High Prevalence of Advanced Fibrosis Among U.S. Adults with Nonalcoholic Fatty Liver Disease Exceeds the Prevalence of U.S. Adults with Chronic Hepatitis C virus and Chronic Hepatitis B virus Combined

randomized to standard of care (Grp A) with instructions in the clinic on healthy diet and daily exercise for weight loss, or to receive additional text messages on their cell phone (Grp B). The NAFLD 22-week-long text-messaging program sent three text messages every week related to nutrition, exercise, and stress management. The messages focused on education about the disease and its control, motivation for improving health to achieve established goal, and dietary advice. Patients were also asked about the challenges they face in making healthy diet changes and were provided tips for overcoming those specific challenges (e.g., not enough time, cost of healthy food and lack of knowledge). Primary outcome was a change in weight and secondary outcome was change in serum alanine aminotransferase (ALT). Results: 21 NAFLD patients were randomized to Grp A (n=13, mean age 51 yrs, 54% males, 85% white, 62% cirrhosis, diabetes 39%, mean weight 235 lbs, mean BMI 37.3, mean MELD score 9, mean ALT 65 IU/L) or Grp B (n=8, mean age 56 yrs, 12% males, 100% white, 50% cirrhosis, diabetes 50%, mean weight 240 lbs, mean BMI 39.8, mean MELD score 7, mean ALT 51 IU/L). Baseline characteristics were not significantly different except higher proportion of females in Grp B (88% vs. 46%, p<0.001). At the end of six months, Grp B lost an average of 11.2 lbs. (p=0.023) with a decrease in ALT level (mean 20 IU/L, p=0.034); whereas Grp A had no significant change in weight (1.6 lbs., p=0.71) or ALT level (-7.8 IU/L, p=.47). All the subjects in Grp B who received text messages responded to a survey at the end of the study confirming their satisfaction to the program and in recommending this program to their friends and relatives. Conclusions: Text message approach improves weight loss and ALT levels in NAFLD patients. Larger studies with longer duration and follow up using this approach are needed to study its impact on liver histology and surrogate markers of survival in patients with NAFLD.

354 CHANGES IN FIBROSIS, BUT NOT THE NAFLD ACTIVITY SCORE (NAS), ARE ASSOCIATED WITH DISEASE PROGRESSION IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS (NASH) AND ADVANCED FIBROSIS Arun Sanyal, Stephen A. Harrison, Vlad Ratziu, Manal F. Abdelmalek, Anna Mae Diehl, Stephen H. Caldwell, Mitchell L. Shiffman, Raul Aguilar, Catherine Jia, Bryan J McColgan, Macky Natha, Robert P. Myers, Mani Subramanian, John McHutchison, Andrew J. Muir, Nezam H. Afdhal, Jaime Bosch, Zachary Goodman Background: Surrogate endpoints that predict complications are necessary for approval of new therapies for NASH. Our objective was to assess associations between histologic changes with disease progression in patients with NASH and advanced fibrosis. Methods: We included adults with NASH and advanced fibrosis (Ishak stages 3-6) enrolled in two phase 2b, controlled trials of simtuzumab. The trials were stopped at 96 weeks due to lack of efficacy; hence treatment groups were combined for this analysis. Liver biopsies (baseline [BL], W48 and W96) were graded according to the NAS and Ishak classifications, hepatic collagen was quantified by morphometry, and the ELF score was calculated. Cox regression determined associations between these endpoints with disease progression (i.e. progression to cirrhosis in those with bridging fibrosis at BL, and adjudicated clinical events [e.g. decompensation, qualification for transplantation, and death] in subjects with BL cirrhosis). Results: 477 subjects with bridging fibrosis (n=219) or cirrhosis (n=258) were randomized (median 56 years, 63% female, 68% diabetic, MELD 7, and 51% NAS ≥5). 68% of cirrhotics had HVPG ≥10 mmHg. After a median of 24.9 months (range, 0.3-41.4), 47 subjects (21.5%) with bridging fibrosis progressed to cirrhosis. Among BL factors, Ishak stage 4 and greater hepatic collagen and ELF were associated with progression (Table). BL NAS was not associated with progression, but severe ballooning (2 vs. 0: HR 7.24; 95% CI 1.74-30.20) increased the risk. During follow-up, increases in Ishak stage, hepatic collagen, and ELF were associated with progression to cirrhosis. Changes in NAS were not significant, but worsening lobular inflammation was associated with increased progression (HR 3.21; 95% CI 1.14, 9.04). After a median of 26.7 months (range, 0.1-42.3), 49 cirrhotic subjects (19.0%) experienced clinical events (ascites [n=19], encephalopathy [n=13], variceal hemorrhage [n=6], newlydiagnosed varices [n=4], ≥2-point increase in Child-Pugh score and/or MELD ≥15 [n=6], death [n=1]). Factors associated with disease progression included higher BL hepatic collagen and ELF, increases in these markers over time, and lack of improvement in Ishak stage (Table). Changes in NAS were not significant although the absence of improved lobular inflammation was associated with increased risk (HR 2.33; 95% CI 1.01-5.35). Conclusions: In patients with advanced fibrosis due to NASH, the primary determinant of disease progression is fibrosis and its change over time.

