Background:Hyperuricemia is associated with non-alcoholic fatty liver disease (NAFLD)1,2, but the relationship to fibrosis remains uncertain3. Moreover, it is not known whether lowering serum urate will affect the course of NAFLD. The availability of data from two randomized trials of pegloticase, a pegylated recombinant mammalian uricase, that profoundly decreases serum urate afforded the opportunity to test the hypothesis that lowering urate might improve NAFLD.Objectives:To determine whether treatment of chronic refractory gout patients with pegloticase was associated with improvement in NAFLD determined by Fibrosis 4 index (Fib4).Methods:Databases from patients with chronic refractory gout who participated in two randomized 6 month clinical trials (RCTs) of pegloticase were analyzed4. Sub-sets who had persistent urate lowering to levels <1 mg/dL in response to biweekly pegloticase (Responders, n=36) were compared to those who received placebo (n=43). Since liver biopsy information was not available on these subjects, we relied on Fib4, a validated non-invasive estimate of liver fibrosis in a variety of liver diseases5,6calculated from measurements of AST, ALT, platelet count and age (Age x AST/platelets x √ALT). A Fib4 value of 1.3 is an indication that further evaluation of liver disease is warranted.Results:At baseline, the mean Fib4 values were 1.40 ± 0.86 in pegloticase responders and 1.04 ± 0.53 in subjects receiving placebo. As shown in figure 1, subjects receiving placebo exhibited a change of 0.26 ± 0.41 in the Fib4 score over the six months of the RCTs compared with 0.13 ± 0.62 in the pegloticase responders (p=0.048; by linear regression). When only the subjects with a Fib4 value > 1.3 were considered, a significant difference in the change in the Fib4 values over the 6 months of the trial between pegloticase responders and those receiving placebo was also observed (-0.15 ± 0.67 vs 0.37 ± 0.42, p=0.004, by linear regression). The correlations between serum urate area under the curve (AUC) over the 6 months of the trial and the change in Fib4 value was rs=0.33, p=0.0.0004 (Spearman rank-order correlation coefficient). Finally, multiple linear regression analysis indicated serum urate AUC (as a surrogate measure for group) is the main contributor to the change in Fib4 (p=0.018 by linear regression).Conclusion:The data are consistent with the conclusion that persistent lowering of serum urate had a significant impact on Fib4 levels, implying a possible effect on the course of NAFLD. The results support a more complete analysis involving biopsy examination of the impact of urate on liver inflammation and fibrosis.References:[1]Yang C et al. PlosOne2017; 12:e0177249[2]Jaruvongvanich V et al. Eur J Gastroenterol Hepatol 2017; 29:1031[3]Jaruvongvanich V et al. Eur J Gastroenterol Hepatol 2017; 29:694[4]Sundy JS, et al. JAMA. 2011; 306 (7):711-20[5]Sterling RK et al. Hepatol 2006; 43:1317[6]Shah AG et al. Clin Gastroenterol Hepatol 2009;7:1104Disclosure of Interests: :Naomi Schlesinger Grant/research support from: Pfizer, Amgen, Consultant of: Novartis, Horizon Therapeutics, Selecta Biosciences, Olatec, IFM Therapeutics, Mallinckrodt Pharmaceuticals, Anthony Yeo Employee of: Horizon Therapeutics, Peter Lipsky Consultant of: Horizon Therapeutics
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