Relationship between uric acid and hepatic steatosis among Koreans

doi:10.1016/j.diabet.2009.04.011

Diabetes & Metabolism

Volume 35, Issue 6, December 2009, Pages 447-451

https://doi.org/10.1016/j.diabet.2009.04.011 Get rights and content

Abstract

Aim

The relationship between high uric-acid levels and hepatic steatosis, according to body mass index (BMI) categories, and their coexistence with the metabolic syndrome (MetS) were examined in the present study.

Methods

The study involved a cross-sectional sample of 13,621 Koreans (7221 men and 6400 women) who visited a health checkup centre between 2005 and 2006. Hepatic steatosis was diagnosed using ultrasonography. Hyperuricaemia was defined as > 7 mg/dL for men and > 6 mg/dL for women. The MetS was defined as the presence of three or more MetS components—obesity (BMI ≥ 25.0 kg/m²), high blood pressure, elevated levels of triglycerides and glucose, and low levels of high-density lipoprotein (HDL)-cholesterol.

Results

In total, 26.2% were diagnosed with hepatic steatosis, of whom 11.9% were non-obese (BMI < 25 kg/m²) and 52.5% were obese. Hyperuricaemia was associated with hepatic steatosis in non-obese (adjusted odds ratio [AOR] of 1.4 in men and 2.2 in women) as well as in obese individuals (AOR of 1.8 in men and 2.3 in women) after adjusting for age, other MetS components and liver function tests. The AOR (95% CI) for hepatic steatosis in obese individuals with hyperuricaemia compared with non-obese individuals with normal uric-acid levels was 7.7 (6.4–9.3) in men and 12.4 (7.8–19.5) in women. The adjusted age and liver-function test ORs (95% CI) for hepatic steatosis in those with hyperuricaemia and no MetS compared with those who had normal uric acid levels and no MetS were 2.0 (1.7–2.4) in men and 3.2 (2.1–4.9) in women. The ORs (95% CI) in those with hyperuricaemia and the MetS increased to 6.9 (5.5–8.8) and 15.2 (8.4–27.4) in men and women, respectively.

Conclusion

Hyperuricaemia is independently associated with hepatic steatosis regardless of BMI category or the presence of the MetS in Korean adults. Further research into the causal relationship is needed.

Résumé

Objectifs

Étudier les relations éventuelles entre l’hyperuricémie et la stéatose hépatique en fonction de l’indice de masse corporelle (IMC) et de la coexistence d’un syndrome métabolique dans un échantillon de la population coréenne.

Méthodes

La population étudiée comportait 13 621 coréens (7221 hommes et 6400 femmes) suivis dans un centre de santé entre 2005 et 2006. Le diagnostic de stéatose hépatique a été porté par l’échographie. L’hyperuricémie a été définie par une uricémie supérieure à 7 mg/dL chez l’homme et supérieure à 6 mg/dL chez la femme. Le syndrome métabolique a été défini par la présence de trois ou plus des éléments suivants : obésité (IMC ≥ 25,0 kg/m²), hypertension artérielle, hypertriglycéridémie, hyperglycémie et HDL cholestérol bas.

Résultats

Au total, 26,2 % des sujets présentaient une stéatose hépatique (11,9 % chez les sujets avec un IMC inférieur à 25 et 52,5 % chez les sujets obèses. Il existait une association hyperuricémie–stéatose chez les sujets de poids normal (odds ratio ajusté [AOR] 1,4 chez les hommes et 2,2 chez les femmes) et chez les obèses (AOR 1,8 chez les hommes et 2,3 chez les femmes) après ajustement pour l’âge, les éléments du syndrome métabolique et les tests fonctionnels hépatiques. L’AOR (intervalle de confiance à 95 %) de la stéatose chez les obèses avec hyperuricémie par rapport aux sujets de poids normal obèses avec uricémie normale était respectivement de 7,7 (6,4–9,3) chez les hommes et de 12,4 (7,8–19,5) chez les femmes. Ajustés pour l’âge et les tests fonctionnels hépatiques, les AOR (IC 95 %) des sujets avec stéatose et hyperuricémie sans syndrome métabolique par rapport aux sujets avec uricémie normale sans syndrome métabolique étaient de 2,0 (1,7–2,4) chez les hommes et 3,2 (2,1–4,9) chez les femmes. Les AOR (IC 95 %) des sujets avec hyperuricémie et syndrome métabolique passaient respectivement à 6,9 (5,5–8,8) chez les hommes et à 15,2 (8,4–27,4) chez les femmes.

Conclusion

L’hyperuricémie est associée de manière indépendante à la stéatose hépatique, quel que soit l’IMC, et avec ou sans syndrome métabolique chez les adultes coréens. Les causes de cette association restent à définir.

