5–0.8%) followed by CAUTI (0.08–0.12%) and VAP (0.01–0.05%). Prevalence of CDAC increased over 2 fold (0.7% in 1998 to 1.6% in 2007). Association of any infection with RI increased linearly from 12% in 1998 to 27% in 2007. IHM amongst infected cirrhotics was 14.7% (15% vs. 13%: HAI vs. CAI) and was about 3 fold higher compared to IHM in uninfected cirrhotics. Sepsis (38–42%), pneumonia (23–30%), SBP (16–22%), CLABSI (14–21%), and CDAC (11–16%) contributed most to IHM. Although, IHM decreased over time for CAI (18% to 14%) or HAI (16% to 13%), odds for IHM increased by 32% and 400% for CAI or sepsis respectively after controlling for liver disease complications and calendar year. LOS and hospital charges were higher amongst infected cirrhotics. Conclusions: Infection is a common complication amongst hospitalized cirrhotics and is associated with a) increasing frequency, b) substantial in-hospital mortality, c) increasing prevalence of renal insufficiency, and d) increased use of hospital resources. Prospective studies are suggested to identify patients at risk of infection, evaluate role of preventative interventions, and develop strategies to reduce renal insufficiency in these patients.

Disclosures:

The following people have nothing to disclose: Habeeb Salameh, Patrick S. Kamath, Whitney Jennings, Kirk B. Russ, Ashwani K. Singal

1396

Atrial Fibrillation after TIPS Predicts Poor Survival

Christopher Steevens, Jessamyn Blau, Benedict Maliakkal; University of Rochester, Rochester, NY

Background: Patients with advanced cirrhosis commonly have cardiac abnormalities but arrhythmia is rare. Transjugular intra-hepatic portosystemic shunt (TIPS) is performed to treat refractory ascites in patients with cirrhosis and is known to cause cardiovascular changes. We assessed for atrial fibrillation post-TIPS and its impact on patient survival. Methods: A review of 185 consecutive patients who received TIPS for refractory ascites was completed. Inclusion criteria were pre-TIPS sinus rhythm and post-TIPS ECG within one year. Exclusion criteria were liver transplant within one year post-TIPS. 64 patients met the criteria. Pre-TIPS variables and post-TIPS survival of patients with atrial fibrillation were compared to subjects who retained sinus rhythm. Results: Within 1 year post-TIPS, 14% of patients developed atrial fibrillation. Of individuals who developed this arrhythmia, pre-TIPS age, sex, MELD, cirrhosis etiology, hepatic venous pressure gradient, left atrial size, and body mass index were similar compared to individuals who retained sinus rhythm. Factors associated with arrhythmia development included history of hypertension (p=0.016) or coronary artery disease (p=0.01). One-year survival was significantly decreased for patients who developed atrial fibrillation post-TIPS (11% vs 58%; p<0.01). Discussion: Atrial fibrillation after TIPS is common and unrelated to the etiology of cirrhosis or severity of liver disease. Prior cardiovascular co-morbidity is associated with post-TIPS atrial fibrillation. Hemodynamic changes following TIPS could trigger this arrhythmia in susceptible individuals. This study identifies atrial fibrillation as a new cardiac complication after TIPS which then predicts dismal patient survival.

image

Disclosures:

The following people have nothing to disclose: Christopher Steevens, Jessamyn Blau, Benedict Maliakkal

1397

Can FOUR Score Help to Diagnose Hepatic Encephalopathy ?

Sarah Mouri1, Marika Rudler1, Géraldine Rousseau4, Hedi Benos-man1, Nicolas Weiss2,3, Dominique Thabut1;

1Hepatology ICU, AP-HP, hôpital Pitié-Salpêtrière, Paris, France; 2Unité de réanimation neurologique, pôle des maladies du système nerveux, AP-HP, hôpital Pitié-Salpêtrière, Paris, France; 3Institut Hospitalo-Universitaire de Neurosciences, IHU-A, AP-HP, hôpital Pitié-Salpêtrière, Paris, France; 4Liver transplantation, AP-HP, hôpital PitiéSalpêtrière, Paris, France

Background and aims : Overt Hepatic Encephalopathy (HE) is a severe complication of cirrhosis, which includes several neurological manifestations ranging from asterixis and/or shortened attention span to coma. There is no gold standard for the diagnosis of overt HE. Severity of HE is usually assessed using West-Haven (WH) scale. The use of some more generalistic score like the Glasgow coma scale (GCS) is useful in ICU patients. However, GCS has some shortcomings : some responses are poorly reproductible, verbal response is sometimes cumbersome to evaluate and it does not account for brainstem reflexes. A new coma scale, the Full Outline of UnResponsivenness (FOUR) score has recently be proposed. Nowadays, the FOUR score is the most validated coma scale. It includes motor, eyes, brainstem responses and respiration.The aim of this study was to assess the FOUR in cirrhotic patients in a hepatology ICU. Methods : All consecutive patients admitted for a complication of cirrhosis between June 2012 and April 2013 were examined by a senior neurointensivist in order to assess Glasgow Coma Scale (GCS) and FOUR score. Presence of overt HE was assessed by a senior hepatologist unaware of neurologist's findings. CHESS and HESA status were assessed. In case of unusual clinical findings, EEG, CT scan and/or MRI were performed in order to rule out any other neurological disorders. Results : 68 patients were included (Male gender=75% ; age=58 ±11; aetiology of cirrhosis : alcohol=68%, viral=26%, other=6% ; Child-Pugh score : A=13%/B=15%/C=72% ; MELD score=18±7 ; presence of hepatocellular carcinoma=16%). 36 patients (53%) had overt EH (CHESS : 3.13±3.10 and HESA : 1.94±1.24) and 32 (47%) no overt HE (CHESS : 1.00±2.13 and HESA : 0.32±0.48). Overt HE compared to no overt HE patients presented with decreased total GCS (12.9±0.5 vs 14.9±0.5, p=0.0025), decreased motor response (5.4±1.6 vs 6.0±0.0, p=0.03), decreased verbal response (4.1±1.4 vs 4.9±0.3, p=0.004) and decreased eyes response (3.3±1.0 vs 4.0±0.2, p=0.001). Similarly, overt HE compared to no overt HE patients presented with decreased total FOUR score (14.0±3.4 vs 16.0± 0.01, p=0.002), decreased eyes response (3.2±1.3 vs 4.0±0.1, p=0.001), decreased motor response (3.3±1.1 vs 4.0±0.0, p=0.001), and decreased respiration response (3.61 ±1.0 vs 4.0±0.0, p=0.04) but no difference in brainstem response (4.0±0.2 vs 4.0±0.0, p=NS). Conclusion : FOUR score seems applicable in cirrhotic patients as well as GCS. The newly proposed FOUR score could be helpful in severe hepatology ICU patients since it enables to assess respiration, to detect herniation, and does not need langage assessment.

Disclosures:

Marika Rudler - Speaking and Teaching: Gilead Sciences, BMS, Gore, Eumedica

The following people have nothing to disclose: Sarah Mouri, Géraldine Rousseau, Hedi Benosman, Nicolas Weiss, Dominique Thabut

1398

Low-grade hepatic encephalopathy: does the Mini Mental State Examination help?

Michela Corrias, Matteo Turco, Michele De Rui, Angelo Gatta, Paolo Angeli, Carlo Merkel, Piero Amodio, Sami Schiff, Sara Montagnese; Department of Medicine, University of Padova, Padova, Italy

The Mini Mental State Examination (MMSE) has been utilised for the quantification of hepatic encephalopathy (HE). However, its threshold of abnormality has not been formally tested in patients with cirrhosis and its diagnostic/prognostic validity remains unknown. The standard MMSE threshold utilised for the diagnosis of mild cognitive impairment is 24. The aim of this study was to assess the diagnostic/prognostic validity of MMSE in a large group of well-characterised outpatients with cirrhosis. One-hundred-and-ninety-one patients underwent clinical assessment (HE grading based on the West Haven criteria), MMSE, quantified EEG and paper-and-pencil psychometry (PHES); 117 were followed up prospectively for 8±5 months in relation to the occurrence of HE-related hospitalisations. On the day of study, 73 (62%) patients had grade I/II overt HE, 81 (69%) had abnormal EEG and 67 (57%) abnormal PHES; 103 (88%) had a history of HE. Average MMSE was 26.6±3.5; 22 (19%) patients had abnormal MMSE based on the standard threshold of 24. Patients with grade I/II HE had worse MMSE performance compared to those with no clinical signs of HE (25.5±4.1 vs. 27.6±2.5, p<0.0001). Similarly, patients with abnormal EEG/PHES/history of HE had worse MMSE performance than their counterparts with normal test/negative history (25.7±4.2 vs. 27.3±2.7; p<0.01; 25.5±3.2 vs. 27.9±1.8, p<0.0001; 26.3±3.7vs. 27.4±2.6, p<0.05, respectively). Based on the above results, MMSE thresholds of 26 and 27 were tested against abnormalities in clinical/EEG/PHES indices and significant associations were observed (MMSE-26 vs. overt HE/EEG/PHES abnormalities: χ2 = 19, p<0.0001; χ2=7, p<0.01; χ2=23, p<0.00001, respectively; MMSE-27 vs. overt HE/EEG/PHES abnormalities: χ2 = 14, p<0.001; χ2 = 13, p<0.001; χ2=28, p<0.00001, respectively). An MMSE threshold of 26 was also a significant predictor of HE-related hospitalisation over the follow-up period (Cox-Mantel: p=0.001). When the MMSE domains where considered separately, those which correlated most significantly with standard HE indices where spatial orientation, writing, working memory and drawing-copying (i.e. mean Z PHES vs. drawing-copying: R=0.40, p<0.001). In conclusion, the MMSE might be helpful in quantifying low-grade HE, most likely with an adjusted threshold of 26.

Disclosures:

The following people have nothing to disclose: Michela Corrias, Matteo Turco, Michele De Rui, Angelo Gatta, Paolo Angeli, Carlo Merkel, Piero Amodio, Sami Schiff, Sara Montagnese

1399

Pathogenesis of solute-free water retention in experimental ascitic cirrhosis: is vasopressin (ADH) the only agent to blame?

