481 Prevalence, Severity and Impact of Renal Dysfunction in Acute Liver Failure on the U.S. Liver Transplant Waiting List

amount of fluorescence in the brain was measured when coma was reached. To assess the role of bile acids in the progression of HE, mice were fed a diet enriched in the bile acid sequestrant cholestyramine, or the bile acids cholic acid (CA), deoxycholic acid (DCA) or ursodeoxycholic acid (UDCA) for 3 days prior to AOM injection. Subsequent assessment of neurological decline and liver damage was performed in these mice. The dose of bile acids given has previously been shown to not cause liver damage. Results: Total bile acids were increased in the brains of mice after AOM injection compared to controls. In parallel, fluorescently-derived bile acids were increased in the brains of AOM mice, suggesting that bile acids are entering from the periphery. Cholestyramine feeding reduced both the serum and brain bile acid levels and delayed the neurological decline associated with acute liver failure without any significant differences in liver damage. In contrast, feeding with CA and DCA worsened the AOM-induced neurological decline and significantly decreased the time taken to reach coma, with DCA having the greatest effect while UDCA feeding had no effect. Conclusions: These data indicate that circulating bile acids may be pathological in the brain during the course of HE, although precisely how they are dysregulating normal brain function is unknown. Strategies to minimize the total bile acid content in the serum may improve the outcome of patients with neurological symptoms associated with liver failure.

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Background: Although renal dysfunction may complicate acute liver failure (ALF), little is known regarding its frequency, severity and impact. Objective: To examine the prevalence, severity and outcomes of patients in the U.S. with renal dysfunction complicating ALF who were listed for liver transplantation (LT). Methods: We analyzed Organ Procurement and Transplantation data of those with ALF listed as status 1 or 1A between 2002 and 2012. We estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine (Cr) 2009 equation (Levey et al. Ann Intern Med 150:604;2009) and categorized eGFR by stages: 1; eGFR ≥90, 2; eGFR=60-<90, 3; eGFR: 30<60, 4; eGFR=15-<30, 5; eGFR<15 or on dialysis (Levey et al. Ann Intern Med 139:137;2003). Serum Cr and eGFR were reported in mg/dl and ml/min/1.73m2, respectively. Results: Of 2,280 persons with ALF, 30% was caused by acetaminophen (APAP) use, 8% by HBV, 5% by autoimmune hepatitis, 1.5% by HAV, 1% by isoniazid (INH), 0.13% by heat stroke and 54.37% by other causes. Of those with ALF, 56% had eGFR<60 at listing. The highest median Cr and lowest median eGFR at listing (Cr=6.9, eGFR=9.1) was in those with heat stroke-induced ALF, followed by fatty liver disease of pregnancy (FLDP) (Cr=3.2, eGFR= 18.2), hemolysis elevated liver enzymes low platelet (HELLP) syndrome (Cr=3.2, eGFR= 18.4), trimethoprim-sulfamethoxazole (TMP-SMX) (Cr=3.2, eGFR=25.8), phenytoin (Cr= 2.4, eGFR=29.8), macrolides (Cr=2.3, eGFR=22.7), HAV (Cr=2.2, eGFR=34.2) and APAPinduced ALF (Cr=2.1, eGFR=32.0). Those with heat stroke-induced ALF had the highest median Cr and lowest median eGFR at last follow-up (Cr=7.7, eGFR=8.3), followed by macrolides (Cr=2.4, eGFR=21.8), HAV (Cr=2.4, eGFR=25.4), HELLP syndrome (Cr=2.4, eGFR=27.5), phenytoin (Cr=2.4, eGFR=29.8), TMP-SMX (Cr=2.4, eGFR=35.9), HEV (Cr= 2.2, eGFR=77.0), FLDP (Cr=2.1, eGFR=30.8) and APAP (Cr=2.0, eGFR=33.8). The highest proportion of patients who were on dialysis at listing and last follow-up was among those who had HELLP syndrome-(60%) and heat stroke-induced (67%) ALF, respectively. Only 1% of ALF patients underwent simultaneous liver-kidney transplantation (SLKT); the greatest proportion among those with phenytoin-induced ALF (15%). There was a significant difference among survival probabilities in ALF with renal dysfunction stages of 1, 2, 3, 4, and 5 (P<0.0001) (Figure 1). Conclusions: During the interval studied, in those listed for LT for ALF, renal dysfunction was very common; the overall prevalence was 56%. The most severe renal dysfunction was observed in ALF caused by heat stroke, HELLP syndrome, FLDP, TMP-SMX, phenytoin, macrolides, HAV and APAP. Compared to normal renal function, our data indicate that renal dysfunction complicating ALF predicts a significantly worse outcome.

