Implication of Hyperuricemia in Metabolic-Associated Hepatic Encephalopathy: Looking Beyond Ammonia

Introduction: Chronic liver disease (CLD) is associated with hepatic encephalopathy (HE), which is not always correlated with increased blood ammonia. In addition, HE is not always reversible and our understanding why, remains unknown. We speculate other factors may be involved. We identified uric acid (UA) as a candidate since hyperuricemia is induced by similar factors to CLD, namely alcohol and fructose consumption. UA also contributes to neuroinflammation, cell loss, anxiety and memory impairments. Our goal is to investigate the impact of hyperuricemia on HE in a rat model of CLD. Methods: CLD was induced in male Sprague-Dawley rats via bile-duct ligation (BDL) including SHAM-operated controls. Hyperuricemia was induced in BDLs by a diet containing 3% UA (HUAD) compared to regular diet (RD). Therefore, 4 experimental groups were included: (1) SHAM+RD, (2), SHAM+HUAD, (3) BDL+RD, (4) BDL+HUAD. UA was assessed at baseline and days 7, 14, 21 and 28. At days 14 and 28, anxiety (Open-Field and Elevated-Plus Maze) and memory (Novel Object Recognition) were assessed. At day 33, animals were sacrificed to collect blood and brain (frontal cortex, amygdala and hippocampus) for analyses of cell death by apoptosis (caspases 3, 8 and 9). Results: HUAD leads to an increase in plasma UA in both SHAM and BDL rats beginning at day 7 until day 33. On day 14, short-term memory in both HUAD groups and long-term memory in BDL+HUAD group was impaired compared to RD animals. Furthermore, increased anxiety in both HUAD groups was detected. At day 28, memory is impaired in both HUAD groups compared to RD animals without any effects on short-term memory. In the frontal cortex of both HUAD groups, the intrinsic and extrinsic pathways of apoptosis were activated. In the amygdala and hippocampus, we detected an activation of the intrinsic pathway of apoptosis for the BDL+HUAD rats as well. Conclusion: In rats with CLD, hyperuricemia induces early-onset anxiety and memory impairments and leads to cerebral cell injury and loss. The synergistic role of UA and ammonia in the context of CLD remains to be determined.