Giovanni Sansoe1, Manuela Aragno2, Raffaella Mastrocola2, Giulio Mengozzi3, Rhys Whomsley4, Maurizio Parola2;

1Gastroenterology Unit, Gradenigo Hospital, Torino, Italy; 2Department of Clinical and Biological Sciences, University of Torino, Torino, Italy; 3Clinical Biochemistry Laboratory, San Giovanni Battista Hospital, Torino, Italy; 4Division of Exploratory Projects, Shire Pharmaceutical Development Ltd., Basingstoke, United Kingdom

Background. Sympathetic nervous system activation and overproduction of angiotensin II reduce tubular fluid delivery to the distal nephron and limit the renal capacity to excrete solute-free water. In ascitic cirrhosis, non-osmotic hypersecretion of vasopressin (ADH) is thought to rule free water retention and dilutional hyponatremia, but ADH V2 receptor antagonists are not beneficial in the long-term treatment of ascites. Aim. We test the hypothesis that free water retention in experimental ascitic cirrhosis could depend on proximal tubular fluid retention rather than on ADH hypersecretion. Methods. Hormonal status, renal function and tubular free water reabsorption (TFWR=osmolar clearance-urinary flow rate) were assessed in 6 groups of 10 rats with ascitic cirrhosis: rats with cirrhosis due to 13-week CCl4 administration (group G1), cirrhotic rats receiving daily diuretics (0.5 mg/kg furosemide plus 2 mg/kg K+-canrenoate during the 11 th-13th weeks of CCl4) (G2), cirrhotic rats treated with the above diuretics associated with daily guanfacine oral prodrug, an α2 adrenergic receptor agonist and sympatholytic agent, 2 (G3), 7 (G4), or 10 mg/kg (G5), during the 11 th-13th weeks of CCl4. G6 included ascitic rats treated with diuretics and daily SSP-004240F1, a vasopressin V2 receptor antagonist, 1 mg/kg. Results. Sodium excretion was lower in G1 than in all other groups (all P<0.05). TFWR was higher in G1 (untreated cirrhosis, 32 ±11 microL/min) than in G6 (diuretics + V2 antagonists, 21 ± 9 microL/min) or G3 (diuretics + guanfacine 2 mg/kg, 20 ± 8 microL/min) (all P<0.03). The addition of guanfacine (2 mg/kg) in G3 to diuretics (G2) reduced serum norepinephrine from 423 ± 122 to 211 ± 111 ng/L (P<0.01), plasma renin activity from 25 ± 12 to 9 ± 7 ng/mL/h (P<0.03), and TFWR from 45 ± 18 to 20 ± 8 microL/min (P<0.01). In the population of 60 rats, TFWR did not correlate with ADH levels (r=0.02, P: n.s.), but showed significant correlations with plasma aldosterone (r=0.51, P<0.01), urinary potassium excretion rate (r=0.90, P<0.001), urinary flow rate (r=0.59, P<0.01) and osmolar clearance (r=0.93, P<0.001), which stresses that secondary aldosteronism, especially when stimulated by diuretics, exacerbates tubular free water retention. Conclusions. Counteracting catecholamines and angiotensin II effects is as effective as ADH V2 receptor blockade to blunt tubular free water retention in ascitic cirrhosis. If ADH secretion were the main cause of free water retention in advanced cirrhosis, ADH should cause extracellular volume expansion and paradoxical urinary sodium loss, and V2 receptor blockade should exacerbate and not ameliorate sodium retention.

Disclosures:

Giovanni Sansoe - Consulting: Shire Pharmaceuticals Ltd., Basingstoke, Hampshire, UK.

Rhys Whomsley - Employment: Shire Pharmaceutical Development; Patent Held/Filed: Shire Pharmaceutical Development; Stock Shareholder: Shire Pharmaceutical Development

Maurizio Parola - Independent Contractor: Shire Pharmaceutical Ltd, Basingstoke, UK

The following people have nothing to disclose: Manuela Aragno, Raffaella Mastrocola, Giulio Mengozzi

1400

Differences in minimal hepatic encephalopathy between alcoholic and viral compensated liver cirrhosis

Ki Tae Suk, Dong Joon Kim, Yunhyeong Lee, Chang Seok Bang, Yong Sub Lee; Hallym University College of Medicine, ChunCheon, Republic of Korea

Background: Minimal hepatic encephalopathy (MHE) is a mild form of HE that is defined as an abnormality in cognitive function presenting abnormality in psychometric tests without clinical symptoms. Few data are available about cognitive function in patients with liver cirrhosis (LC) who had no history of HE. Especially, since alcohol induces organic changes in the frontal cortex primarily involved in cognition, we can suppose that cognitive function and treatment may be different between alcoholic and viral compensated LC. In this study, we evaluated the difference of cognitive function in 2 groups. Methods: From October 2011 to December 2012, 78 patients (virus:36 and alcohol:42) with compensated LC (child-pugh score≤6) prospectively enrolled. Patients who presented previous HE, neurologic sign, or old age (> 60 years) were excluded. liver cirrhosis was diagnosed by image study, endoscopy, or liver biopsy. We evaluated characteristics and neuropsychological tests including attention by digit-span forward/backward, language by Korean-Boston naming test, visuospatial function by Ray-complex figure test (RCFT) copy score, verbal memory by Seoul-verbal learning test, visual function by RCFT delayed recall, and frontal/executive function by controlled oral ward association test, Korean-color word Stroop test, and Korea-Mini mental status examination (K-MMSE). Results: The mean age of patients is 48.7±6.1 years. Between alcoholic and viral LC, there were no significant differences in education-period and laboratory findings except γGT (366±390 and 160±160 IU/L) and albumin (3.7±0.7 and 4.1 ±0.4 g/dL). In the neuropsychological tests, visuospatial functions by RCFT copy score (65.8±34.7 and 83.6±11.2), frontal/executive function by Korean-color word Stroop test (35.2±34.8 and 67.3±34.7) and K-MMSE (recall [1.9±0.9 and 2.5±0.5] and total [25.9±3.3 and 28.1 ±1.5]) showed worse scores in patients with alcoholic LC (p<0.05). Other neuropsychological tests did not show difference (p>0.05). Conclusions: Visuospatial functions and frontal lobe/executive function is significantly impaired in patients with alcoholic LC compared with viral LC. As a result, in patients with alcoholic LC, tests and treatment for the prevention of MHE might be considered.

Disclosures:

The following people have nothing to disclose: Ki Tae Suk, Dong Joon Kim, Yunhyeong Lee, Chang Seok Bang, Yong Sub Lee

1401

Hyponatremia is a significant risk factor for minimal encephalopathy in patients with liver cirrhosis

Sun Young Yim1, Yeon SeokSeo1, TaeJung Yun1, Seok Bae Yoon1, Ji Hoon Kim1, Hyonggin An2, Hyung Joon Yim1, Jong Eun Yeon1, Kwan Soo Byun1, Soon Ho Um1, Chang Duck Kim1, Ho Sang Ryu1;

1Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea; 2Biostatistics, Korea University College of Medicine, Seoul, Republic of Korea

Backgrounds/Aims: The clinical significance of minimal hepatic encephalopathy is emphasized in cirrhotic liver patients since it not only affects quality of life but also disease prognosis. There are several studies showing correlation between hyponatremia and overt HE but none has been reported in MHE patients. Therefore we aimed to clarify the association between hyponatremia and MHE in cirrhotic liver patients. Methods: Cirrhotic patients without overt HE were enrolled in this study. Laboratory tests including serum Na level and PHES were performed. MHE was defined as ≤-5 of PHES score. Hyponatremia was defined as serum Na level <135 mmol/L. The liver function was assessed by Child-Pugh classification and MELD score. Results: A total of 176 patients with liver cirrhosis were enrolled in this study. Age was 55.5±8.5 years and male was 119 (67.6%). The most common cause of liver disease was chronic hepatitis B (70.5%), followed by alcoholic liver disease (18.2%) and chronic hepatitis C (6.8%). Child-Pugh score and MELD scores were 6.0±1.7 and 10.7±5.9, respectively, and 134 (76.1%) and 42 (23.9%) patients were classified as Child-Pugh grade A and B/C, respectively. Serum Na level was 139.2±3.1 mmol/L. Hyponatremia was noted in 16 patients (9.1%) and its prevalence differed significantly according to the Child-Pugh grade: grade A, 3.0%; grade B, 19.4%; and grade C, 54.5% (P<0.001). PHES score was-3.1 ±3.5. PHES score differed significantly according to the Child-Pugh grade and hyponatremia. Forty-six patients (26.1%) were diagnosed as MHE. Hyponatremia (β, 1.845; OR, 6.326; 95% CI, 1.780–22.473; P=0.004) and Child-Pugh grade B/C ( β, 1.232; OR, 3.428; 95% CI, 1.521–7.726; P=0.003) were significantly associated factors with MHE. Conclusions: Hyponatremia was significantly associated with MHE in patients with liver cirrhosis. Therefore, correction of hyponatremia is expected to/may improve MHE as well as quality of life.

Disclosures:

Hyung Joon Yim - Grant/Research Support: GSK Korea, Handok Pharm, Gilead Korea; Speaking and Teaching: BMS Korea

The following people have nothing to disclose: Sun Young Yim, Yeon Seok Seo, Tae Jung Yun, Seok Bae Yoon, Ji Hoon Kim, Hyonggin An, Jong Eun Yeon, Kwan Soo Byun, Soon Ho Um, Chang Duck Kim, Ho Sang Ryu

1402

The burden of sexual dysfunction in female patients with liver cirrhosis

Rafael Paternostro1, Remy Schwarzer1, Michaela M. Bayerle-Eder2, Markus Peck-Radosavljevic1, Arnulf Ferlitsch1;

1Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; 2Division of Endocrinology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

Background & Aims: Patients with liver cirrhosis are known to have several physical problems due to their disease, especially data on their sexual function is rare. Methods: 39 female patients diagnosed with liver cirrhosis filled the FSFI 19(Female Sexual Function Index) questionnaire to evaluate sexual dysfunction (SD). Child-Pugh Score (CPS), MELD-Score, comorbidi-ties and current medication were recorded. Hepatic Encephalopathy and a Karnofsky Index of <90 were exclusion criterias. Results: Mean age of patients was 49.29 (+-15) years. The mean BMI was 25.16 (+-5). 69.7% were in a relationship when filling the scoring sheet. Median FSFI score was 12.4 (+-11.9). SD (FSFI-Score <27) was found in 76.9% of the patients. 28.6% of the patients were found in CPS stage A, 57.1% in B and 14.3 % in stage C. FSFI scores worsened significantly with increasing CPS (p=0.022). The median MELD Score was 11.8 (+-6.4). FSFI was significantly lower with higher MELD score(p=0.023). 30.6% of the patients were under betablocker-therapy for portal hypertension (PH) but no correlation with the FSFI scores could be found. 38.4% of the patients were decompensated with ascites and within this group 86.6% were found with SD. 66.6% of compensated cirrhotics had SD . 15.6% were suffering from diabetes but correlation to SD could not be found. Von-Willebrand-Factor antigen, a non-invasive marker of PH (median 369) correlated significantly with sexual dysfunction (p=0.037). FSFI was lower with increasing age (p=0.001). Conclusion: Sexual Dysfunction seems to be present in more than three quarters of female cirrhotics. Betablocker-therapy and diabetes do not seem to play a key role in this patients sexual dysfunction. Both impaired hepatic synthesis and portal hypertension deteriorate sexual function. Word count abstract: 271 Keywords: FSFI 19, liver cirrhosis, sexual dysfunction, von-Willebrand-Factor Antigen

