AASLD Abstracts Mo1462 Effect of Recombinant Human Soluble Thrombomodulin in Lipopolysaccharide/D-Galactosamine-Induced Acute Liver Failure in Mice Wataru Osumi, Denan JIn, Yoshiro Imai, Yuta Miyaoka, Keitarou Tashiro, koji Komeda, Fumitoshi Hirokawa, Michihiro Hayashii, Shinji Takai, Kanji Nishiguchi, Kazuhisa Uchiyama Objective: Thrombomodulin plays a crucial role in regulating coagulation and also activates protein C, resulting in anti-inflammatory effects such as the suppression of tumor necrosis factor (TNF)- . Although recombinant human soluble thrombomodulin (TM- ) has been useful in treating disseminated intravascular coagulationin Japan, the effect of TM- on ALF is unclear. In this study, we elucidated the effect of TM- in lipopolysaccharide (LPS)/d- galactosamine (GalN)-induced ALF in mice. Methods: The effect of TM- on the survival rate over the 24 h period following administration of LPS (4 μg/kg)/GalN (600 mg/kg) was evaluated by administering TM- (100 mg/kg) or placebo 1 h after LPS/GalN injection (each group: n=20). Plasma and liver parameters were measured before and 1, 3, and 7 h after LPS /GalN injection (n=6). The effects of TM- were evaluated following administration of TM- or placebo 1 h after LPS/GalN injection, and blood and liver tissue were obtained at 7 h (n=8). Age-matched normal mice were used as a control group (n=6). Results: Survival rates were significantly higher in the TM- -treated group than in the placebo group. Both AST and ALT activities in plasma were not significantly altered until 3 h after LPS/GalN administration, compared with the pre-administration; however, activities were significantly increased at 7 h. Their activities were significantly attenuated by treatment with TM- at 7 h. A significant augmentation of plasma high-mobility group box 1 protein (HMGB1), which induces the production of TNF- , was observed 7 h after LPS/GalN administration. In the TM- -treated mice, plasma HMGB1 was significantly lower than in the placebo group. A significant augmentation of hepatic nuclear factor- B p65 was observed in the placebo- treated group, whereas a significant reduction was observed in the TM- -treated group. Hepatic expression of TNF- and myeloperoxidase were significantly increased in the placebo group, and were similarly significantly attenuated in the TM- -treated group. TM- treatment also produced a significant attenuation of liver neutrophil accumulation after LPS/GalN administration. Conclusion: TM- post-treatment attenuated liver damage and improved survival rates following LPS/GalN-induced ALF in mice. The mechanism underlying these effects of TM- may be mediated by the attenuation of LPS/GalN-induced HMGB1 levels. Mo1463 Acute Liver Failure Due to Sickle Hepatopathy: A Role for Molecular Adsorbent Recirculation Therapy? Brett D. Van Leer-Greenberg, Parit Mekaroonkamol, James R. Spivey, Ram Subramanian Sickle cell hepatopathy (SCH) is a severe complication of acute sickle cell crises with hepatic sequestration leading to biliary stasis, hypoxia, hepatic infarction, and acute liver failure. Reducing sickle hemoblobin (HbS) level to the goal of less than 30% using exchange blood transfusion (EBT) is the current standard of care. We report here a case of SCH-induced acute liver failure despite aggressive EBT and a successful implementation of Molecular Adsorbent Recirculating System (MARS) as a salvage treatment in reducing HbS index to abate acute liver failure. A 26-year-old male with a history of sickle cell disease presented with a 3-day history of altered mental status and jaundice. Physical examination showed a disoriented, dysarthric young man with marked icteric sclera. Laboratory studies revealed: AST 537 U/L, ALT 308 U/L, total bilirubin 46.9 mg/dL, direct bilirubin 32.2 mg/dL, INR 3.7, ammonia 118 mcmol/L, hemoglobin 4.9 g/dL, Creatinine 3.0 mg/dL, LDH 537 U/L, and HbS index of 86%. Viral serologies, autoimmune markers, toxic drug screen including alcohol history, iron panel, and ceruloplasmin were all unremarkable. CT abdomen showed no evidence of chronic liver disease. Diagnosis of sickle cell crisis with SCH-induced acute liver failure and acute tubular necrosis was made. EBT and continuous renal replacement S-1122 AASLD Abstracts therapy were promptly initiated. However, his coagulopathy and mental status continued to worsen to grade 4 encephalopathy despite achieving low HbS index of 19%, adequate dialysis, and maximal medical therapy with lactulose and rifaximin. MARS therapy was then delivered. After three daily sessions, all liver function tests significantly improved with AST of 151 U/L, ALT of 86 U/L, total bilirubin of 25.3 mg/dL, , INR of 1.8, ammonia level of 56 mcmol/L, LDH of 59 U/L, and HbS of 3%. His hepatic encephalopathy dramatically resolved to grade 1 encephalopathy within 48 hours. He fully recovered with ongoing supportive measures and was subsequently discharged. Our case is the first to demonstrate the benefit of MARS as a salvage therapy for acute liver failure due to SCH despite adequate EBT. Accentuated clearance of albumin-bound toxins by MARS could not only relieve refractory encephalopathy, but could also effectively remove sickled red blood cells in his peripheral circulation abating ongoing intrahepatic cholestasis and ischemic hepatopathy. As hepatic dysfunction is common in sickle cell crisis and liver transplant option is limited in this population, MARS therapy should be considered as a salvage treatment when EBT fails to restore liver function. Its role in acute liver failure from other etiologies and for sickle cell crisis