Introduction

It is well known that hepatic steatosis is an additional feature of insulin resistance. The evidence also suggests that hepatic steatosis is predictive of coronary heart disease (CHD) risk [1], [2]. Epidemiological studies have found that uric acid may be an independent risk factor for CHD [3], [4]. Therefore, there appears to be a close relationship between hepatic steatosis and high uric-acid levels, as uric acid may play a role in insulin resistance [5]. However, the association between uric acid and hepatic steatosis remains controversial, and differs according to weight status. Most studies that have controlled for other metabolic risk factors suggest a positive relationship between serum uric acid and hepatic steatosis in obese individuals while, in non-obese individuals, uric acid is not consistently associated with the presence of hepatic steatosis [1], [6], [7]. Moreover, few studies have examined this difference in association with other metabolic abnormalities. Therefore, the objective of the present study was to clarify the relationship between high uric acid and the presence of hepatic steatosis according to body mass index (BMI) and the coexistence of the metabolic syndrome (MetS).

Section snippets

Study subjects

This study used data generated from 15,791 Korean adults (8667 men and 7124 women) who visited the Center of Health Promotion at the Inje University Busan Paik Hospital between March 2005 and June 2006. Subjects with evidence of excessive alcohol intake (≥ 20 g/day) and those with positive seromarkers for hepatitis B or C, biliary disease, liver cirrhosis or malignant disease were excluded, using surveys on alcohol intake, self-reported past medical history, laboratory tests and ultrasonography.

Results

Of the 13,621 subjects, 26.2% were diagnosed with hepatic steatosis by ultrasonography. Of the total number of subjects, 11.9% of the non-obese and 52.5% of the obese individuals had hepatic steatosis. The risk of hepatic steatosis was 1.8-fold higher in men compared with women (35.0% vs 16.3%, respectively; Table 1). However, the prevalence of hepatic steatosis in women increased sharply with age regardless of BMI category, so that the gender discrepancy decreased with age (Fig. 1).

Discussion

Many studies have examined the risk factors for hepatic steatosis and found that the MetS components are strongly associated with the presence of hepatic steatosis [12], [13]. However, the relationship between elevated uric-acid levels and hepatic steatosis according to BMI category is not clear. In the present study of 13,621 Korean adults who visited a health checkup centre, there was a significant and independent relationship between increasing levels of uric acid and the presence of hepatic

Conflicts of interest

None.

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Cited by (31)