Disclosures:

Markus Peck-Radosavljevic - Advisory Committees or Review Panels: Bayer, Gilead, Janssen, BMS; Consulting: Bayer, Boehringer-Ingelheim, Jennerex, Eli Lilly; Grant/Research Support: Bayer, Roche, Gilead, MSD; Speaking and Teaching: Bayer, Roche, Gilead, MSD, Eli Lilly

The following people have nothing to disclose: Rafael Paternostro, Remy Schwarzer, Michaela M. Bayerle-Eder, Arnulf Ferlitsch

1403

Plasma copeptin as prognostic biomarker in patients with cirrhosis

Elsa Solà1, Rebeca Moreira1, Chiara Elia1, Pablo Ruiz1, Ezequiel Rodriguez1, Rogelio Barreto1, Raquel Cela1, Isabel Graupera1, Xavier Ariza1, Manuel Morales-Ruiz2, Javier Fernandez1, Wladimiro Jiménez2, Vicente Arroyo1, Pere Gines1;

1Liver Unit, Hospital Clinic, Barcelona, Spain; 2Biochemistry and Molecular Genetics Service, Hospital Clinic, Barcelona, Spain

Background&Aims: Copeptin is a stable peptide secreted from the neurohypophysis derived from the vasopressin precursor, the plasma levels of which reflect vasopressin release. Copeptin levels have prognostic value in a variety of diseases, but information in cirrhosis is scarce. Copeptin may have prognostic value in cirrhosis because it may reflect the degree of severity of impairment of systemic hemodynamics and kidney function. The current study was designed to test whether plasma copeptin may be useful as prognostic biomarker in cirrhosis. Patients and Methods: Prospective study of 324 consecutive patients with cirrhosis (mean age 60±11yr, 66% men, 56% alcoholic cirrhosis, MELD 16±9, Child-Pugh 9±2) seen at the clinic (n= 59) or hospitalized (n=265) for an acute complication of the disease. Demographic, clinical, laboratory data as well as plasma vasopressin and copeptin levels were collected at time of inclusion in the study. Main outcomes were a composite end-point of complications of cirrhosis (encephalopathy, infections, gastrointestinal bleeding, ascites, kidney failure, or shock) within 3 months after inclusion and 3-month transplant-free survival. Results: Plasma copeptin levels were higher in patients with decompensated than in patients with compensated cirrhosis (29±44 vs 6±6; p<0.001), and correlated directly with plasma vasopressin levels (r=0.61, p<0.0001), plasma renin activity (r=0.50, p<0.0001, n=59), serum creatinine concentration (r=0.57, p<0.0001), and MELD score (r=0.42, p<0.0001). Seventy-eight percent of patients developed complications during follow-up. A logistic regression model including individual variables showed that both plasma copeptin levels and serum sodium concentration were independent predictive factors of the composite end-point of complications (plasma copeptin and serum sodium in patients meeting and not meeting the composite end-point were: 33±49 vs 15±19 pmol/mL; 134±5 vs 136±5 mEq/L, respectively; p<0.05 for both). Among the 324 patients, 68 patients had died (21%) and 19 had been transplanted (6%) at the end of follow-up. The multivariate model that best predicted 3-month transplant-free survival included serum sodium, Child-Pugh score, leukocyte count, and plasma copeptin levels (AUC: 0.709, CI 0.634–0.785). Conclusions: Plasma copeptin levels are increased in decompensated cirrhosis and correlate with plasma vaso-pressin levels and the severity of the disease. Plasma copeptin levels are an independent predictive factor of disease progression and short-term survival in cirrhosis.

Disclosures:

Wladimiro Jiménez - Grant/Research Support: Ferring Research Institute

Vicente Arroyo - Speaking and Teaching: GRIFOLS

Pere Gines - Advisory Committees or Review Panels: Ferring ; Grant/Research Support: Sequana Medical, Grifols

The following people have nothing to disclose: Elsa Solà, Rebeca Moreira, Chiara Elia, Pablo Ruiz, Ezequiel Rodriguez, Rogelio Barreto, Raquel Cela, Isabel Graupera, Xavier Ariza, Manuel Morales-Ruiz, Javier Fernandez

1404

Long-term supplementation of oral branched-chain amino acid improves Model for End-Stage Liver Disease (MELD) score in advanced liver cirrhosis patients: A Korean nationwide multicenter study

Se Young Jang1, Jung Gil Park1, Yu Rim Lee1, EunJeong Kang1, Jun Young Choi1, Sun Young Ahn1, Soo Young Park1, Won Young Tak1, Young Oh Kweon1, Si Hyun Bae2, Jae Young Jang3, Do Young Kim4, June Sung Lee5, Ki Tae Suk6, In Hee Kim7, Heon Ju Lee8, Woo Jin Chung9, Byoung KukJang9, Jeong Ill Suh10, Jeong Heo11;

1Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 2Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 3Internal Medicine, College of Medicine, Soonchunhyang University, Seoul, Republic of Korea; 4Internal Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea; 5Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea; 6Internal Medicine, College of Medicine, Hallym University, Chuncheon, Republic of Korea; 7Internal Medicine, School of Medicine, Chonbuk National University, Chungju, Republic of Korea; 8Internal Medicine, College of Medicine, Yeungnam University, Daegu, Republic of Korea; 9Internal Medicine, School of Medicine, Keimyung University, Daegu, Republic of Korea; 10Internal Medicine, College of Medicine, Dongguk University, Gyeongju, Republic of Korea; 11 Internal Medicine, School of Medicine, Pusan National University, Pusan, Republic of Korea

Background/aims : Protein-calorie malnutrition is frequently observed in patients with advanced liver cirrhosis. The long-term supplementation of oral branched-chain amino acid (BCAA) is believed to improve hepatic functional reservoir, decreasing frequency of complications in liver cirrhosis. However, there are controversies on the potential benefit of long-term BCAA supplementation due to lack of clinical evidences. The present study aimed to evaluate the treatment outcome of long-term oral BCAA supplementation by analyzing the Model for End-State Liver Disease (MELD) score and occurrence of complications in advanced liver cirrhosis patients. Patients and Methods: We enrolled 382 patients in thirteen centers in Korean nationwide tertiary hospitals. Those advanced liver cirrhosis patients had Child-Pugh score from 8 to 10. Those excluded patients are with abnormal serum creatinine level, and viable hepatocellular carcinoma (HCC). Patients were divided into either BCAA group or control group and followed-up with laboratory tests and ultrasonography in 3 to 6 month intervals. We analyzed the improvement in MELD score and frequency of cirrhosis-related complications between two groups. Results: Among 382 patients, 182 patients met the inclusion criteria. Eighty-nine patients (48.9%) received daily dose of 12.45g of BCAA containing 3.4g of L-valine, 5.7g of L-leucine, and 2.9g of L-isoleucine for over 12 months whereas 93 patients (51.1%) received standard nutritional therapy as control group. There were no significant differences between 2 groups in baseline characteristics. The BCAA group showed significantly better MELD score than control group in follow-up periods (15.2 vs 14.1 at 6 months, 13.2 vs 14.3 at 12 months, 12.4 vs 15.7 at 18 months, and 12.1 vs 16.1 at 24 months, p=0.019). The total episode of cirrhosis related complications were 41 in BCAA group (variceal bleeding 12 cases, spontaneous bacterial peritonitis 9 cases, and hepatic encephalopathy 20 cases) and 54 in control group (variceal bleeding 28 cases, spontaneous bacterial peritonitis 15 cases, and hepatic encephalopathy 1 case). However, there were no significant differences in rate of cirrhosis related complications between two groups. The mortality cases related to cirrhosis were 10 in control group and 8 in BCAA group (p=0.868) Conclusion: Long-term BCAA supplementation improves liver function reservoir in patients with advanced liver cirrhosis. Improved nutritional status with oral BCAA supplementation appears to decrease cirrhosis related complications with improved survival. Further studies are required to identify patients who might benefit most from BCAA supplementation.

Disclosures:

Won Young Tak - Advisory Committees or Review Panels: Gilead Korea; Grant/Research Support: SAMIL Pharma; Speaking and Teaching: BMS Korea

Jeong Heo - Grant/Research Support: Jennerex, Green Cross

The following people have nothing to disclose: Se Young Jang, Jung Gil Park, Yu Rim Lee, Eun Jeong Kang, Jun Young Choi, Sun Young Ahn, Soo Young Park, Young Oh Kweon, Si Hyun Bae, Jae Young Jang, Do Young Kim, June Sung Lee, Ki Tae Suk, In Hee Kim, Heon Ju Lee, Woo Jin Chung, Byoung KukJang, Jeong Ill Suh

1405

Hospital Readmissions Metrics (HRM) Related to Hepatic Encephalopathy (HE)

Guy W. Neff1, Nyingi Kemmer1, Erin Parkinson1, Elizabeth Cece Fallon1, Angel Alsina2;

1Hepatology, Tampa General Medical Group, Tampa, FL; 2Transplant Surgery, Tampa General Hospital, Tampa, FL

Introduction Health care reform (HCR) and value-based medicine (VBM) are quickly changing the financial landscapes in the field of medicine. The purpose of this review is to identify HRM results in patients suffering from HE that markedly affect VBM. Methods The medical charts of hospitalized patients admitted with overt HE (Conn Score grade 3 or 4) from December 2010 to May 2013 were reviewed. Patients included with at least one hospitalization at Tampa General Hospital within six-month period of time. Information collected included gender, age, ethnicity, MELD score, treatment course, management protocol, out patient healthcare follow-up HE hospitalization number (frequency), medication compliance, social and employment setting, and days to readmission (range). Results There were 145 patients identified and evaluated with the following results; 81 males, 64 females, age 54.5 years (range 22–75), ethnicity (67% Caucasian, 16% African American, 14% Hispanic, 3% other), mean MELD 14.5 points (range 8–14). Conclusions The above results demonstrate the important HRM data that will impact future value based medicine protocols. The critical components of poor social support, lack of follow up with health care provider, and neglect to fill prescription signify a high likelihood of impending readmission. Further investigations and methodologies are required toward managing HE VBM as healthcare reform steers towards value based medicine.