without overt liver failure should be further investigated. Mo1464 Evaluation for Liver Transplantation for Acute Liver Failure: A Single-Center Experience John Holden, Marwan Ghabril, Marco Lacerda, Saurabh Agrawal, David Muschi, Joseph Tector, Jonathon Fridell, Paul Y. Kwo BACKGROUND: Acute liver failure (ALF) is an uncommon, but life-threatening entity. Despite the evolution of medical therapies, emergent evaluation for orthotopic liver transplan- tation (OLT) and when needed, OLT, remain essential in the management of ALF. AIMS: To evaluate patient outcomes and their determinants in a cohort of patients referred for emergent OLT evaluation at a large-volume liver transplant center. METHODS: We performed a retrospective review of all patients admitted to Indiana University Hospital with ALF who underwent evaluation for OLT from July 1999 to July 2015. Abstracted data included demographics, etiology of ALF, comorbidities, severity of illness (pressor use, ventilation, CVVH), and laboratory data. Prognostic scores, including MELD and King's college criteria were calculated. Outcomes included survival to hospital discharge, listing for OLT, and OLT. RESULTS: From July 1999 to July 2015, 92 patients were diagnosed with acute liver failure and underwent emergent evaluation for OLT. Mean patient age was 38 years and the majority of patients (69/92; 75%) were female. Etiologies of ALF were APAP (n=47), AIH (n=8), DILI (n=6), ischemic hepatitis (n=6), and hepatitis B (n=5). 31/92 patients (34%) were listed for OLT and 21 (23%) underwent OLT at a median of 3 days. Those who were listed for and underwent OLT had lower presenting ALT, higher presenting bilirubin, and higher pH values (all p<0.05 for comparisons). Non-white races were more likely to undergo transplant (p<0.05). Those who were listed for OLT had lower rates of alcohol or illicit substance abuse/dependence (p<0.05), lower rates of psychiatric comorbidities (p=0.04), higher rates of ascites (p=0.05), higher rates of Kings College criteria for non-APAP (p<0.005), but lower rates of King's College criteria for APAP (p<0.02). 21 individuals underwent OLT with survival at 1 month post-OLT of 76%. Overall survival (to discharge) was 57% and transplant free survival (to discharge) was 40%. Significant factors (p<0.05) associated with survival to discharge (both those who recovered and those who underwent OLT) included admission INR, peak NH3 and lactate, peak stage of encephalopathy, cardiac arrhythmia, mechanical ventilation, pressor use, CVVH, MELD score and King's college non-APAP criteria. CONCLUSIONS: In our setting, one third of patients referred for emergent OLT evaluation are listed. APAP toxicity was the most common reason for OLT evaluation. Overall survival in ALF is 57%, but transplant free survival is notably lower, at 40%. ALT levels, bilirubin, pH, alcohol and illicit substance abuse/dependence and King's College criteria are associated with listing for OLT. Admission INR, peak NH3 and lactate, stage of encephalopathy, cardiac, mechanical ventilation, pressor use, CVVH, MELD score and King's college non-APAP criteria are associated with overall survival. Mo1465 VTL C3A Cell Bile Acid Profile and Processing Capabilities Jason Lapetoda, Patricia W. Bedard, Lee R. Hagey, Alan F. Hofmann, Lee K. Landeen Introduction Acute alcoholic hepatitis (AAH) subjects have elevated serum bile acids (BA) secondary to cholestasis and hepatocellular injury. Down regulation of the farnesoid X receptor (FXR) from chronic ethanol exposure drives increases in BA synthesis and alters gut microbiota BA species. The ELAD System is an investigational human cell-based liver treatment comprised of four metabolically-active ELAD C3A cell cartridges, an ancillary delivery device, and cell support circuit intended to continuously treat subjects with liver failure due to AAH. The aim of this study was to evaluate BA metabolism and secretion by VTL C3A cells using metabolomic profiling and gene expression to define the effects of ELAD treatment on BA metabolism. Methods Spent media collected during manufacture of ELAD cartridges, normal pooled plasma, and plasma from select subjects who survived at least 91 days of the ELAD VTI-208 clinical study (n=8 Control, n=8 ELAD-treated) were evaluated for BA species (glycine-, taurine-, and un-conjugated forms of the 5 main human BA) using standard LC/MS methods (Lipomics). Relative mRNA expression analyses for major BA transporters and regulatory factors in VTL C3A cells (pre/post-treatment) were performed using real-time PCR. Results All 15 BA species were found in measurable levels. ELAD C3A cell cartridges secreted on average 1.7 μmoles/g total BA into spent medium during clinical manufacture, a value similar to total BA concentration in fasting-state plasma (2.1 μmoles/g). Conjugated primary BA species predominated (e.g. glycocholic, glycocheno- deoxycholic, taurocholic, and taurochenodeoxycholic acids) and C 27 BA were not present. Most hepatic BA metabolism genes examined (e.g. CYP7A1, CYP8B1, UGT1A1, UGT1A3, and UGT1A4) and genes of key BA regulatory proteins (e.g. FXR, FGFR4, and FGF19) were moderately expressed in VTL C3A cells. Notably, FGF19, involved in down-regulating BA synthesis in hepatocytes, was significantly upregulated (p=0.03, t-test) in cells from post- treatment ELAD cartridges. However, total BA levels at end of treatment to 91 days were not significantly different in ELAD-treated vs. Control subjects (Fig1). The major transporter involved in hepatocyte uptake of conjugated bile acids (NTCP) was not measurably expressed,