We were pleased by the comments of Loria et al. on our recent paper published in HEPATOLOGY.1 The finding that the Polistena study, recruiting a completely different population, reached the same conclusions, strengthen our results and points to insulin resistance as major factor in predicting fibrosis in nonalcoholic fatty liver disease (NAFLD).
Interestingly, uric acid was also significantly higher in Polistena patients with severe fibrosis, compared with mild fibrosis. Raised uric acid levels have been associated with insulin-resistance metabolic syndrome,2 and NAFLD represents its hepatic feature.3 Uric acid is a selective antioxidant that protects the ability of vascular endothelium to mediate vasodilatation in the presence of oxidative stress.4 Elevation of uric acid occurs as a physiological response to increased oxidative stress and, as a consequence of its relatively high concentrations in blood, is the most abundant scavenger of free radicals in humans.5 In prospective studies, uric acid was associated with increased total antioxidant capacity among individuals with atherosclerosis.6 Accordingly, increased uric acid in NAFLD might simply represent a physiological response to advanced hepatic lipoperoxidation, the stimulus for progressive fibrosis.
To test this hypothesis, we extracted urate concentrations from the clinical records of our 263 NAFLD patients. Uric acid levels were available for 141 patients (89 patients submitted to liver biopsy). At histology, 31 cases had been classified as pure fatty liver, 41 had fibrosis grade 1 or 2, and 17 had severe fibrosis grade 3 or 4. Uric acid increased progressively with the presence and severity of fibrosis (Fig. 1; median, 5.6, 6.1, and 6.9 mg/dL, respectively; P = .06, Kruskal-Wallis test), but no significant differences among the groups were observed. In logistic regression analysis, uric acid was not associated with the presence and severity of fibrosis (mild fibrosis: OR, 1.21; 95% confidence interval, 0.82-1.79, P = .335; severe fibrosis: OR, 1.56; 95% confidence interval, 0.97-2.52, P = .068). These data do not support a specific role of hyperuricemia as an indirect marker of oxidative stress in NAFLD severity, but they need validation in prospective studies.
A “second hit” was advocated to explain the passage from fatty liver to nonalcoholic steatohepatitis7 and was tentatively related to oxidative stress. Oxidative stress is operative in NAFLD,8 but our data suggest that it is more the effect than the cause of advanced disease. Insulin resistance remains the major culprit.