Background/Purpose: Hyperuricemia is associated with non-alcoholic fatty liver disease (NAFLD) (Yang C et al. PlosOne2017; 12:e0177249; Jaruvongvanich V et al. Eur J Gastroenterol Hepatol 2017; 29:1031), but the relationship to fibrosis remains uncertain (Jaruvongvanich V et al. Eur J Gastroenterol Hepatol 2017; 29:694). 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.

Methods: Databases from patients with chronic refractory gout who participated in two randomized 6-month clinical trials (RCTs) of pegloticase were analyzed (Sundy JS et al. JAMA. 2011; 306 (7):711-20). 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 the Fibrosis-4 Index (Fib-4), a validated non-invasive estimate of liver fibrosis in a variety of liver diseases (Sterling RK et al. Hepatol 2006; 43:1317; Shah AG et al. Clin Gastroenterol Hepatol 2009;7:1104) calculated from measurements of AST, ALT, platelet count and age (Age x AST/platelets x√ALT). A Fib-4 value of 1.3 is an indication that further evaluation of NAFLD is warranted.

Results: At baseline, the mean Fib-4 values were 1.40 ± 0.86 in pegloticase responders and 1.04 ± 0.53 in subjects receiving placebo. Subjects receiving placebo exhibited a change of 0.26 ± 0.41 in the Fib-4 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 Fib-4 value > 1.3 were considered (n=27), a significant difference in the change in the Fib-4 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=0.04, 2-sample Wilcoxon test). The correlation between serum urate area under the curve (AUC) over the 6 months of the trial and the change in Fib-4 value was r_s=0.33, p=0.0004 (Spearman rank-order correlation coefficient). Finally, multivariate analysis indicated serum urate AUC (as a surrogate measure for group) is the main contributor to the change in Fib-4 values (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 Fib-4 levels, implying a possible effect on the course of NAFLD. These results support consideration of a more complete analysis, involving liver biopsy examinations, of the impact of profound urate-lowering on liver inflammation and fibrosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/improvement-in-hepatic-fibrosis-estimated-by-fibrosis-4-fib-4-index-in-subjects-with-chronic-refractory-gout-treated-with-pegloticase/