Hypouricemic Therapy: A Novel Potential Therapeutic Option for Nonalcoholic Fatty Liver Disease (2010)

We read with great interest the article by Afzali et al.,1 who showed that increased serum uric acid levels are associated with a higher incidence of cirrhosis-related hospitalization or death or with the presence of elevated serum liver enzymes. Their results indeed provide novel data for improving our understanding of the relationship between serum uric acid and chronic liver disease. However, whether hyperuricemia is a direct cause of chronic liver disease or just a marker remains unclear; it is also unclear whether hypouricemic therapy is effective for the prevention of chronic liver disease. Recently, we conducted an experimental study to investigate the effect of hypouricemic therapy on the prevention of nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease in Western countries. We successfully established a Mongolian gerbil model of NAFLD induced by a high-fat diet. A nearly 4-fold increase in serum uric acid levels was observed in Mongolian gerbils fed the high-fat diet versus controls fed a standard diet (102.99 ± 42.02 versus 26.00 ± 20.59 μmol/L, P < 0.001). When the animals fed a high-fat diet were treated with allopurinol and benzbromarone, two drugs used clinically to lowering uric acid levels, serum uric acid levels significantly decreased from 102.99 ± 42.02 μmol/L in animals fed the high-fat diet to 56.94 ± 29.71 μmol/L in the treated animals (P = 0.02). Serum biochemical analyses showed that total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly reduced by hypouricemic therapy (for both, P < 0.01; Fig. 1A), whereas serum alanine aminotransferase (ALT), triglyceride (TG), and glucose (GLU) levels were not affected (Fig. 1A,B). Notably, serum creatinine (Cr) and blood urea nitrogen (BUN) levels were significantly increased in the therapy group, and this indicates that hypouricemic therapy may cause deterioration of renal function (Fig. 1B). Effect of hypouricemic therapy on a Mongolian gerbil model of NAFLD induced by a high-fat diet: (A) serum TC and LDL-C levels were significantly decreased by hypouricemic therapy, (B) serum Cr and BUN levels were significantly increased by hypouricemic therapy, and (C) hepatic steatosis was significantly ameliorated by hypouricemic therapy. Hepatic histology was analyzed to explore the effect of hypouricemic therapy on NAFLD. The hematoxylin and eosin staining of liver tissues from the NAFLD group showed that simple fatty liver (predominantly macrovesicular) occurred with various degrees of fat deposition, whereas the degree of hepatic steatosis in the therapy group was significantly ameliorated (Fig. 1C). Together, our results provide evidence that hypouricemic therapy could significantly ameliorate hepatic steatosis in an animal model of NAFLD. Further studies investigating whether this effect also holds true in humans may eventually guide the development of novel therapeutic and prevention strategies for the disease. Cheng-Fu Xu M.D.*, Chao-Hui Yu M.D., Ph.D.*, Lei Xu M.D.* , Xiao-Ying Sa , You-Ming Li M.D.*, * Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China, Department of Gastroenterology, Ningbo No. 1 Hospital, Ningbo, China, Experimental Animal Center, Zhejiang Academy of Medical Science, Hangzhou, China.