Clinical Science| Volume 62, ISSUE 3, P392-399, March 2013

Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: Liver ultrasound data from the National Health and Nutrition Examination Survey

Published:October 04, 2012DOI:



      Experimental and observational studies suggest a role for uric acid in non-alcoholic fatty liver disease (NAFLD). We examined the association between serum uric acid levels and NAFLD in a large population-based study from the United States.


      A cross-sectional analysis of 10,732 nondiabetic adults who participated in the National Health and Nutrition Examination Survey 1988–1994. Sex specific uric acid quartiles were defined: ≤5.2, 5.3–6.0, 6.1–6.9, and >6.9 mg/dL for men and ≤3.7, 3.8–4.5, 4.6–5.3, and >5.3 mg/dL for women. NAFLD presence and severity were defined by ultrasonographic detection of steatosis in the absence of other liver diseases. We modeled the probability that more severe NAFLD would be associated with the highest quartiles of uric acid.


      Compared to the 1st quartile, the odds ratio for NAFLD was 1.79 (95% C.I. 1.49–2.15, p<0.001) and 3.14 (95% C.I. 2.63–3.75, p<0.001) for the 3rd and 4th quartiles, respectively. After adjusting for demographics, hypertension, waist circumference, triglycerides, high-density lipoprotein-cholesterol, homeostasis model assessment-estimated insulin resistance, estimated glomerular filtration rate, and aspartate aminotransferase, uric acid (4th quartile) was significantly associated with NAFLD (odds ratio 1.43; 95% C.I. 1.16–1.76, p<0.001). Positive parameter estimates suggest increasing uric acid is associated with greater severity of NAFLD.


      Elevated uric acid level is independently associated with ultrasound-diagnosed NAFLD in a nationally representative sample of United States nondiabetic adults. Increasing uric acid is associated with increasing severity of NAFLD on ultrasonography. These findings warrant further studies on the role of uric acid in NAFLD.


      NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), NHANES (National Health and Nutrition Examination Survey), HDL-C (high density lipoprotein cholesterol), eGFR (estimated glomerular filtration rate), HOMA-IR (homeostasis model assessment of insulin resistance), AST (aspartate aminotransferase), ALT (alanine aminotransferase), MDRD (Modification of Diet in Renal Disease), OR (odds ratio), C.I. (confidence interval)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Metabolism - Clinical and Experimental
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Day C.P.
        • Saksena S.
        Non-alcoholic steatohepatitis: definitions and pathogenesis.
        J Gastroenterol Hepatol. 2002; 17: S377-S384
        • Sanyal A.J.
        AGA technical review on nonalcoholic fatty liver disease.
        Gastroenterology. 2002; 123: 1705-1725
        • Rector R.S.
        • Thyfault J.P.
        • Wei Y.
        • et al.
        Non-alcoholic fatty liver disease and the metabolic syndrome: an update.
        World J Gastroenterol. 2008; 14: 185-192
        • Amarapurkar D.
        • Kamani P.
        • Patel N.
        • et al.
        Prevalence of non-alcoholic fatty liver disease: population based study.
        Ann Hepatol. 2007; 6: 161-163
        • Adams L.A.
        • Lymp J.F.
        • St Sauver J.
        • et al.
        The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
        Gastroenterology. 2005; 129: 113-121
        • de Alwis N.M.
        • Day C.P.
        Non-alcoholic fatty liver disease: the mist gradually clears.
        J Hepatol. 2008; 48: S104-S112
        • Targher G.
        • Day C.P.
        • Bonora E.
        Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.
        N Engl J Med. 2010; 363: 1341-1350
        • Gagliardi A.C.
        • Miname M.H.
        • Santos R.D.
        Uric acid: a marker of increased cardiovascular risk.
        Atherosclerosis. 2009; 202: 11-17
        • Tsouli S.G.
        • Liberopoulos E.N.
        • Mikhailidis D.P.
        • et al.
        Elevated serum uric acid levels in metabolic syndrome: an active component or an innocent bystander?.
        Metabolism. 2006; 55: 1293-1301
        • Godsland I.F.
        • Johnston D.G.
        Co-associations between insulin sensitivity and measures of liver function, subclinical inflammation, and hematology.
        Metabolism. 2008; 57: 1190-1197
        • Cirillo P.
        • Sato W.
        • Reungjui S.
        • et al.
        Uric acid, the metabolic syndrome, and renal disease.
        J Am Soc Nephrol. 2006; 17: S165-S168
        • Ames B.N.
        • Cathcart R.
        • Schwiers E.
        • et al.
        Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.
        Proc Natl Acad Sci U S A. 1981; 78: 6858-6862
        • Stocker R.
        • Keaney Jr., J.F.
        Role of oxidative modifications in atherosclerosis.
        Physiol Rev. 2004; 84: 1381-1478
        • Kang D.H.
        • Han L.
        • Ouyang X.
        • et al.
        Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter.
        Am J Nephrol. 2005; 25: 425-433
        • Kanellis J.
        • Watanabe S.
        • Li J.H.
        • et al.
        Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2.
        Hypertension. 2003; 41: 1287-1293
        • Baldwin W.
        • McRae S.
        • Marek G.
        • et al.
        Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome.
        Diabetes. 2011; 60: 1258-1269
        • Sautin Y.Y.
        • Nakagawa T.
        • Zharikov S.
        • et al.
        Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress.
        Am J Physiol Cell Physiol. 2007; 293: C584-C596
        • Xu C.F.
        • Yu C.H.
        • Xu L.
        • et al.
        Hypouricemic therapy: a novel potential therapeutic option for nonalcoholic fatty liver disease.
        Hepatology. 2010; 52: 1865-1866
        • Lonardo A.
        • Loria P.
        • Leonardi F.
        • et al.
        Fasting insulin and uric acid levels but not indices of iron metabolism are independent predictors of non-alcoholic fatty liver disease. A case–control study.
        Dig Liver Dis. 2002; 34: 204-211
        • Li Y.
        • Xu C.
        • Yu C.
        • et al.
        Association of serum uric acid level with non-alcoholic fatty liver disease: a cross-sectional study.
        J Hepatol. 2009; 50: 1029-1034
        • Lee Y.J.
        • Lee H.R.
        • Lee J.H.
        • et al.
        Association between serum uric acid and non-alcoholic fatty liver disease in Korean adults.
        Clin Chem Lab Med. 2010; 48: 175-180
        • Yamada T.
        • Suzuki S.
        • Fukatsu M.
        • et al.
        Elevated serum uric acid is an independent risk factor for nonalcoholic fatty liver disease in Japanese undergoing a health checkup.
        Acta Gastroenterol Belg. 2010; 73: 12-17
        • Ferreira V.S.
        • Pernambuco R.B.
        • Lopes E.P.
        • et al.
        Frequency and risk factors associated with non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus.
        Arq Bras Endocrinol Metabol. 2010; 54: 362-368
        • Petta S.
        • Camma C.
        • Cabibi D.
        • et al.
        Hyperuricemia is associated with histological liver damage in patients with non-alcoholic fatty liver disease.
        Aliment Pharmacol Ther. 2011; 34: 757-766
        • Ryu S.
        • Chang Y.
        • Kim S.G.
        • et al.
        Serum uric acid levels predict incident nonalcoholic fatty liver disease in healthy Korean men.
        Metabolism. 2011; 60: 860-866
        • Flegal K.M.
        • Carroll M.D.
        • Kit B.K.
        • et al.
        Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010.
        JAMA. 2012; 307: 491-497
        • Reynolds K.
        • Gu D.
        • Whelton P.K.
        • et al.
        Prevalence and risk factors of overweight and obesity in China.
        Obesity (Silver Spring). 2007; 15: 10-18
        • Tsujimoto T.
        • Sairenchi T.
        • Iso H.
        • et al.
        Impact of obesity on incident hypertension independent of weight gain among nonhypertensive Japanese: the Ibaraki Prefectural Health Study (IPHS).
        J Hypertens. 2012; 30: 1122-1128
      1. IDF, 2006, Internation Diabetes Federation.