356 HIGH PREVALENCE OF ADVANCED FIBROSIS AMONG U.S. ADULTS WITH NONALCOHOLIC FATTY LIVER DISEASE EXCEEDS THE PREVALENCE OF U.S. ADULTS WITH CHRONIC HEPATITIS C VIRUS AND CHRONIC HEPATITIS B VIRUS COMBINED Yu-Chi Lapid, Aristeo Lopez, Taft Bhuket, Benny Liu, Robert J. Wong Background: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease with over 75 million adults affected in the U.S. While the majority of NAFLD patients do not progress to advanced fibrosis and cirrhosis, current diagnostic tools are sub-optimal in predicting risk of disease progression. Identifying NAFLD patients at high risk for progression to advanced fibrosis will help guide more aggressive management to prevent NAFLD related complications. Aim: To evaluate the prevalence and predictors of NAFLD among U.S. adults and to evaluate the prevalence and predictors of advanced fibrosis among individuals with NAFLD in the U.S. Methods: Using the 2011-2014 National Health and Nutritional Examination Survey, we defined NAFLD as presence of both abnormal alanine aminotransferase (ALT>20 U/L in women, ALT>30 U/L in men) and metabolic syndrome after excluding other chronic liver disease etiologies (e.g. hepatitis C, hepatitis B, alcohol). The presence of advanced fibrosis among NAFLD individuals (NAFLD-AF) was evaluated with NAFLD fibrosis score (NFS>0.676) and AST to Platelet Ratio Index (APRI > 0.7). Multivariate logistic regression models evaluated the predictors of NAFLD and predictors of NAFLD-AF among those with NAFLD. Results: Overall, the prevalence of NAFLD was significantly higher in women compared to men (30.7% vs 15.3%, p<0.01). While there was no significant race/ethnicity-specific difference in NAFLD prevalence, increasing age was associated with increasing NAFLD prevalence, such that individuals age >60 had NAFLD prevalence of 46.5%. On multivariate regression, men were significantly less like to have NAFLD compared to women (OR 0.32, 95% CI 0.24-0.42, p<0.001). Concurrent diabetes mellitus (OR 3.10, 95% CI 2.33-4.36, p<0.001) or obesity (OR 2.70, 95% CI 2.02-3.59, p<0.001) were both associated with increased odds of NAFLD. The prevalence of NAFLDAF ranged from 9.7% when using NFS>0.676 to 23.8% when using APRI>0.7. When using NFS, the prevalence of NAFLD-AF was significantly higher in women compared to men (12.1% vs. 5.9%, p<0.001). Increasing age, concurrent diabetes and obesity were also associated with higher prevalence of NAFLD-AF among those with NAFLD (figure). On multivariate regression, obesity (OR 9.10, 95% CI 2.37-35.0, p=0.001) and concurrent diabetes (OR 18.2, 4.70-70.1, p<0.001) were associated with significantly higher odds of NAFLD-AF. However, when evaluating with APRI, only sex-specific differences were seen with significantly lower odds of NAFLD-AF among men compared to women (OR 0.53, 95% CI 0.29-0.98). Conclusion: Among U.S. adults, the prevalence of NAFLD-AF among those with NAFLD ranges from 9.7% to 23.8%, representing 7.3 - 17.9 million individuals, exceeding the prevalence of all U.S. adults with chronic HCV and chronic HBV combined.

