608 Sustained Virological Response Prevents the Development of New Type 2 Diabetes in Patients With Chronic Hepatitis C

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(HR 1.187, 95%CI 1.086-1.298), older age (HR 1.081, 95%CI 1.072-1.089), increased waist circumference (HR 1.267, 95%CI 1.031-1.558), and low HDL (HR 1.116, 95%CI 1.0201.221). Serum ALT and metabolic syndrome (MS) were not the predictors of mortality. The independent predictors of cardiovascular-related mortality among NAFLD were male (HR 1.115, 95%CI 1.027-1.211), older age (HR 1.005, 95%CI 1.002-1.008), and low HDL (HR 1.101, 95%CI 1.014-1.197). Independent predictors of cancer-related mortality were male(HR 1.100, 95%CI 1.014-1.193), older age (HR 1.007, 95%CI 1.004-1.010), low HDL (HR 1.113, 95%CI 1.026-1.208), and metabolic syndrome (HR 1.144, 95%CI 1.049-1.249). Summary: NAFLD subjects had higher overall mortality compared to controls. "NAFLD patients at risk" for increased mortality are male, elderly, and those with high waist circumference and low HDL. Conclusion: More studies are needed to confirm various factors that place patients with NAFLD at risk for increased mortality, so these factors can be therapeutically targeted to improve their prognosis.

Changes in Serum Cytokeratin 18 Levels Significantly Predict Changes in Liver Histology in Adults With Nonalcoholic Steatohepatitis: Results From the Pivens Trial Raj Vuppalanchi, Ross B. Deppe, Katherine P. Yates, Megan Comerford, Howard C. Masuoka, Brent A. Tetri, Rohit Loomba, Elizabeth Brunt, David E. Kleiner, James Tonascia, Naga P. Chalasani Background: Previous cross-sectional studies have shown that serum levels of cytokeratin fragments (CK18) are associated with the presence of steatohepatitis in individuals with nonalcoholic fatty liver disease (NAFLD). However, it is unknown if serial serum CK18 levels can predict longitudinal changes in liver histology in NAFLD. Aim: To determine the degree to which changes in serum CK18 associate with changes in liver histology over a 96-week period in adult patients with nonalcoholic steatohepatitis (NASH). Methods: Serum CK18 levels were measured at baseline and 16, 48, and 96 weeks in 231 of the 247 adults with NASH who participated in the PIVENS trial which investigated the efficacy of pioglitazone vs. vitamin E vs. placebo in non-diabetic individuals with histologically confirmed NASH over a 96-week period. Liver biopsies at baseline and after 96 weeks of treatment were centrally evaluated by the NASH CRN Pathology Committee. Multiple logistic (for categorical outcomes) and linear (for continuous outcome variables) regression models were used to determine the association between changes in histological features, ALT, and % collagen assessed by Sirius red staining, and change in CK18 levels, controlling for baseline CK18 levels and treatment group. Results: At baseline, CK18 levels among the 3 treatment groups were similar (placebo: 440± 350 U/L, vit E: 510± 350 U/L, and pioglitazone: 490± 410 U/L). Compared to placebo, serum CK18 levels among individuals treated with vit E were reduced at week 16 (mean change from baseline -160± 300 vs. -50 ±380 U/L, p= 0.02), week 48 (-220± 390 vs. -10± 370 U/L, p=0.009), and week 96 (-200± 400 vs. 30± 400 U/L, p=0.009). Similarly, compared to placebo, serum CK18 levels among individuals treated with pioglitazone were reduced at week 16 (mean change from baseline -240 ± 390 vs. -50± 380 U/L, p,=0.001), week 48 (-180± 370 vs. -10± 370 U/L, p=0.001, and week 96 (-260 ±400 vs. 30 ± 400 U/L, p=0.001). Strong correlations were seen with change in CK18 levels and the primary histologic endpoint, resolution of NASH, and individual histologic features of NASH (Table 1). In addition, change in CK18 levels strongly correlated with change in ALT levels (b=0.06, 95% CI: 0.04, 0.08; P ,0.001).Percent collagen measurements were not related to change in CK18 (b=-0.17 %/100*U/L , 95% CI:-0.70, 0.37; P= 0.54). Summary: (1) Compared to placebo, treatment with vit E or pioglitazone had significant reduction in serum CK18 levels. (2) Changes in serum CK18 correlated with histologic improvement in non-diabetic adults with NASH treated with vitamin E or pioglitazone. Conclusion: Serum CK18 is a potential useful surrogate marker for detection of improvement in clinical trials.