HRMfrequency (%)(p value; risk of admission)
Lack of Medication Compliance750.0025
Lack of Health Care Follow-up550.045
Social Support  
Lives Alone660.035
Married150.065
Employed200.060
Unemployed720.0028
Increasing MELD-INR Related430.055
Increasing MELD-Bilirubin Related150.065
Previous LOS250.055
Previous Indications for Admission  
Infection200.060
GI Bleed150.065
Renal Failure200.060
Dehydration120.068
Insurance (n=)  
Medicare (n=2l)280.05
Medicaid (n=34)550.045
Insurance (n=60)250.048
Uninsured (n=30)680.032

Disclosures:

Guy W. Neff - Consulting: Genentech, Vertex, Salix; Speaking and Teaching: Genentech, Vertex, Salix, BMS, Merck

Erin Parkinson - Advisory Committees or Review Panels: Gilead; Speaking and Teaching: Merck

Angel Alsina - Advisory Committees or Review Panels: Bayer; Grant/Research Support: Novartis; Speaking and Teaching: Bayer, Novartis

The following people have nothing to disclose: Nyingi Kemmer, Elizabeth Cece Fallon

1406

Impact of isoleucine and exercise on metabolic state, muscle mass and hepatic encephalopathy in cirrhotic rats

Chantal Bemeur2,1, Cristina R. Bosoi1, Melanie Tremblay1, Christopher F. Rose1;

1Neuroscience Res. Unit, CHUM-St-Luc Hospital, Montreal, QC, Canada; 2Nutrition, Montreal University, Montreal, QC, Canada

Background: Malnutrition is an important prognostic factor which can influence clinical outcome of patients suffering from chronic liver disease (CLD). Believed to cause hypermetabolism, malnutrition exacerbates hepatic encephalopathy and sarcopenia in cirrhotic patients. New management strategies focussing on improving nutritional status and attenuating CLD complications are an unmet clinical need. We hypothesize supplementation with branched-chain amino acid isoleucine (ILE) and exercise (EX) could possibly attenuate muscle mass loss and prevent brain edema in CLD. Methods: CLD was induced in rats following 6-week bile-duct ligation (BDL). Five experimental groups were tested; 1) BDL; 2) BDL + ILE; 3) BDL + EX; 4) BDL + ILE + EX; 5) Sham-operated rats. Two weeks post BDL, BDL + EX rats were submitted to 15 min exercise (10 cm/s) every other day and, BDL rats receiving ILE were gavaged daily (1.5 mg/kg) for 4 weeks. Body weight, muscle (gastrocnemius) mass, metabolic state (calculation of energy expenditure independent of food intake and fecal mass) and cerebral edema (specific gravity method) were measured in all groups. Results: BDL + EX + ILE demonstrated a significant gain in body weight (BDL + ILE + EX: 112.3 g vs BDL: 33.7 g; p < 0.05), an increase in muscle mass (weight/body weight ratio) (BDL + ILE + EX: 0.0056 vs BDL: 0.0047; p < 0.05) and attenuated hyper-metabolic status. Brain water content was decreased in BDL + ILE + EX rats compared to BDL animals. Conclusion: Our results demonstrate that EX and supplemental ILE improve body weight, muscle mass, metabolic activity and attenuate cerebral edema. These findings suggest that strategies aiming at muscle mass optimization and improving nutritional status attenuate complications and therefore improve outcome in patients with CLD. EX and ILE supplementation could rapidly be translated into clinical practice.

Disclosures:

The following people have nothing to disclose: Chantal Bemeur, Cristina R. Bosoi, Melanie Tremblay, Christopher F. Rose

1407

Pleural implantable access system in the management of symptomatic refractory hepatic hydrothorax

Sophie Hillaire1,2, Laure Elkrief2, Claire Francoz2, Aurelie Plessier2, Jocelyn Bellier3, Caroline De Kerguenec4,2, Francois Durand2, Edouard Sage3;

1Medicine, Hopital Foch, Suresnes, France; 2Hepatologie, Hopital Beaujon, Clichy, France; 3Chirurgie Thoracique, Hopital Foch, Suresnes, France; 4Hepatologie, Hopital Delafontaine, Saint-Denis, France

Refractory hepatic hydrothorax is an uncommon but severe complication of cirrhosis. This condition justifies a MELD score exception for appropriate access to liver transplantation (LT). In spite of a low MELD score, the short term prognosis is poor in these patients without LT. The repeated thoracentesis increases morbidity and mortality. The efficacy of thoracoscopic talc pleurodesis in refractory hepatic hydrothorax is poor. TIPSS is efficient but with a major risk of encephalopathy. The pleural implantable access system (PIAS) has been validated in the management of malignant pleural effusion. The aim of this study was to assess the feasability, safety and efficiency of the PIAS in patients with refractory hepatic hydrothorax. Methods: All consecutive patients who had a PIAS for refractory cirrhotic hepatic hydrothorax, in the thoracic surgery unit, were retrospectively analyzed. Results:The PIAS was inserted in 11 patients, for hepatic hydrothorax, between August 2011 and March 2013. Median (range) MELD score was 16 (9–28). Nine patients were on the waiting list for liver transplantation. The delay between hydrothorax occurrence and pleural catheter insertion was 3–11 months. Throracocentesis had been complicated by bleeding and/or pneumothorax in 3 patients. Three patients with anticoagulant or antiaggregant therapy, were at high risk of bleeding. Thoracoscopic talc pleurodesis had been unsuccessfully performed in 2 patients. The PIAS was inserted in outpatients, under local anesthesia, after correction of coagulation disorders in accordance with local guidelines. The procedure was complicated by transient spontaneously resolutive pneumothorax in one patient. Median follow-up was 3 months. Repeated drainage was performed by nurses, 0.5–4 times per week until death (n=1) or liver transplantation (n=5), and the median amount of fluid removed was 1.5L. No patient required thoracocentesis. Two patients developed hydrothorax infection associated with spontanous bacterial peritonitis. They recovered after antibiotic therapy and albumin perfusion. One patient developed recurrent hydrothorax infection, requiring ablation of the implantable pleural catheter. The device was removed at the time of liver transplantation (n=5). Conclusion: Patient tolerance of the PIAS was excellent. Repeated drainage, according to the patient's symptoms, is easily performed through the port body and can be done by a nurse, in outpatients. This is safe without risk of pneumothorax or bleeding. These results suggest that the implantable pleural catheter could be the first-line therapy in the management of symptomatic refractory hepatic hydrothorax.

Disclosures:

Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis; Speaking and Teaching: Gilead

The following people have nothing to disclose: Sophie Hillaire, Laure Elkrief, Claire Francoz, Aurelie Plessier, Jocelyn Bellier, Caroline De Kerguenec, Edouard Sage

1408

Pain, Inflammation, and Psychiatric Symptoms Among Patients with Cirrhosis

Shari Rogal1, Klaus Bielefeldt1, Brian M. Davis1, Francis Lotrich2, Eva Szigethy2, Andrea DiMartini2;

1Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA; 2Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA

BACKGROUND: The purpose of this study was to better understand the relationships between pain, psychopathology, and inflammation among patients with cirrhosis. METHODS: Patients with alcohol, NASH, and hepatitis C virus (HCV) cirrhosis were recruited from an outpatient hepatology clinic to complete psychometric measures (Pittsburgh Sleep Quality Inventory, Hospital Anxiety and Depression Score (HADS), and McGill Pain Questionnaire) and provide blood for standardized luminex assays of pro-inflammatory cytokines (IL-1 β, IL-6, and TNF-α) and C-reactive protein (CRP). Predictors of pain severity, number of pain locations throughout the body, and abdominal pain were assessed using negative binomial and logistic regression models. RESULTS: Of 193 patients (40% women, mean age: 58), cirrhosis was due to alcohol in 25%, HCV in 40%, and NASH in 34%. Nearly half of patients met criteria for symptoms of either depression or anxiety. The number of pro-inflammatory cytokines more than 2 standard deviations above the mean of healthy controls was 0 in 27%, 1 in 31 %, 2 in 30%, and 3 in 10% of patients, and the median CRP level was 1.32 mg/dl. Seventy-nine percent of patients had pain at the time of the visit, and 30% of those with pain were taking prescription opioids. Among the 41% with abdominal pain, 40% had been told that the pain was due to their liver disease. However, in univariate testing pain severity and number of pain locations were most strongly associated with psychiatric symptoms (depression, anxiety, and sleep disturbance) but not with severity of liver disease. In multivariate logistic regression the only significant predictor of pain severity was anxiety (IRR=1.05, 95% CI=1 .01,1.09). The number of regions of the body causing pain was significantly associated with etiology of liver disease (with HCV having significantly more than alcohol), depressive symptoms (IRR=1.07, CI=1 .03,1.12), and sleep disturbance (IRR=1.04, 95% CI=1.004,1.09). Abdominal pain was significantly related to depressive symptoms (OR=1.16, 95% CI = 1.03,1.31) and splenomegaly (OR=2.54, 95% CI=1 .14,5.97), though not to MELD score, ascites, or systemic inflammation. Pain was significantly associated with selfreported disability. While inflammatory markers were not associated with pain, they were significantly associated with severity of liver disease (ascites and MELD score). CONCLUSIONS: Pain is common in cirrhosis and is associated with psychiatric symptoms. While patients often attribute their pain to liver disease, pain is not strongly related to inflammation or severity of liver disease. Inflammation, in contrast, is associated with more advanced liver disease.