355 TEXT MESSAGING APPROACH IMPROVES WEIGHT LOSS AND ALT LEVELS IN PATIENTS WITH NAFLD Page D. Axley, Sudha Kodali, Sujan Ravi, Toni Seay, Nina Parikh, Ashwani K. Singal Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is rapidly rising in the US, with a potential of progressing to advanced liver disease, liver cirrhosis and cancer. Because of lack of FDA approved pharmacological treatments, the only effective treatment is control of risk factors for metabolic syndrome and loss of at least 7-10% body weight. In routine practice, this weight loss can be difficult to achieve. As these patients are usually seen in the clinic for 30 minutes every 6-12 months, provider recommendations may not be often followed by patients. This study was performed to test our hypothesis that a text messaging approach to remind and reiterate the recommendations provided in the clinic would result in more effort and better compliance in regard to control of risk factors and the disease. Methods: After obtaining IRB approval, well-characterized NAFLD patients were

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p=0.001) compared to not drinking. Drinking 2 drinks (HR 1.27, CI 0.87-1.87, p=0.218), or 3 or more drinks (HR=1.10, CI 0.66-1.56, p=0.952) per day did not show a significant effect on survival. After further adjustment for race, physical activity, educational level, diabetes, and fiber and polyunsaturated fatty acid intake, drinking 1 drink per day continued to show a significant protective effect (HR 0.58, CI 0.38-0.87, p=0.009), and drinking 2 drinks ( HR 1.44, CI 0.94-2.19, p=0.094), and 3 or more drinks (HR 1.19, CI 0.73-1.93, p=0.487) showed a trend towards harm. Conclusions: Compared to non-drinkers, drinking an average of 0.5 to less than 1.5 drinks of alcohol per day was associated with decreased risk of mortality in a large cohort of NAFLD patients. This can be a reflection of the importance of cardiovascular comorbidities among these patients. These results help to inform the discussion of potential risks and benefits of alcohol use in these patients.

treatment completion. We ascertained HCC based on VA Cancer Registry or >2 instances of ICD-9/10 codes for HCC. We excluded patients diagnosed with HCC prior to DAA treatment. We calculated HCC incidence for DAA treated patients with vs. those without SVR. In a sensitivity analysis, we excluded patients who developed HCC during treatment. Among patients with SVR, we used Cox proportional hazard models to examine demographic, clinical, and virological factors associated with HCC risk. Results: We identified 22,579 patients treated with DAA. Mean age was 61.5 (SD 6.0) years, 49.3% were white, 36.5% Black, and 3.8% Hispanics. At baseline, 33.6% of patients had cirrhosis, 19.3% cirrhosis complications, 43.6% diabetes, and 61.4% had history of alcohol use. DAAs resulted in SVR in 19,518 (86.8%) patients. During a mean follow up of 12.3 (SD 3.6) months, 369 patients developed HCC (88 during and 281 following treatment) at the incidence rate of 1.28 per 100 patient-year (py). HCC risk was significantly lower in patients with vs. those without SVR (0.95 vs. 3.47/100 py, log-rank p<0.0001); this risk reduction persisted after we excluded patients who developed HCC during treatment (0.89 vs. 3.65/100 py in SVR vs. non-SVR, respectively; p<0.0001). Among patients with SVR, HCC risk was higher in patients with cirrhosis (2.0/100 py, adj HR=4.79, 95% CI, 3.45-6.65) and those with history of alcohol use (1.0/100 py, HR=1.42, 95% CI, 1.03-1.95). Conclusion: DAA related SVR is associated with a significant reduction in HCC risk both during as well as after end of treatment compared to those without SVR. However, HCC remains considerably high in patients treated and cured with DAA. Presence of cirrhosis or history of alcohol use at the time of DAA treatment is associated with high enough risk to warrant ongoing HCC surveillance.

