Background: Hyperuricemia is associated with non-alcoholic fatty liver disease (NAFLD) ^1,2 , but the relationship to fibrosis remains uncertain ³ . 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 analyzed ⁴ . 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 diseases ^5,6 calculated 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 r _s =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;7:1104

Disclosure 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