480 A Pre-Transplant Risk Factor Model Predicts Post-Transplant Cardiac Events in Patients With Liver Cirrhosis Axel Josefsson, Michael Fu, Einar Bjornsson, Maria Castedal, Evangelos Kalaitzakis Background & Aims Cardiovascular disease and is common in cirrhotic transplant candidates and liver transplant recipients. We aimed to create a risk model for prediction of cardiac events (events) following liver transplantation Methods All adult patients with cirrhosis undergoing first-time liver transplantation 1999-2007 in a single institution were retrospectively enrolled. Pretransplant rate corrected QT-time (QTc,bazett formula,>440msec was considered prolonged) was also registered. Patients were followed and events were analyzed, until death or last follow-up, end of 2009. Renal function was assessed by 51Cr-EDTA clearance in all patients, impairment was defined as glomerular filtration rate (GFR)<60ml/ min/sqm. An event was defined as arrhythmia, acute coronary syndrome or sudden cardiac death. Results In all 202 patients were included (140 male (69%), mean MELD 16.5 (SD6.2), coronary artery disease in 13 (6.5%), QTc>440 in 53 (26%)). Events occurred in 56 (28%) patients after transplantation in a mean follow-up time of 3.8 years (2.2). In Cox regression analysis, independent predictors of events were age >52 (HR 3.55, 95% CI 1.82-6.94), GFR<60 (HR 2.19, 95% CI 1.25-3.85) QTc>440 (HR 4.75, 95% CI 2.07-10.9). A pretransplant score was developed for prediction of 3- and 12-months (mo) events with these factors. Depending on the number of pretransplant predictors present, each patient received a score between 0-3, one point for each predictor. We divided patients in 4 risk groups: "low" (0 factor -70 patients, 34.5%), "intermediate" (1-71 patients, 35%), "high" (2-46 patients, 23%) and "very high" (3-15 patients, 7.5%). In Kaplan-meier analysis, occurrence of events was significantly different among the groups (figure). Using the low-risk group as reference, odds ratios (OR) were calculated for 3 and 12 mo risk of events: Intermediate, 3 mo OR 2.40 (95% CI 0.70-8.18), 12 mo OR 2.17 (95% CI 0.77-6.15); high, 3 mo OR 5.82 (95% CI 1.75-19.43), 12 mo OR 4.67 (95% CI 1.64-13.29) and very high, 3 mo OR 33.00 (95% CI 7.56-144.02), 12 mo OR 29.33 (95% CI 7.11-121.08). The model c-statistic was 0.75, 95% CI 0.66-0.84 for the prediction of events 3 mo 0.73, (95% CI 0.64-0.82) for events 12 mo post-transplant. To validate the model, a population of 202 was randomly drawn with replacement from the original population. Logistic regression was performed (excluding time) to validate the c-statistic. This was repeated 1000 times. Our model was the most frequently selected in this process, 469 times (46.9%), c-statistic 0.73 (0.64-0.84). Conclusions A score model consisting of age >52, pretransplant renal impairment and prolonged QTc interval may be a useful tool for predicting cardiac events following liver transplantation in patients with cirrhosis. Further validation, in a prospectively collected cohort, is needed to confirm the prognostic value of the model

Figure 1. Comparison of survival probabilities in patients with ALF based on renal dysfunction at listing (P<0.0001). Thirty-day survival probabilities were 87%, 77%, 75%, 75% and 66% in ALF with renal dysfunction stages of 1, 2, 3, 4, and 5, respectively. Analysis was based on Kaplan-Meier method and log-rank test (Kaplan EL, Meier PJ. Amer Statist Assn 53:457,1958). 482 NASH Recurrence and Rate of Fibrosis Progression Following Liver Transplantation Achuthan Sourianarayanane, Sowminya Arikapudi, Arthur J. McCullough, Abhinav Humar Background: Non-alcoholic fatty liver disease (NAFLD) is known to recur following liver transplantation (LT) for non-alcoholic steatohepatitis (NASH) etiology. Metabolic factors are associated with NASH and is pronounced following LT along with the use of immune suppression. Hence, NASH along with fibrosis can occur with rapid progression following transplant. Aim: This study evaluates the incidence of steatosis, NASH and rate of progression of fibrosis following LT for NASH by liver histology. We also compared with patients transplanted for alcoholic liver disease (ALD) who had similar exposure to immunosuppression and have histological features similar to NASH. Method: All patient's records who had LT for NASH at our institution between 2001 and 2006 were reviewed. Patients data were compared with 1: 2 near matched LT recipients transplanted for ALD. Patients who had no liver biopsies beyond 2 months following LT and those with concurrent other liver etiology were excluded. The rate of progression of liver disease (steatosis, NAS, fibrosis) was defined as the appropriate scores (steatosis, NAS, fibrosis) on liver histology over time (in years) to biopsy following LT. Interval rate of change in fibrosis (1st year, 2-3 years, 4-5 years) were calculated by the difference in fibrosis scores in the histology for the difference in the time period between the biopsies. Results: Patients transplanted for NASH (n=77) were older (59.4 vs 54.8 years; p=0.0006) and had fewer men (50.6 vs 77.8%; p=<0.001) compared to ALD patients (n=108). The mean number of biopsies per patient was 3±2. By one-year >50% of all recipients had recurrence of steatosis on post transplant biopsy. There was an increasing incidence of moderate or severe steatosis, NASH, stage of fibrosis among biopsies with time (1, 3, 5 years) following LT in both groups. The rate of steatosis (0.49 vs 0.4

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AASLD Abstracts

AASLD Abstracts

Prevalence, Severity and Impact of Renal Dysfunction in Acute Liver Failure on the U.S. Liver Transplant Waiting List Nathalie H. Urrunaga, Ayse L. Mindikoglu