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IMPACT OF SHARE 35 ON WAITLIST OUTCOMES IN CANDIDATES WITH MELD > 40 Chiranjeevi Gadiparthi, Eddie L. Copelin, Rosann Cholankeril, Osama Siddique, Mairin Joseph-Talreja, Muhammad Ali Khan, Satheesh Nair, Menghan Hu, George Cholankeril, Aijaz Ahmed

420 USING THE ICELANDIC GENEALOGICAL DATABASE TO DEFINE MULTIGENERATIONAL RISK OF DEVELOPING PRIMARY BILIARY CHOLANGITIS Kristjan T. Ornolfsson, Sigurdur Olafsson, Eric Gershwin, Ottar Bergmann, Einar Bjornsson

Background and Aims: In 2013, the United Network for Organ Sharing (UNOS) implemented the Share 35 policy to improve organ allocation by prioritizing liver transplant (LT) for local and regional waitlist (WL) candidates with Model for End-Stage Liver Disease (MELD) scores of 35 or higher. While this policy improved donor pool by preventing surgeries in candidates not in immediate need for LT, no policies have been formulated to identify candidates who are too sick to undergo LT. We aim to assess the impact on WL survival in the sickest candidates with laboratory MELD scores > 40. Methods: Utilizing the UNOS database, we compared WL candidates for LT with initial (at the time of listing) MELD scores 30-34, 35-39 and > 40. We studied candidates who were listed from June 2013 to June 2015. We compared 90-day WL survival using Kaplan-Meier methods and probability of LT within these three MELD cohorts. We conducted multivariate analysis of demographic data (age, gender, and ethnicity) and clinical covariates (international normalized ratio (INR), albumin, bilirubin, creatinine, ascites, hepatic encephalopathy, etiology of liver disease, hepatocellular carcinoma, diabetes and dialysis) to determine prognostic factors associated with poor WL survival within the MELD > 40 cohort. Results: Overall, from June 2013 to June 2015, there were 5,528 listed candidates with a MELD 30 and above (1,851 candidates had a MELD 30-34, 2,048 candidates had a MELD 35-39, and 1,629 candidates had a MELD > 40). We noted that the 90-day WL survival was highest in MELD 30-34, and lowest in MELD > 40 (30-34, 80.5%; 35-39, 77.7%; > 40, 68.3%; p-value, < 0.05) (Figure). Probability of transplant was highest in MELD 35-39 and lowest in MELD > 40 (30-34, 68.3%; 35-39, 69.9%; > 40, 65.3%; p-value = 0.91). In our multi-variate analysis, age 65 years and above (reference, age under 65; OR, 0.90, p = 0.01) was the only statistically significant variable correlating to poor waitlist survival in > MELD 40 group Conclusion: Even with the implementation of Share 35 policy, candidates with MELD > 40 have inferior waitlist outcomes to less acutely sick candidates. Candidates. 65 and older with MELD > 40 are more likely to have a higher WL mortality while awaiting LT surgery. Further efforts are needed to identify predictors within this cohort to improve WL mortality.

Background: Primary biliary cholangitis (PBC) is an autoimmune liver disease secondary to a genetic predisposition and environmental interactions. Although multiple GWAS studies have been performed the relative role of heredity in developing PBC within families, and in subsequent generations, requires clarity. In Iceland we have a unique resource involving extensively well-defined genealogical databases and have applied these data to study the relative risk of developing PBC within a pedigree. Material and Methods: All patients who had anti-mitochondrial antibodies measurements (AMAs) in Iceland from 1991-2015 in the entire country of Iceland were identified. In our medical system 100% of such patients are identifiable. Patients who fulfilled biochemical and/or histological parameters based upon International Criteria for PBC were included in this study. The Icelandic Genealogical Database maintained by deCODE Genetics, a computerized database of the genealogy of Icelanders, was used. These records include almost all individuals born in Iceland in the last two centuries, and, indeed, for that period approximately 95% of parental connections are known. For each case of PBC, 10.000 control subjects matched for age, gender and number of known relatives were randomly chosen from this database, in order to calculate the relative risk of disease. Results: A total of 222 subjects fulfilled the International criteria for PBC during the study period, 182 females and 40 males. First-, second- and third degree relatives of PBC patients had a significantly increased relative risk of developing PBC: 9.13 (p<0.001), 3.61 (p=0.014) and 2.59 (p=0.008), respectively. In fourth and fifth degree relatives the relative risk was also increased, with 1.66 (p=0.08) and 1.42 (p=0.08), respectively. Conclusions: Relatives of PBC patients had a markedly higher risk for the development of the PBC in comparison with subjects from the general population. This study, taking advantage of this valuable database, was able, in contrast to previous studies, to demonstrate that the relative risk was also increased in subsequent generations.