Disclosures:

Eva Szigethy - Grant/Research Support: NIH; Speaking and Teaching: Merck

The following people have nothing to disclose: Shari Rogal, Klaus Bielefeldt, Brian M. Davis, Francis Lotrich, Andrea DiMartini

1409

Utility of Serum Procalcitonin Level In Early Diagnosis of Spontaneous Bacterial Peritonitis

Muhammad Bilal, Umair Sohail, Nader Dbouk, Sanjaya K. Satapathy, Satheesh Nair; Gastroenterology and Hepatology, University of Tennesse Health Science Center/Methodist Transplant Institue, Memphis, TN

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a frequent complication in patients with cirrhosis and is associated with high morbidity and mortality. Obtaining timely ascitic fluid studies has several logistic limitations resulting in overuse of empiric antibiotics when patients are admitted to the hospital with suspected SBP. Serum procalcitonin is a useful marker for bacterial infection.Our Aim was to assess the utility of serum procalcitonin level in predicting spontaneous bacterial peritonitis. METHODS: In an IRB approved protocol, consecutive patients admitted to our institution with suspected SBP were enrolled. Patients with confirmed source of infection other than ascitic fluid were excluded. Serum procalcitonin (0.5–2 ng/ml) and serum C-reactive protein (0.5–3 mg/L) were determined at the time of paracentesis, prior to giving the antibiotics. Serum levels of procalcitonin and CRP were compared between patients who had SBP and those who did not have SBP. RESULTS: A total of 43 patients met criteria for enrollment. Nine patients (20.9%) were diagnosed with SBP (6 patients with neu-trocytic and 3 patients with non-neutrocytic culture positive SBP). Baseline characteristics, demographics and MELD scores were similar in two groups (table). The serum procalcitonin levels were significantly higher in patients with SBP compared to patients without SBP (2.8±2.2 ng/ml vs 0.42±0.41 P value of 0.003 Man Whitney U test). 5 out of 6 patients with neutrocytic SBP had elevated serum procalcitonin while all three patients with non neutrocytic ascites had normal procalcitonin levels. More importantly, 34 patients with no evidence of SBP had normal procalcitonin level (specificity 100%; Positive Predictive Value = 100%). This is in contrast to CRP levels, which were elevated in 76% of patients without SBP (specificity 6%,positive predictive value 23%, p value not significant, by Fisher exact test). Area under the curve on a ROC plot for elevated procalcitonin levels (> 2.0 ng/ml) in predicting SBP is 0.81 (95% CI 0.619–1.00 p value =0.004). If we include only patients with neutrocytic ascites, the area under the curve is 0.99 (95% CI is 0.96–1.00 p value <0.0001). CONCLUSIONS: Serum procalcitonin is a useful, noninvasive marker that predicts SBP in hospitalized patients with cirrhosis. Serum procalcitonin is superior to serum CRP in predicting SBP.

 SBP(n=9)Non-SBP (n=34)P value
  1. NS=Not Significant

Age (mean)53±1454±9NS
MELD (mean)21.1±520.5±7NS
Procalcitonin > 2.0 ng/ml (%)5(56% )0%0.0001
CRP >3.0 mg/L (%)9(100%)32(94%)NS

Disclosures:

Satheesh Nair - Speaking and Teaching: Vertex, Genetech

The following people have nothing to disclose: Muhammad Bilal, Umair Sohail, Nader Dbouk, Sanjaya K. Satapathy

1410

Diagnostic performance of C-reactive protein and neutrophil-to-lymphocyte ratio for infection in patients with decompensated cirrhosis

Jung Hyun Kwon1, Jeong Won Jang2, Young Woon Kim1, Soon woo Nam1, Kyu Won Chung1, Se Hyun Cho;

1Internal Medicine, College of Medicine, Catholic University, Incheon, Republic of Korea; 2Internal Medicine, College of Medicine, Catholic University, Seoul, Republic of Korea

BackgroundsInfection is associated with poor prognosis, but often difficult to diagnose in cirrhotic patients. The role of clinical parameters such as systemic inflammatory response syndrome (SIRS) criteria in diagnosing infection remains unclear in the cirrhotic population. The aim of this study was to determine the prevalence of infection in decompensated cirrhotic patients and evaluate the usefulness of inflammatory markers including C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) in the diagnosis of infection. Methods The study population consisted of 263 consecutive events in a cohort of 184 decompensated cirrhotic patients admitted to a tertiary centre from September 2011 to September 2012. The presence of SIRS and overt infection were evaluated. CRP and NLR were measured. Results The main cause of admission was uncontrolled ascites (34.8%), followed by varix bleeding (23.9%), and hepatic encephalopathy (13.6%). Thirty six patients (19.6%) had overt infection and 14 of 36 (38.9%) patients only met the SIRS criteria. For the diagnosis of infection, baseline CRP (≥12 mg/L) and NLR (>4.4) were the significant factors compared to the Child-Pugh and MELD scores. Particularly in patients of the Child-Pugh C group, combined baseline CRP and NLR enhanced diagnostic accuracy of infection. Nine out of 36 patients developed delayed infection after admission and increased CRP from baseline to day 3 predicted the diagnosis of delayed infection. However, there were no differences in the presence of SIRS, WBC counts, Child-Pugh and MELD scores at baseline between the patients with or without infection. Conclusions The present study suggests that NLR as well as CRP are significant indicators of the diagnosis of infection and survival among decompensated cirrhotic patients. Combined CPR and NLR increase diagnostic ability of infection in the Child-Pugh C group. Decompensated cirrhotic patients with elevated CRP level and NLR should be carefully checked the presence of infection and considered for antibiotic therapy.

Disclosures:

The following people have nothing to disclose: Jung Hyun Kwon, Jeong Won Jang, Young Woon Kim, Soon woo Nam, Kyu Won Chung, Se Hyun Cho

1411

Covert hepatic encephalopathy: agreement and predictive validity of different indices

Sara Montagnese1, Esmeralda Balistreri1, Sami Schiff1, Michele De Rui1, Paolo Angeli1, Giacomo Zanus2, Umberto Cillo2, Gian-carlo Bombonato1, Massimo Bolognesi1, David Sacerdoti1, Angelo Gatta1, Carlo Merkel1, Piero Amodio1;

1Department of Medicine, University of Padova, Padova, Italy; 2Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padova, Padova, Italy

The diagnosis of hepatic encephalopathy (HE) is problematic. Recently, the term Covert Hepatic Encephalopathy (CHE) has been proposed. CHE encompasses both minimal HE (i.e. abnormalities on neuropsychological, neurophysiological and/or psychophysic tests) and any clinical abnormality < grade II overt HE, based on the West Haven criteria. CHE has been agreed upon but not formally assessed. The aim of this study was to investigate the agreement/prognostic validity of clinical, neurophysiological, psychometric and psychophysical CHE indices. One-hundred-and-thirty-two cirrhotic outpatients underwent clinical assessment, EEG recording, paper-and-pencil psychometry (PHES) and Critical Flicker Frequency, scored on the original (CFFo)/modified (CFFm) thresholds. Abdominal echo-Doppler evaluations were obtained in 84 (64%) patients, who were qualified as having portal-systemic shunts if large, convoluted, anechoic channels were detected, and venous flow confirmed by colour-Doppler. Seventy-nine patients were followed up prospectively for 11 ±7 months in relation to the occurrence of HE-related hospitalisations. On the day of study, 47 (36%) patients had grade I overt HE. Of these, 72% had abnormal EEG, 64% abnormal PHES and 43/30% abnormal CFFo/m. Patients with grade I HE had slower EEG (theta power: 43±17 vs. 26±17%, p<0.0001), worse PHES (-5.2±4.0 vs. -0.9±3.0, p<0.0001) and worse CFF (40±5 vs. 42±5 Hz, p<0.05) than their neuropsychiatrically normal counterparts. Of the 85 patients with no overt HE, 26% had abnormal EEG, 16% abnormal PHES and 31/16% abnormal CFFo/m; no associations between test abnormalities were observed. Seventy-six (57%) patients had a history of HE. These had slower EEG (p<0.001) and worse PHES performance (p=0.05) than their counterparts with a negative history, while CFF was comparable in the two groups. Sixty (71%) patients were qualified as having portal-systemic shunts. These had slower EEG (p<0.05) and a trend for worse PHES performance than their counterparts with no shunt, while CFF was comparable in the two groups. During follow-up, 10 patients died, 10 were transplanted and 29 had HE-related hospitalisation. Grade I HE (p=0.004), abnormal EEG (p=0.008) and abnormal PHES (p=0.04) at baseline all predicted the subsequent occurrence of HE; CFF did not. In conclusion, CHE is a heterogeneous entity, which should probably be sought for by a combination of clinical, neurophysiological and neuropsychological indices.

Disclosures:

Umberto Cillo - Grant/Research Support: Novartis, Bayer, Astellas

The following people have nothing to disclose: Sara Montagnese, Esmeralda Balistreri, Sami Schiff, Michele De Rui, Paolo Angeli, Giacomo Zanus, Giancarlo Bombonato, Massimo Bolognesi, David Sacerdoti, Angelo Gatta, Carlo Merkel, Piero Amodio

1412

A new score for predicting the mortality in cirrhotic patients with infections

Simona Bota, Ioan Sporea, Roxana Sirli, Alina Popescu, Felix B. Bende, Cristina Popescu, Tudor Voicu Moga, Cristian Ivascu, Mirela Danila, Dragos Suseanu, Alina Martie, Madalina Sendroiu; Gastroenterology and Hepatology, “Victor Babes” Univerisity of Medicine and Pharmacy, Timisoara, Romania

Aim: to assess the factors correlated with mortality in cirrhotic patients with infections and to obtain a new score for predicting the mortality in these patients. Methods: Our retrospective study included 170 episodes of infection in 141 cirrhotic patients admitted in our Department between January 2011-December 2012. We performed univariant analysis to evaluate the correlation of the following parameters (obtained at admission) with mortality: age, gender, Child-Pugh score, MELD score, AST, ALT, total bilirubin, direct bilirubin, INR, blood nitrogen urea (BUN), serum creatinine, serum Na, serum K, albumin, prothrombin time, serum cholinesterase, hemoglobin, white blood count and platelet count. The factors correlated with mortality in univariant analysis were included in multiple regression analysis in order to create a new score for predicting mortality in cirrhotic patient with cirrhosis. Results: In our cohort of cirrhotic patients with infections, 20/141 (14.1%) died during hospital-ization. In univariant analysis, the following factors were correlated with mortality: BUN (r=0.342, p<0.0001), serum creatinine (r=0.285, p=0.002), MELD score (r=0.260, p=0.001), white blood count (r=0.248, p=0.001) and INR (r=0.216, p=0.007), while the following factors were not correlated with the mortality: age (r=-0.059, p=0.43), gender (r=-0.025, p=0.76), Child-Pugh score (r=0.116, p=0.14), AST (r=0.053, p=0.45), ALT (r=0.022, p=0.77), total bilirubin (r=0.072, p=0.35), direct bilirubin (r=0.188, p=0.06), serum Na (r=0.029, p=0.70), serum K (r=0.083, p=0.28), serum albumin (r=-0.121, p=0.16), prothrombin time (r=-0.134, p=0.09), serum cholinesterase (r=0.013, p=0.87), hemoglobin (r=-0.150, p=0.06) and platelet count (r=-0.031, p=0.68). Using multiple regression analysis the following score was obtained: Prediction mortality in infected cirrhotic patients (PMIC): -0.125+0.005×creatinine (mg/dl) + 0.02×INR+ 0.0015×white blood count/1000 (cells/mm3) + 0.0005×MELD + 0.002xBUN (mg/dl). For a cut-off value >0.120, PMIC score had 86.7%Se, 77.9% Sp, 30.2% PPV, 98.1% NPV and 78.8% accuracy (AUROC=0.854, p=0.0001) for predicting mortality in cirrhotic patients with infections. Conclusions: PMIC score had a good accuracy and an excellent NPV for predicting mortality in cirrhotic patients with infections.