Obese female mice do not exhibit overt hyperuricemia despite hepatic steatosis and impaired glucose tolerance
2022, Advances in Redox Research
Recent reports have clearly demonstrated a tight correlation between obesity and elevated circulating uric acid levels (hyperuricemia). However, nearly all preclinical work in this area has been completed with male mice, leaving the field with a considerable gap in knowledge regarding female responses to obesity and hyperuricemia. This deficiency in sex as a biological variable extends beyond unknowns regarding uric acid (UA) to several important comorbidities associated with obesity including nonalcoholic fatty liver disease (NAFLD). To attempt to address this issue, herein we describe both phenotypic and metabolic responses to diet-induced obesity (DIO) in female mice. Six-week-old female C57BL/6J mice were fed a high-fat diet (60% calories derived from fat) for 32 weeks. The DIO female mice had significant weight gain over the course of the study, higher fasting blood glucose, impaired glucose tolerance, and elevated plasma insulin levels compared to age-matched on normal chow. While these classic indices of DIO and NAFLD were observed such as increased circulating levels of ALT and AST, there was no difference in circulating UA levels. Obese female mice also demonstrated increased hepatic triglyceride (TG), cholesterol, and cholesteryl ester. In addition, several markers of hepatic inflammation were significantly increased. Also, alterations in the expression of redox-related enzymes were observed in obese mice compared to lean controls including increases in extracellular superoxide dismutase (Sod3), heme oxygenase (Ho)-1, and xanthine dehydrogenase (Xdh). Interestingly, hepatic UA levels were significantly elevated (∼2-fold) in obese mice compared to their lean counterparts. These data demonstrate female mice assume a similar metabolic profile to that reported in several male models of obesity in the context of alterations in glucose tolerance, hepatic steatosis, and elevated transaminases (ALT and AST) in the absence of hyperuricemia affirming the need for further study.
The relationship of serum uric acid with non-alcoholic fatty liver disease
2014, Clinical Biochemistry
Citation Excerpt :
In literature, Lonardo et al. first described an association between NAFLD and SUA in a small case–control study of patients with ultrasound-diagnosed NAFLD [12]. Although several studies have suggested that SUA is significantly associated with NAFLD and an elevated SUA level is an independent risk factor for NAFLD [13–17], the underlying mechanism(s) has not yet been clarified. Some studies have reported that patients with NAFLD have higher SUA levels than healthy controls [12,18].
Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological entity which is characterized by the presence of fat droplets in hepatocytes without alcohol consumption, representing a spectrum of hepatic injuries, ranging from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. In recent years, experimental and observational studies suggest a role for serum uric acid (SUA) in NAFLD. However, there are few reports investigating SUA in histologically proven NAFLD. The aim of the present study was to evaluate the relationship of SUA with liver histology in non-diabetic patients with NAFLD.
A total of 242 male patients with NAFLD (102 with NASH and 140 with SS) were included. Histopathological evaluation was carried out according to Kleiner's scoring scale. Hyperuricemia was diagnosed as SUA of more than 7 mg/dL.
The prevalence of hyperuricemia was 33.4%. SUA levels in patients with NASH were significantly higher than those of SS (p = 0.035). Univariate and multivariate analyses both demonstrated that hyperuricemia had a significant association with younger age [OR (95%CI), 0.930 (0.884–0.979), p = 0.005], higher body mass index [OR (95%CI), 1.173 (1.059–1.301), p = 0.002] and hepatocellular ballooning [OR (95%CI), 1.678 (1.041–2.702), p = 0.033].
Hyperuricemia is a common finding in patients with NAFLD and is independently associated with early histological findings in this clinically relevant condition. Further longitudinal studies are needed to characterize the role of SUA in the natural history of NAFLD.
Prevalence and associated metabolic factors of fatty liver disease in the elderly
2013, Experimental Gerontology
Citation Excerpt :
The present study demonstrates a close relationship between high SUA and FLD in the elderly. Indeed, SUA has been found to predicate FLD independently of body weight and MS (Lee, 2009; Ryu et al., 2011). The underlying mechanism is not well studied but may depend on uric acid-induced endothelial dysfunction (Khosla et al., 2005; Ryu et al., 2011), inflammation, and oxidative stress (Sautin et al., 2007).
The aim of this study was to investigate the metabolic risk factors for fatty liver disease in the elderly, and determine the prevalence of fatty liver disease in the elderly in Wuhan, central China.
The study was a case–control study based on all 4226 adults above 60 years of age from a cohort investigated in 2010–11 at the medical examination center of Zhongnan hospital, using 3145 randomly selected adults under 60 years of age from the same cohort as controls. Fatty liver disease (FLD) was identified with ultrasound imaging. The risk factors measured were body mass index (BMI), and plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low density lipoprotein (LDL) and serum uric acid (SUA). The probability of steatohepatitis with advanced fibrosis was predicted using a score based on BMI, age, ALT, and TG (BAAT),and using AST/ALT ratio (AAR).
FLD was higher in the elderly (26.7%) than in the non-elderly (22.8%) and similar in the elderly between men and women (26.6% vs 27.0%, p > 0.05). BMI, TC, TG, LDL, SUA, AST and ALT were all significantly higher in FLD, whereas the level of HDL was markedly lower. Multiple regression analyses showed that obesity, high TC, TG, SUA, low HDL, and elevated ALT, AAR < 1 were closely related to the elderly FLD, while male sex, obesity, high TC, TG, low HDL, elevated ALT, AST and AAR < 1 were closely related to the non-elderly FLD. The prevalence of steatohepatitis with advanced fibrosis estimated as BAAT index ≥ 3 was 2.4% in all subjects, and was higher in the elderly FLD patients than in the non-elderly FLD patients.
The prevalence of FLD is higher in the elderly, and is broadly related to the same metabolic risk factors as in the non-elderly. However, female-sex is no longer protective with increasing age, and the prevalence of steatohepatitis with advanced fibrosis is estimated to be considerably higher in the elderly FLD patients than in the non-elderly FLD controls.
Association of uric acid levels with components of metabolic syndrome and non-alcoholic fatty liver disease in overweight or obese children and adolescents