421 NACSELD ACUTE-ON-CHRONIC LIVER FAILURE (NACSELD-ACLF) PREDICTS 30-DAY MORTALITY IN ADMITTED CIRRHOTIC PATIENTS Jacqueline G. O'Leary, K. Rajender Reddy, Puneeta Tandon, Patrick S. Kamath, Florence Wong, Guadalupe Garcia-Tsao, Jennifer C. Lai, Scott Biggins, Michael B. Fallon, Ram Subramanian, Paul J. Thuluvath, Benedict Maliakkal, Leroy Thacker, Jasmohan S. Bajaj NACSELD (North American Consortium for the Study of End-Stage Liver Disease) acuteon-chronic liver failure (NACSELD-ACLF), defined as ≥2 extra-hepatic organ failures, has previously been proposed as a simple bedside tool to assess risk of mortality in admitted infected cirrhotic patients. Aim: We validated NACSELD-ACLF's ability to predict 30-day mortality (defined as in-hospital death or discharge to hospice) in a separate multicenter prospectively enrolled cohort of both infected and uninfected admitted cirrhotic patients. Methods: We utilized the NACSELD database of 16 tertiary care hepatology centers that prospectively enroll admitted cirrhotic patients (N=2675). For this validation the cohort was randomly split 60%/40% into training (N=1605) and testing (N=1070) groups. Organ failures assessed were: 1) shock, 2) hepatic encephalopathy (grade III/IV; HE), 3) renal (need for dialysis), and 4) respiratory (mechanical ventilation). Results: Admitted cirrhotic patients were most commonly Caucasian (79%) men (62%) with a mean age of 57 and alcoholinduced cirrhosis (45%). 1079 patients in total had an infection during hospitalization. Because of random splitting of the cohort no demographic differences were present between the 2 groups. Overall the mean MELD was 19, serum creatinine was 1.43, serum albumin was 2.8, and median Child score was 10. Multivariable modeling revealed NACSELD-ACLF as the strongest predictor of mortality after controlling for admission age, WBC, serum albumin, MELD score, and infection status (Table). The training set AUC was 0.8073 and the testing set AUC improved to 0.8433. Conclusion: Although infection status remains an important predictor of death, NACSELD-ACLF was independently validated in a separate large multinational prospective cohort as a simple reliable bed-side tool to predictor 30-day mortality in both infected and uninfected admitted cirrhotic patients.

419 RISK OF HEPATOCELLULAR CANCER IN U.S. PATIENTS TREATED WITH DIRECT ACTING ANTIVIRAL AGENTS Fasiha Kanwal, Jennifer R. Kramer, Yumei Cao, Hashem B. El-Serag Background: With the advent of direct acting antivirals (DAA), most of the HCV patients seen in clinical practice may be in sustained virological response (SVR) within the next decade. While treatment to SVR represents a "virological cure", indirect data suggest that subsequent risk of HCC may persist. Few recent studies suggested that DAA may even increase HCC risk. There are no studies that have examined the effect of DAA on HCC risk in U.S. patients with HCV. Methods: We conducted a large cohort study of patients who received DAAs from 1/1/2015 to 3/31/2016 in the national Veterans Affairs (VA) healthcare system. All patients had >6 months for treatment completion and SVR testing by 9/31/2016 (end of follow up). We used date of first filled DAA prescription as treatment initiation and last date covered by the final prescription as treatment end date. SVR12 was defined if all RNA tests were negative after end of treatment with one being recorded > 12 weeks after

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