Disclosures:

The following people have nothing to disclose: Simona Bota, Ioan Sporea, Rox-ana Sirli, Alina Popescu, Felix B. Bende, Cristina Popescu, Tudor Voicu Moga, Cristian Ivascu, Mirela Danila, Dragos Suseanu, Alina Martie, Madalina Sendroiu

1413

Danaparoid sodium monotherapy for portal vein thrombosis in cirrhotic patients is as effective as combination therapy with antithrombin III

Hajime Takatori, Takehiro Hayashi, Hajime Sunagozaka, Kuniaki Arai, Kazuya Kitamura, Takashi Kagaya, Taro Yamashita, Tatsuya Yamashita, Eishiro Mizukoshi, Shuichi Kaneko; Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan

Background: Portal vein thrombosis is sometimes seen in cirrhotic patients, and often causes portal hypertension and the resultant gastrointestinal hemorrhage from gastroesophageal varices. Danaparoid sodium is an anticoagulant that works by inhibiting activated factor X, and was first reported to have efficacy for the treatment of portal vein thrombosis in 2003. Given the association with reduced antithrombin III (AT-III) levels in cirrhotic patients, danaparoid sodium is usually used with AT-III. However, additive effect of AT-III has not been clarified. This study compared the efficasy of danaparoid sodium monotherapy and that of danaparoid sodium and AT-III combination therapy in our hospital. Subjects: We successively recruited 28 cirrhotic patients (21 men, 7 women; median age, 65.4 years) between November 2008 and August 2012. Sixteen were diagnosed as chronic hepatitis C, three chronic hepatitis B, one chronic hepatitis B and C, two primary biliary cirrhosis, one autoimmune hepatitis, and five alcoholic cirrhosis. Eleven, 10, and 7 patients were classified into Child-Pugh A, B, and C, respectively. Methods: The presence of portal vein thrombosis was evaluated with contrast enhanced computed tomography (CT). Patients on monotherapy received intravenous injections of 1,250 units of danaparoid sodium twice daily for 14 days. Patients on combination therapy received the same danaparoid sodium treatment together with 1,500 units of AT-III infused on Days 1–5 and 8–12. Nineteen patients were treated by the combination therapy during November 2008 and September 2011 (combination group), and 9 patients were treated by the monotherapy during October 2011 and August 2012 (monotherapy group). Bilirubin level of combination group had a significantly higher than that of monotherapy group (2.0 vs 1.1 mg/dl, p<0.05).Serum AT-III activities were similar between the two groups (62.2% vs. 62.1%).The efficacy was evaluated by CT on day 14 post-therapy. More than 50% reduction of thrombus size in diameter was defined as effective. Results: Both treatments were performed without severe side effects including bleeding. Both treatments showed high efficacy (8 out of 9 in monotherapy group, and 18 of 19 in combination group) irrespective of serum AT-III levels. However, AT-III activity of one patient who failed to show efficacy by the monotherapy was 27%. Conclusion: Danaparoid sodium monotherapy showed high efficacy as combination therapy in our hospital. AT-III administration may not be necessary except a patient with very low level of AT-III. Further study is clearly necessary to see the safety and the efficacy of Danaparoid sodium monotherapy.

Disclosures:

Shuichi Kaneko - Grant/Research Support: MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co., Inc, MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co., Inc, Bayer Japan

The following people have nothing to disclose: Hajime Takatori, Takehiro Hayashi, Hajime Sunagozaka, Kuniaki Arai, Kazuya Kitamura, Takashi Kagaya, Taro Yamashita, Tatsuya Yamashita, Eishiro Mizukoshi

1414

Analysis of bacterial infections among patients who died waiting for liver transplant in a high MELD center

Theresa Lee2, Angela M. DeLisle2, David Banach2, Sofia Simona Jakab1;

1Medicine/Digestive Diseases, Yale University, NEW HAVEN, CT; 2Medicine, Yale University, New Haven, CT

Background and aim: Antibiotic use is common among hospitalized patients with cirrhosis, as infections are frequent precipitants of multi-organ system failure and death. Exposure to systemic antibiotics may lead to selection of multi-drug resistant (MDR) organisms. There is limited data on the characteristics and impact of MDR infections in cirrhotic patients listed for liver transplantation who died during their hospitalization. Methods: We reviewed all infection episodes occurring during the last hospitalization of the patients who died while awaiting liver transplantation at a US center between January 1 and December 31, 2012. Data were collected on disease severity including Model for End-Stage Liver Disease (MELD) score on admission and during hospitalization, presence of septic shock and other end organ failure, infection site, causative organism, and antibiotic resistance. Asymptomatic rectal carriage of van-comycin-resistant enterococci (VRE) was detected using surveillance swabs on admission. Results: 27 patients listed or in expedited evaluation for liver transplantation were hospitalized and ultimately died. The majority were male (62%), Caucasian (74%), mean age of 59, with alcoholic and/or hepatitis C cirrhosis (61%). MELD on admission was 26.5, and average MELD during hospitalization was 31.2. Infections were very frequent - 50 bacterial infection episodes were identified in 20 patients, with half having 3 or more culture-positive infections. The most common culture-positive sites were: peritoneal fluid (24%), urinary tract (24%), and blood (22%). Overall, 60% of the identified organisms were gram-negative organisms. Twenty (40%) were MDR infections: 8 (16%) were VRE, and 10 (20%) were third-generation cephalosporin-resistant, including 2 car-bapenem-resistant Enterobacteriaceae. Septic shock was noted in 24 (88%) patients, and 9 of these patients had positive bacterial cultures within 72 hours from demise (blood 3, ascites 4, sputum 1, urine 3). Of the 20 patients identified with asymptomatic colonization with a drug-resistant organism, 5 developed culture-positive infection with the same organism (2 bacteremia, 3 peritonitis). Conclusions: We detected a high rate of MDR infections in our patients, and asymptomatic colonization with MDR organisms preceded subsequent infection with the same organism in some patients. Detecting asymptomatic colonization may be helpful in guiding empiric antibiotic therapy to reduce MDR infection associated mortality in this population.

Disclosures:

The following people have nothing to disclose: Theresa Lee, Angela M. DeLisle, David Banach, Sofia Simona Jakab

1415

Embolization of Spontaneous Portosystemic Shunt Improves Survival of Patients with Recurrent Hepatic Encephalopathy

Jihyun An1, Young-Suk Lim1, Kyoung Won Kim2, Seungbong Han3, Gi Ae Kim1, Hyung-Don Kim1, Dong Jin Suh1;

1Department of Gas-troenterology and Liver Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea;2Department of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea; 3Department of Biostatistics and Clinical Epidemiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea

Background: Spontaneous portosystemic shunt (SPSS) is a frequent cause of recurrent hepatic encephalopathy (HE) in patients with cirrhosis. Embolization of SPSS may prevent the recurrence of HE and also restore portal blood flow to the liver. Methods: Data of seventeen patients who had recurrent HE and achieved complete occlusion of SPSS by angiographic embolization were compared with seventeen control patients. Results: Most baseline characteristics were similar in the two groups. Two-year recurrence rate of HE was significantly lower in the embolization than in the control group (39.9% vs. 79.9%, P=0.02), whereas their 2-year overall survival rates were similar (64.7% vs. 53.4%, P=0.97). INR, Model for end-stage liver disease (MELD), and Child-Turcotte-Pugh (CTP) score were significant predictors of 2-year patient mortality in the embolization group. When patients with INR <1.5 in the absence of hepatocellular carcinoma (HCC) were analyzed, overall patient survival was significantly better in the embolization than in the control group with 100% and 67.3%, respectively, at 2-years (P=0.04). The median changes in MELD (-1.6 vs. 1.8, P=0.01), CTP score (-3 vs. 0, P<0.01), and liver volume (61 mL vs. -36 mL; P=0.049) at 1-year significantly favored the embolization group. Serious clinical complications after embolization occurred only in patients who had INR >1.5 and/or HCC at baseline, with all six dying within 1 year. Conclusion: Embolization of SPSS was associated with improvement of survival and liver function as well as prevention of the HE in cirrhotic patients with recurrent HE and modestly preserved liver function.

Disclosures:

The following people have nothing to disclose: Jihyun An, Young-Suk Lim, Kyoung Won Kim, Seungbong Han, Gi Ae Kim, Hyung-Don Kim, Dong Jin Suh

1416

Delta neutrophil index as a prognostic factor of mortality in patients with spontaneous bacterial peritonitis

Tae Seop Lim, Beom Kyung Kim, Seung Up Kim, Do Young Kim, Sang Hoon Ahn, Chae Yoon Chon, Jun Yong Park; Yonsei University, College of medicine, Seoul, Republic of Korea

Backgrounds & Aims: Spontaneous bacterial peritonitis (SBP) is the most common and life threatening infection in patients with advanced cirrhosis. Here, we investigated the prognostic value of novel marker, the difference in leukocyte subfractions (delta neutrophil index, DNI), for mortality in patients with SBP. Methods: Seventy five patients with SBP were enrolled from April 2010 to May 2012. DNI at initial diagnosis of SBP was adopted and the primary end-point was 30-day mortality. Results: The median age of the included patients was 59.0 years old, and 87.7% were men. The median Child-Pugh score was 11.0 and 11 patients (14.7%) had prior history of SBP. The median DNI at the onset of SBP was 3.2%, and the DNI ranged from 0% to 56.1%. The 30-day mortality was 25.3%. The area under the receiver-operating characteristic curve (ROC) of DNI for the 30-day mortality was 0.701 (95% confidence interval [CI], 0.553–0.849; P = 0.009), higher than that of C-reactive protein (0.640, 95% CI, 0.494–0.786; p = 0.076) or the model for end-stage liver disease (MELD) score (0.592, 95% CI, 0.436–0.748; p = 0.235). From the ROC curve, the cutoff value of DNI was determined as 5.7% with the sum of sensitivity and specificity. In the high DNI group (DNI>5.7%), septic shock and 30-day mortality were more prevalent compared to the low DNI group (84.2% vs. 48.2%, p=0.007 and 57.9% vs. 14.3%, p<0.001, respectively). Patients with a higher DNI are at a higher risk of 30-day mortality compared with those with a lower DNI (adjusted hazard ratio 3.490, 95% CI 1.302–9.352; p =0.013). Conclusion: A higher DNI at the time of SBP diagnosis was an independent predictor for 30-day mortality in patients with SBP.

