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

Abstract

We read with great interest the practice guidelines for the diagnosis and management of autoimmune hepatitis recently issued by the American Association for the Study of Liver Diseases (AASLD). 1 In particular, we appreciate the new definition of biochemical remission, which now requires not only normal bilirubin and gamma-globulin levels but also normal serum aminotransferases; this is at variance with the 2002 definition, 2 which considers aminotransferase levels lower than twice the upper limits of normal to be sufficient. According to the 2002 criteria, nearly 80% of patients with autoimmune hepatitis enter remission within 3 years. The recently coined new definition will result in a tremendous change in the rate of response to immunosuppressive treatment for autoimmune hepatitis. Here we present our own experience, which has already been published in part, 3 and compare the different response rates according to the 2002 and 2010 definitions of remission. Among 163 consecutive Italian patients with autoimmune hepatitis diagnosed at a single center, 119 (73%) entered remission according to the 2002 AASLD criteria, whereas only 42 patients (26%) of the same cohort fulfilled the 2010 AASLD criteria. Among 89 patients with a follow-up longer than 60 months, 65 (73%) had aminotransferase levels lower than twice the upper limit of normal (2002 criteria), but only 23 (25.8%) consistently maintained normal aminotransferase levels (2010 criteria) with low steroid doses (2-4 mg of methylprednisolone daily or every other day). Interestingly, from a clinical standpoint, after a mean follow-up longer than 100 months, only 1 of the 23 patients (4%) fulfilling the 2010 criteria of remission experienced histological worsening of the disease (mild to severe liver histology), whereas 36 of the 66 patients (54.5%) whose aminotransferase levels did not normalize had histological (14 with severe histology and 9 with cirrhosis) or clinical evidence (11 with endstage liver disease, 1 with decompensated cirrhosis, and 1 with hepatocellular carcinoma) of uncontrolled and evolving liver disease. In summary, in our experience, the application of the 2010 criteria flips the previously codified remission rate from 73% to 26%. Complete-response patients have a very good long-term prognosis virtually free of significant clinical events, whereas patients whose serum aminotransferases are unable to be stably normalized are those with the highest probability of developing long-term complications, which not rarely may prove to be lethal. These are the patients most likely to benefit from new pharmacological, cellular, and molecular therapies. 4,5

Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes

“…11,12 Recent experimental studies have reported a benefit of hypouricemic therapy in ameliorating fat deposition in liver, [13][14][15] suggesting an etiological contribution of uric acid in the development of NAFLD or metabolic syndrome. In this study, we have demonstrated uric acidinduced fat accumulation in hepatocytes by enhancing the expression of lipogenic enzymes, which was associated with ER stress-mediated SREBP-1c cleavage and nuclear translocation.…”

“…12 Recently, uric acid has been shown to have direct effects to increase hepatic fat accumulation via a mechanism involving the induction of mitochondrial oxidative stress, 13 and lowering uric acid has been found to block hepatic fat accumulation in a variety of animal models. [13][14][15] However, the role of ER stress in uric acidmediated hepatic fat accumulation has not been previously examined.…”

Uric acid as a modulator of glucose and lipid metabolism

“…Previous studies have shown that lowering uric acid through allopurinol treatment reduces hepatic steatosis in several models, such as, ethanol treatedrats [30], high fat diet-fed Mongolian gerbils [31], fructose-fed rats [21], and the Pound mouse [29]. The Pound mouse is a model of prediabetes/metabolic syndrome (Charles River, Wilmington, MA) As some xenobiotics, lactate activates the URAT-1 carrier, reducing the excretion of uric acid.…”

Association of the serum uric acid level with liver histology in biopsy-proven non-alcoholic fatty liver disease

“…The study reported that lowering the hepatic uric acid level reduced fatty liver in the fructose-exposed hepatocytes (10). Another study also indicated that hypouricemic therapy using allopurinol and benzbromarone significantly ameliorated hepatic steatosis and decreased serum cholesterol levels in a Mongolian gerbil model of NAFLD (19). In fact, a population-based prospective study showed that SUA was significantly associated with the development of NAFLD, suggesting that high SUA levels may have a causal role in the development of NAFLD (9).…”