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Background and Aims: Hepatitis C virus (HCV) infection is associated with insulin resistance and has been shown to be an independent risk factor for development of type 2 diabetes in epidemiological studies. However, it is not know whether treatment of HCV infection correlates with a decreased incidence of type 2 diabetes. Studies from Europe and Asia suggest that a sustained virologic response (SVR) to treatment for HCV may lower the risk of type 2 diabetes. Methods: The Veterans Affairs Clinical Case Registry was used to identify all patients with HCV infection without pre-existing diabetes who initiated anti-HCV therapy between 1998 and 2007. The incidence of diabetes following antiviral treatment was calculated in those who achieved sustained virological response (responders) and those who did not successfully clear the infection (non-responders). We used multivariate Cox proportional hazards analysis to identify additional variables implicated in the development of diabetes mellitus, including age, sex, race, body mass index, hypertension, coronary artery disease, cerebrovascular disease, peripheral vascular disease, and cirrhosis. Results: Of the 20,486 chronic HCV patients without known diabetes who initiated antiviral therapy between 1998 and 2007 with available results, 7, 856 patients (38%) achieved SVR and 12,630 patients (62%) did not achieve SVR. New onset diabetes mellitus was diagnosed in 902 (11.5%) responders and 2, 191 (17.3%) non-responders after a median follow up period of approximately 5 years. In multivariate analysis controlling for known diabetes risk factors, SVR was independently associated with significantly decreased incidence of diabetes (hazard ratio 0.76, 95% confidence interval 0.70-0.82, p-value ,.0001). In addition, increasing age, nonwhite race, hypertension, and cirrhosis were associated with an increased risk for new onset diabetes. Conclusions: SVR is associated with lower incidence of type 2 diabetes independent of other known diabetes risk factors. This finding strongly suggests the importance of HCV in the pathogenesis of diabetes in individuals at risk and supports significant benefit of HCV clearance on health outcome beyond liver-related morbidity and mortality. 609 A Disease Severity Index Based on Dual Cholate Clearances and Shunt Outperforms Biopsy At Predicting Clinical Outcomes in Chronic Hepatitis C Steve M. Helmke, Jennifer DeSanto, Andrea Herman, Shannon Lauriski, Gregory T. Everson

Table 1

Background and Aims. Dual cholate clearances and shunt were among the quantitative liver function tests that were most predictive of clinical outcomes in hepatitis C patients (Hepatology 2012; 55: 1019-1029). The aims of this study were to reanalyze archived cholate testing samples using an improved validated LCMS method, and to derive a clinically useful disease severity index (DSI). Methods. Cholate testing was performed at baseline in 224 chronic HCV patients (Ishak F2-6) enrolled in the HALT-C Trial, characterized by CTP scores of 5 or 6 and no prior history of clinical complications. Patients were followed for up to 8.3 years (mean ± SD, 4.9 ± 2.2 years) and clinical outcomes (n=54) were defined as CTP progression, variceal bleeding, ascites, hepatic encephalopathy, and liver-related death. Oral cholate-2,2,4,4-d4 (40 mg) is taken up by enteric bile salt transporters directly into the portal vein and its clearance defines the Portal Hepatic Filtration Rate (HFR). IV cholate24-13C (20mg) clearance defines the Systemic HFR. The ratio of Systemic to Portal HFR is a measure of the portal-systemic SHUNT. Labeled cholate clearances were determined using only 5 serum samples (Aliment Pharmacol Ther 2007; 26: 401-410) and an LCMS method validated to FDA guidelines for accuracy, precision, and freedom from interferences. Results. The relationships between outcomes and each of the cholate test results or their LOGe transformations were analyzed by univariate Cox Proportional Hazard Regressions (Table 1). The test results with the highest Chi-Square values, SHUNT and LOGe Portal HFR, were used to generate an equation of the form DSI = A(SHUNT) - B(LOGe Portal HFR) + C. DSI scores ranged from ~10 for healthy controls to ~50 for the most severely dysfunctional liver disease patients. ROC curves (c-statistics: SHUNT 0.75, Portal HFR 0.84, DSI 0.83) were used to find optimum cutoffs for predicting outcomes. The prognostic performance of cholate testing was compared to that of cirrhosis by biopsy (Table 2). The highest sensitivity, specificity, PPV, NPV, and balanced accuracy were all achieved by a cholate test based DSI. Conclusions. Cholate tests could outperform biopsy diagnosed cirrhosis in predicting clinical outcomes in hepatitis C patients. The highest prognostic performance was achieved by combining cholate test results into a DSI. Table 1. Cox Proportional Hazard Regression Analysis

519 Predictors of Mortality in Individuals With Nonalcoholic Fatty Liver Disease (NAFLD) in the United States: Results From the Third National Health and Nutrition Examination Survey (NHANES III) Kavitha Nutakki, Suthat Liangpunsakul, Naga P. Chalasani Background: Recent data showed the increased in overall mortality in NAFLD patients, when compared to general population. However, some studies reported the opposing results. The plausible explanations are due to different length of follow up and methods to identify NAFLD. It is also possible that not all NAFLD subjects pose the same risk for increased mortality. We hypothesized that NAFLD is a serious condition but only in a subgroup of individuals who will suffer from increased mortality risk. Aim: To determine the overall and cause-specific mortalities in subjects with/without NAFLD, and to identify the risk factors of mortality among NAFLD cases. Methods: We analyzed data from NHANESIII from 1988-94 and the mortality follow-up data till 2006. NAFLD was defined by the presence of ‘moderate/severe hepatic steatosis' by ultrasonography, in the absence of iron overload, hepatitis B/C, and excessive alcohol consumption. Controls were those without liver disease, normal ultrasound and liver tests. Survival analyses were conducted using log rank test. Univariate analysis was performed to identify predictors of mortality. The variables with a P value ,0.05 were entered into multivariate Cox Hazard model to identify the predictors of overall/cause specific mortalities among NAFLD subjects. Results: 10,864 subjects constituted our study cohort. 8,423 (mean age 42.3 ± 16.1 y, 56% female, and 39% White) were controls, whereas 2,441 (mean age 47.9 ± 15.5 y, 51% female, and 37% White) had NAFLD. 1,193 (14%) controls and 501 (21%) NAFLD cases died during a median follow-up period of 14.3 y (IQR: 12.8-15.8 years). Survival analyses between controls and NAFLD are shown in table below. The independent predictors of overall mortality in NAFLD cases were male

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AASLD Abstracts

AASLD Abstracts

Sustained Virological Response Prevents the Development of New Type 2 Diabetes in Patients With Chronic Hepatitis C Sarah M. Hyder, Sheela Krishnan, Kittichai Promrat