Disclosures:

The following people have nothing to disclose: Tae Seop Lim, Beom Kyung Kim, Seung Up Kim, Do Young Kim, Sang Hoon Ahn, Chae Yoon Chon, Jun Yong Park

1417

Bacteriological spectrum and outcome of cellulitis in cirrhotics in comparison to non-cirrhotics

Mallikarjun Patil, Harshad Devarbhavi, Keyur A. Sheth, Adarsh Ck; Gastroenterology, St.Johns medical college,Bangalore. India, Bangalore, India

Aims: Infections including cellulitis are a common cause of morbidity and mortality in patients with cirrhosis. Prospective study of patients with cellulitis in cirrhotic and comparison with those without cirrhosis is lacking. We prospectively assessed the outcome and the causative spectrum of bacterial organisms in patients with cirrhosis and cellulitis and compared with those with cellulitis but without cirrhosis. Material and methods: Consecutive patients with cirrhosis and cellulitis admitted in Gastroenterology ward from February 2009 to February 2013 were compared with consecutive patients of cellulitis without cirrhosis admitted in surgical wards. Clinical features, biochemical characteristics, skin and blood culture details, Child Pugh's status and outcome were prospectively collected. Results: There were 62 patients with cirrhosis and cellulitis and 55 patients with cellulitis and no cirrhosis. The commonest cause of cirrhosis was alcohol and a majority belonged to Child's B class (59.7%) followed by Child's C (30.6%) and Child's A (9.7%).The commonest site of cellulitis was lower limb in both the groups. Patients with cirrhosis and cellulitis were significantly younger had gram negative bacilli as causative agents for cellulitis and had a significantly higher mortality (24.1% v/s 9%) compared to patients with cellulitis without cirrhosis (See Table). In 2 patients with cirrhosis who had spontaneous bacterial peritonitis, ascitic fluid and wound culture isolated same organism ( E.coli). Conclusions: Gram negative organisms are the predominant cause of cellulitis in cirrhosis, occur in younger age but at advanced stage of disease and are associated with higher mortality compared to those without cirrhosis. Contrary to popular perception, Gram negative bacilli are the commonest causative agent and antibiotic coverage should incorporate this finding.

VariablesCellulitis in cirrhosis (N=62)Cellulitis without cirrhosis (N=55)p-value
Age (mean years)45.962.5<0.001
Sex (males)57450.102
Child-Pugh Class A (%)9.7  
Child-Pugh Class B (%)59.7  
Child-Pugh Class C (%)30.6  
Etiology of cirrhosis (%)Ethanol(54.8)  
 Hepatitis B (14.5)  
 Ethanol & hepatitis B (11.2)  
 Hepatitis C (3.2)  
 Cryptogenic (16.1)  
Culture Gram negative bacilli (%)55.520<0.005
Culture Gram positive organisms (%)33.366.7 
Culture Mixed organisms (%)11.i13.3 
Diabetes mellitus (%)30.652.70.015
Mortality (%)24.199<0.005

Disclosures:

The following people have nothing to disclose: Mallikarjun Patil, Harshad Devarb-havi, Keyur A. Sheth, Adarsh Ck

1418

The role of intrarenal ANGII in latent sodium retention in patients with cirrhosis

Annette D. Fialla1, Helle C. Thiesson2, Peter Bie3, Aleksander Krag1;

1Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark; 2Department of Nephrology, Odense University Hospital, Odense, Denmark; 3Cardiovascular and Renal Research, Southern University of Denmark, Odense, Denmark

Introduction: Activation of the renin angiotensin aldosterone system (RAAS) is considered a hallmark of antinatriureses in the sodium retention in cirrhosis. A proportion of patients with cirrhosis and evident sodium retention do not have an activated systemic RAAS. Whether the intrarenal angiotensin II (ANGII) plays a role is not known. In this study we aimed to assess the dynamics of RAAS, urinary ANGII and the sodium excretion in patients with normal renin activity. Patients and healthy controls were studied during postural change and sodium/volume loading. Method: In 8 patients with stable liver cirrhosis (Child 5A, 3B) with normal creatinine (mean 91 μmol/l) and 6 healthy controls the activity of the systemic RAAS, urinary ANGII, GFR, effective renal plasma flow (ERPF) and sodium excretion was examined. To unmask subtle pathophysiology we challenged the system by studying patients in the supine position, upright standing position and during a isotonic sodium load of 1.2 mmol/kg/hour. All received a continuous water load of 200 ml/hour orally. Results: Despite the normal plasma renin concentration (PRC) at supine position, there was 1.7 fold increase in PRC in patients compared with controls upon standing, p<0.01. An equivalent response was seen in plasma ANGII with a 2- fold difference between the groups while standing. Plasma aldosterone was higher in supine position among patients (155 ±35 pg/ml) than in controls (90±41 pg/ml), p<0.05. The activation of RAAS upon standing was followed by a decrease in ERPF (51%) and GFR (32%) compared to baseline. Both GFR and ERPF were restored when assuming sitting position and in response to saline infusion. The sodium excretion in the patients was comparable to the healthy controls during rest but impaired after standing (33.7 ±7.0 vs. 89.9±24.4 μmol/min, p<0.01). The urinary excretion of ANGII was similar in the two groups and did not respond to changes in posture, sodium or volume loading. Conclusion: Patients with cirrhosis and normal PRC at rest had pathological impaired sodium handling and hyper activation of RAAS upon standing. There was no evidence of a separate role of intrarenal ANGII in the early and latent sodium retaining mechanisms in cirrhosis.

Disclosures:

The following people have nothing to disclose: Annette D. Fialla, Helle C. Thiesson, Peter Bie, Aleksander Krag

1419

Vitamin D deficiency is associated with decreased functional capacity in patients with cirrhosis

Anitha Yadav1, Yu-Hui H. Chang2, Alvin C. Silva3, Bashar Aqel1, Thomas J. Byrne1, David D. Douglas1, Hugo E. Vargas1, Elizabeth J. Carey1;

1Transplant Hepatology, Mayo Clinic AZ, Pheonix, AZ; 2Health Sciences Research, Mayo Clinic AZ, Pheonix, AZ; 3Radi-ology, Mayo Clinic AZ, Pheonix, AZ

Background Vitamin D deficiency is commonly seen in patients with cirrhosis. In the elderly, low vitamin D level is associated with sarcopenia, frailty and decreased physical performance. It is not known if vitamin D affects skeletal muscle mass or functional status in cirrhosis patients. Aims To investigate whether vitamin D deficiency is associated with decreased bone mineral density (BMD), muscle mass or functional status (as measured by 6 minute walk distance (6MWD)) in patients with end stage liver disease (ESLD). Also, strength of relationship between vitamin D, sarcopenia and 6MWD were evaluated. Methods Data collected were: demographics, etiology of liver disease, MELD score, body mass index (BMI) and 6MWD. Vitamin D deficiency was defined as serum 25(OH) vitamin D level less than 20ng/ml, insufficiency as 21–29ng/ml and serum level above 30ng/ml was considered optimal. BMD was obtained using DEXA scan and reported as: normal BMD (T score: -1 or higher), osteopenia (T score: between -1 and -2.5) and osteoporosis (T score: -2.5 or lower). Sarcopenia was assessed by the total psoas area (TPA) on pre-LT cross-sectional imaging. Pearson's correlation coefficient was used to assess the association between the 6MWD, TPA and vitamin D. Results A total of 277 cirrhosis patients were included in the study. 25(OH) vitamin D levels were available for 196 patients. Mean age was 55 8.9, 62.5% were males. The mean MELD score was 15.2, mean body mass index (BMI) was 28.6 5.7 kg/m2 and mean BMD was 1.00.2. Fragility fractures were seen in 7% of study patients. The results of BMD, 6MWD and TPA are shown in table 1.6MWD moderately correlated with vitamin D levels (r=0.36, p<0.0001). No significant correlation was found between vitamin D and TPA (r=0.15, p= 0.042). Conclusions Vitamin D deficiency was associated with higher MELD and low 6MWD. However, No correlation between vitamin D deficiency and sarcopenia was noted. Low vitamin D levels may potentially affect global functional capacity in cirrhosis patients. Larger studies are needed to identify the role of vitamin D in muscle mass and exercise capacity

Table 3. Results of vitamin D, BMD, TPA and 6MWD
VariableVitamin D deficiency N=104Vitamin D insufficiency N=48Optimal vitamin D N=44P value
BMD1.01.01.00.854
Normal BMD (%) Osteopenia (%) Osteoporosis (%)31 (33) 41(43.6) 22(23.4)16(37.2) 18(41.8) 9(21)10(25.6) 22(56.4) 7(18) 
MELD scoreI7.6±7.513.8 ±6.212.4 ±5.4<0.0001
TPA (mm2)2013 ±6352157±5902168.4 ±6240.2442
Mean psoas density (HU)94.296.797.40.2840
6MWD (m)343.5416.6442.4<0.0001

Disclosures:

Hugo E. Vargas - Advisory Committees or Review Panels: Eisai; Grant/Research Support: Merck, Gilead, Idenix, Novartis, Vertex, Janssen, Bristol Myers, Ikaria, Abbott

The following people have nothing to disclose: Anitha Yadav, Yu-Hui H. Chang, Alvin C. Silva, Bashar Aqel, Thomas J. Byrne, David D. Douglas, Elizabeth J. Carey

1420

The Prevalance of Adrenal Insufficiency in Cirrhosis and The Role of Salivary Cortisol in Diagnosis

Filiz Araz, Birol Özer, Baris Soydas, Ender Serin; Baskent University Faculty of Medicine, Department of Gastroenterology, Adana, Turkey