        • Grundy S.M.
        • Brewer Jr., H.B.
        • Cleeman J.I.
        • et al.
        Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition.
        Arterioscler Thromb Vasc Biol. 2004; 24: e13-e18
        • Ruhl C.E.
        • Everhart J.E.
        Joint effects of body weight and alcohol on elevated serum alanine aminotransferase in the United States population.
        Clin Gastroenterol Hepatol. 2005; 3: 1260-1268


        • Janssen I.
        • Katzmarzyk P.T.
        • Ross R.
        Waist circumference and not body mass index explains obesity-related health risk.
        Am J Clin Nutr. 2004; 79: 379-384

        • Vos M.B.
        • Colvin R.
        • Belt P.
        • et al.
        Correlation of vitamin E, uric acid, and diet composition with histologic features of pediatric NAFLD.
        J Pediatr Gastroenterol Nutr. 2012; 54: 90-96
        • Kuo C.F.
        • Yu K.H.
        • Luo S.F.
        • et al.
        Gout and risk of non-alcoholic fatty liver disease.
        Scand J Rheumatol. 2010; 39: 466-471
        • Xu C.
        • Yu C.
        • Xu L.
        • et al.
        High serum uric acid increases the risk for nonalcoholic fatty liver disease: a prospective observational study.
        PLoS One. 2010; 5: e11578
        • Lee J.W.
        • Cho Y.K.
        • Ryan M.
        • et al.
        Serum uric Acid as a predictor for the development of nonalcoholic fatty liver disease in apparently healthy subjects: a 5-year retrospective cohort study.
        Gut Liver. 2010; 4: 378-383
        • Marangella M.
        Uric acid elimination in the urine. Pathophysiological implications.
        Contrib Nephrol. 2005; 147: 132-148
        • Waring W.S.
        • Webb D.J.
        • Maxwell S.R.
        Systemic uric acid administration increases serum antioxidant capacity in healthy volunteers.
        J Cardiovasc Pharmacol. 2001; 38: 365-371
        • Loria P.
        • Lonardo A.
        • Carulli N.
        Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver.
        Hepatology. 2004; 39: 1748
        • Bugianesi E.
        • Marchesini G.
        Uric acid levels and liver fibrosis in nonalcoholic fatty liver disease.
        Hepatology. 2004; 39: 1749
        • Vuppalanchi R.
        • Chalasani N.
        Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management.
        Hepatology. 2009; 49: 306-317
        • Hamaguchi M.
        • Kojima T.
        • Itoh Y.
        • et al.
        The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation.
        Am J Gastroenterol. 2007; 102: 2708-2715
        • Ballestri S.
        • Lonardo A.
        • Romagnoli D.
        • et al.
        Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD.
        Liver Int. 2012;
        • Holt H.B.
        • Wild S.H.
        • Wood P.J.
        • et al.
        Non-esterified fatty acid concentrations are independently associated with hepatic steatosis in obese subjects.
        Diabetologia. 2006; 49: 141-148
        • Dasarathy S.
        • Dasarathy J.
        • Khiyami A.
        • et al.
        Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study.
        J Hepatol. 2009; 51: 1061-1067
        • Lanaspa M.A.
        • Tapia E.
        • Soto V.
        • et al.
        Uric acid and fructose: potential biological mechanisms.
        Semin Nephrol. 2011; 31: 426-432
        • Lim J.S.
        • Mietus-Snyder M.
        • Valente A.
        • et al.
        The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome.
        Nat Rev Gastroenterol Hepatol. 2010; 7: 251-264