Objective: Objective of this study is to assess the prevalance of adrenal insufficiency according to total and salivary cortisol and evaluating the discrepency between these parameters for diagnosis among stable cirrhotic patients. Material and Method: A total of 110 consecutive patients with cirrhosis and 30 healthy controls were enrolled into the study. Baseline complete blood count, albumin, bilirubin, prothrombin time, total and salivary cortisol levels were measured and free cortisol level was calculated according to Coolens formula for both patients and controls. One hour after the administration of 250 μg synacten, total and salivary cortisol levels were measured and free cortisol was calculated accordingly. Results: Mean age of patients was 62.7±11.4 years and there were 54 males (49.1%). Adrenal insufficiency was present in 23 (20.9%) and 17 (15.5%) patients according to total and free cortisol, respectively. At least one of the criteria of adrenal insufficiency for salivary cortisol was existed in 24 (21.8%) patients. Those patients with baseline salivary cortisol less than 1.81 ng/ml and without satisfactory cortisol increase following ACTH test, and all patients in whom, in terms of salivary cortisol, measured level is less than 4.96 at 1 hour and delta is less than 3 ng/ml, regardless of baseline value were approved of adrenal insufficiency with highest probability and constituted 12.7% of all patients. Baseline total cortisol shows low correlation with salivary and free cortisol (r:0.502 and r:0.579, respectively). In contrast, correlation between salivary and free cortisol is relatively higher (r: 0.706, p< 0.0001). Conclusion: Adrenal insufficiency was diagnosed more commonly according to total cortisol with respect to salivary and free cortisol. Regarding the higher correlation of free cortisol with salivary cortisol relative to total cortisol, salivary cortisol could be a suitable alternative for the diagnosis of adrenal insufficiency in patients with cirrhosis. Key Words: Cirrhosis, adrenal insufficiency, salivary cortisol

Disclosures:

The following people have nothing to disclose: Filiz Araz, Birol Özer, Baris Soydas, Ender Serin

1421

Rifaximin for overt hepatic encephalopathy in real life: effective for prevention but not for cure

Fiona Chautant1, Véronique Duhalde1, Pierre Berlioux2, Camille Christol2, Marie Angele Robic2, Jean-Marie Peron2, Jean-Pierre Vinel2, Christophe Bureau2;

1Pharmacy, University Hospital, Pur-pan, Toulouse, France; 2Hepato-gastroenterology, University Hospital, Purpan, Toulouse, France

Purpose The current management of overt hepatic encephalopathy (OHE) is mainly based on the use of lactulose. NM Bass et al showed that the use of rifaximin decreases the risk of recurrence of OHE in patients who experienced at least 2 episodes of spontaneous OHE [1]. Rifaximin is available in France in this indication since 2010. The objective of this work was to evaluate in “real life” the efficacy of rifaximin for OHE. Patients and Methods Between July 2010 and December 2012, all the patients treated with rifaximin for OHE were included. The clinical and biological characteristics were collected. Two periods were considered: six months before (period 1) and six months after (period 2) the introduction of rifaximin. The main end criteria assessed and compared between the 2 periods were: the number of episodes of OHE, the number of hospitalizations for OHE, the cumulative number of days in hospitalization for OHE. Results 49 patients were included: 37 men, mean age 59 ± 11 years (38–80 years). Alcohol was the cause of cirrhosis in 65 % of patients. Mean Child and MELD scores were 9.1 ± 2.0 and 16.4 ± 6.2. Rifaximin was started for the secondary prevention of OHE in 53% of cases and for the treatment of a persistent OHE in 47% of cases. Lactulose was associated with rifaximin in 88% of patients. Twenty-one patients (43%) received rifaximin for at least 6 months. The main causes of discontinuation were improvement of symptoms (n=4), death (n=5) or liver transplantation (n=5). In the whole cohort, the number of OHE (2.9 ± 2.2 vs 0.94 ± 0.9), the number of hospitalizations (2.47 ± 1.7 vs 0.84 ± 0.9) and the number of days in hospital (29.0 ± 28.8vs. 12.9 ± 19.8 days) were significantly decreased in period 2 as compared to period 1. In the “secondary prevention” group, the same differences were observed. However no difference was observed for these 3 criteria in the group treated for persistent OHE. Conclusion In our first real life experience, the efficacy of rifaximin is observed in patients for the prevention of recurrence of OHE. Rifaximin seems to be not effective in the treatment of persistent OHE. [1]Bass NM. etal. Rifaximin treatment in hepatic encephalopathy. N EnglJMed2010;362:1071–81.

Disclosures:

Jean-Marie Peron - Board Membership: BAYER; Consulting: BAYER, BMS Jean-Pierre Vinel - Grant/Research Support: Roche, Gore, LFB Christophe Bureau - Speaking and Teaching: Gore

The following people have nothing to disclose: Fiona Chautant, Véronique Duhalde, Pierre Berlioux, Camille Christol, Marie Angele Robic

1422

MELDNa is a strong predictor of 90 day readmission in patients with cirrhosis and ascites

Suong T. Le1,2, Chia Pei Chong3, Julian Lim2, Tony He2, Lukas Sah-har2, Phil Ha2, Neel Heerasing3, William Sievert1,2;

1Gastroenterology and Hepatology, Monash Health, Clayton, VIC, Australia; 2Monash Univeristy, Clayton, VIC, Australia; 3General Medicine, Monash Health, Clayton, VIC, Australia

Background & Aims: The MELDNa was developed to improve the prognostic value of the MELD score in predicting mortality for patients with cirrhosis. The utility of MELDNa to predict other clinical outcomes in patients with cirrhosis and an initial presentation of decompensation with ascites has not been assessed. Our study evaluated the prognostic value of MELDNa as a predictor of health care utilization and overall mortality among such patients. Methods: A retrospective cohort study was performed in patients with cirrhosis and new onset ascites admitted to a large tertiary hospital between January 2002 and January 2012. Patient histories were interrogated for demographic and clinical data including serum sodium, MELD, aetiology of cirrhosis, readmission, frequency of hospitalization and mortality. The predictive factors for re-admission, frequency of hospitalization and overall mortality were analyzed and compared using logistic regression. Results: We identified 302 patients with cirrhosis and new onset ascites; of these 71% were readmitted within 90 days of their index admission. The top 3 diagnoses for re-admission were recurrence of symptomatic ascites (42%), hepatic encephalopathy (15%) and variceal haemorrhage (10%). Multivariate logistic regression analysis (Table 1) showed that MELDNa was the only independent risk factor for re-admission (OR 3.806, CI 1.69–8.52, p = 0.006). Gender, serum sodium, MELD, aetiology of cirrhosis, living alone and prescription of diuretics or prophylactic antibiotics upon discharge from the index admission were not risk factors for re-admission. While a predictor of readmission, MELDNa failed to predict mortality (p = 0.950). Interestingly, younger age appeared to be a protective factor for re-admission. Conclusions: In patients with cirrhosis presenting with ascites as their initial episode of decompensation, MELDNa predicted readmission but not long- term mortality, which may reflect effective therapy for ascites.

Multivariate logistic regression analysis for risk factors associated with re-admission

 Beta-coefficientORp-valueCI
Age-0.0240.9770.0450.95–0.99
MELD score0.0671.0690.3730.92–1.23
MELD-Na score1.3373.8060.0061.69–8.52
Serum sodium0.0211.0050.3800.86–1.17

Disclosures:

William Sievert - Speaking and Teaching: Gilead Sciences, Bristol Myers Squibb, Merck, Roche, Gilead Sciences, Bristol Myers Squibb, Merck, Roche, Gilead Sciences, Bristol Myers Squibb, Merck, Roche, Gilead Sciences, Bristol Myers Squibb, Merck, Roche

The following people have nothing to disclose: Suong T. Le, Chia Pei Chong, Julian Lim, Tony He, Lukas Sahhar, Phil Ha, Neel Heerasing

1423

Repeat diagnostic paracentesis is unlikely to alter the management of Spontaneous Bacterial Peritonitis

Mohammad Ashfaq, Pierre M. Gholam, Stanley M. Cohen, Anthony B. Post, Badar Muneer; Digestive Health Institute, Case western Reserve University, Cleveland, OH

OBJECTIVE: Repeat diagnostic paracentesis beyond 48 hours after the initiation of antibiotic treatment for Spontaneous Bacterial Peritonitis (SBP) to document the decline in absolute neutrophil count in ascitic fluid is supported by EASL but not by AASLD guidelines. Its utility in routine practice remains unclear. METHODS: We identified 54 consecutive patients who were diagnosed with SBP between January 2007 and December 2011.42 out of 54 patients had repeat diagnostic paracentesis while 12 did not have a repeat diagnostic paracentesis. Records were reviewed for parameters of interest including the need for change in antibiotic regimens or other interventions following repeat ascites sampling. We also compared the index hospitalization survival of the patients with or without repeat diagnostic paracentesis. Patients were considered to have a diagnosis of SBP if they had either an ascites ANC > 250 cells/μL and/or positive ascites culture. RESULTS: Mean age was 55.8 years and 55% of the patients were male. Etiology of cirrhosis was alcohol abuse (35.7%), ETOH+HCV infection 26.2 %,HCV infection in 14.3% .19% (8/42) had positive ascites cultures at baseline. Among the 12 patients who did not receive a repeat paracentesis, index hospitalization survival was 66.7% (8/12), while it was 69 %( 29/42) in patients with repeat diagnostic paracentesis. Among the 42 patients who received antibiotics and had a repeat paracentesis within 2 to 7 days after the initiation of the antibiotics, 32 (76%) were either found to have ANC< 250 cells/μL or negative peritoneal fluid cultures, 7 (16.6%) had a decline in ANC> 20% while one had< 20% decrease and 2 had an increase in ANC from baseline. There was no antibiotic or other management alteration in the management of the 40 patients with decline in ANC on subsequent paracentesis. Of the 2 patients who had an increase in ANC, one died within 3 days after the diagnosis of SBP due to multi-organ failure and in the other patient, antibiotics were changed after repeat paracentesis and subsequent paracentesis showed a gradual decline in ANC CONCLUSION: Repeat paracentesis did not lead to change in management or antibiotics in all but one patient with a diagnosis of SBP. We conclude that the routine use of repeat paracentesis has a limited role in the management of SBP

Disclosures:

Pierre M. Gholam - Advisory Committees or Review Panels: ONYX, Gilead; Grant/Research Support: ONYX, Gilead; Speaking and Teaching: ONYX, Vertex, Merck, Salix

Stanley M. Cohen - Advisory Committees or Review Panels: Gilead, BMS; Speaking and Teaching: Gilead, BMS, Vertex, Genentech

Anthony B. Post - Advisory Committees or Review Panels, Schering Plough, onyx, Gilead, Schering Plough, onyx, Gilead, Schering Plough, onyx, Gilead, Schering Plough, onyx; Speaking and Teaching: Gilead, Roche, vertex, Roche, vertex, Roche, vertex, Roche, vertex; Stock Shareholder: amgen, amgen, amgen, amgen

The following people have nothing to disclose: Mohammad Ashfaq, Badar Muneer

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