2013, Jornal de Pediatria
Citation Excerpt :
The finding of hyperglycemia in this age group is unusual, as the more frequent manifestation of glucose metabolism is IR, which is a compensatory mechanism, while glucose tolerance remains normal.24 Although no association with hepatic steatosis was observed in this sample, recent studies have described a significant association between high levels of uric acid and NAFLD, representing an independent risk factor for liver disease.25–27 The most plausible explanation for this association, which has been inferred from the current understanding of NAFLD progression, would be the “two-hit” theory.
To investigate the association between serum uric acid concentration according to the presence or absence of non-alcoholic fatty liver disease (NAFLD) and/or metabolic syndrome (MS) in overweight or obese children and adolescents.
This was a cross-sectional study conducted from April of 2009 to March of 2010, including 129 children and adolescents treated at the Center for Childhood Obesity. Anthropometric data, blood pressure measurements, and laboratory test results were obtained, and NAFLD diagnosis was made by ultrasound. The diagnosis of MS was made using the criteria of the National Cholesterol Education Program/Adult Treatment Panel III, adapted to age range. The chi-squared test or or Fisher's test were used to evaluate the association of uric acid with the groups, with a 95% confidence interval. One-way analysis of variance (ANOVA) was used for comparison of means. Multiple logistic regression was used for adjustment of variables. The data were analyzed with the Statistical Package for Social Sciences (SPSS), release 17.
High levels of uric acid were significantly associated with adolescence, MS, and systolic blood pressure. The highest quartile of uric acid showed significantly higher values of body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, triglycerides, total cholesterol, and homeostatic model assessment index (HOMA-IR), and lower mean values of HDL cholesterol. In the final model, only age range and the presence of MS remained associated with uric acid levels.
High levels of uric acid were associated with MS and adolescence, which was not observed with NAFLD.
Verificar a relação entre a concentração de ácido úrico sérico de acordo com a presença ou não de esteatose hepática não alcoólica e/ou síndrome metabólica (SM) em crianças e adolescentes com sobrepeso ou obesidade.
Estudo transversal desenvolvido no período de abril/2009 a março/2010, incluindo 129 crianças e adolescentes atendidos no Centro de Obesidade Infantil. Foi realizada antropometria, aferição da pressão arterial, dosagem dos exames laboratoriais e o diagnóstico de esteatose hepática por exame ultrassonográfico. Para o diagnóstico de SM, foram utilizados os critérios da National Cholesterol Education Program/Adult Treatment Panel III adaptados para faixa etária. Para avaliação da associação do ácido úrico com os grupos, foi realizado o teste do Qui-quadrado ou Fisher, adotando-se o intervalo de confiança de 95%. Para comparação de médias, utilizou-se o ANOVA One Way. Para o ajuste das variáveis foi utilizada a regressão logística múltipla. Os dados foram processados no SPSS versão 17.
Níveis elevados de ácido úrico associaram-se significativamente à adolescência, SM e pressão arterial sistólica. O maior quartil de ácido úrico apresentou valores médios significativamente mais elevados de índice de massa corpórea, circunferência abdominal, pressão arterial sistólica, pressão arterial diastólica, triglicerídeos, colesterol total e HOMA-IR, e menor média do colesterol HDL. No modelo final só permaneceram associadas aos níveis de ácido úrico a faixa etária e a presença de síndrome metabólica.
Níveis elevados de ácido úrico estiveram associados à síndrome metabólica e à adolescência, o que não foi observado com a esteatose hepática.
Relation of uric acid to serum levels of high-sensitivity c-reactive protein, triglycerides, and high-density lipoprotein cholesterol and to hepatic steatosis
2012, American Journal of Cardiology
Citation Excerpt :
These findings suggest that the relation between UA and early cardiometabolic risk conditions may occur before the development of obesity and metabolic syndrome. Although some studies have documented the association of UA with inflammation,5,6 insulin resistance,1 or hepatic steatosis17 adjusted for body mass index, few have explored the relation of UA with these cardiometabolic risk conditions in the presence and absence of obesity and metabolic syndrome. Previous publications have similarly found that UA was initially associated with hs-CRP in simple or multivariable regression analyses and that this association was substantially attenuated or lost significance after adjusting for body mass index.5,6
Increased uric acid (UA) is strongly linked to cardiovascular disease. However, the independent role of UA is still debated because it is associated with several cardiovascular risk factors including obesity and metabolic syndrome. This study assessed the association of UA with increased high-sensitivity C-reactive protein (hs-CRP), increased ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL), sonographically detected hepatic steatosis, and their clustering in the presence and absence of obesity and metabolic syndrome. We evaluated 3,518 employed subjects without clinical cardiovascular disease from November 2008 through July 2010. Prevalence of hs-CRP ≥3 mg/L was 19%, that of TG/HDL ≥3 was 44%, and that of hepatic steatosis was 43%. In multivariable logistic regression after adjusting for traditional cardiovascular risk factors and confounders, highest versus lowest UA quartile was associated with hs-CRP ≥3 mg/L (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.01 to 2.28, p = 0.04), TG/HDL ≥3 (OR 3.29, 95% CI 2.36 to 4.60, p <0.001), and hepatic steatosis (OR 3.10, 95% CI 2.22 to 4.32, p <0.001) independently of obesity and metabolic syndrome. Association of UA with hs-CRP ≥3 mg/L became nonsignificant in analyses stratified by obesity. Ascending UA quartiles compared to the lowest UA quartile demonstrated a graded increase in the odds of having 2 or 3 of these risk conditions and a successive decrease in the odds of having none. In conclusion, high UA levels were associated with increased TG/HDL and hepatic steatosis independently of metabolic syndrome and obesity and with increased hs-CRP independently of metabolic syndrome.
Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: Potential role in fructose-dependent and -independent fatty liver
2012, Journal of Biological Chemistry
Citation Excerpt :
These findings were paralleled with significantly decreased activity of NOX4 in the mitochondria of pound mice receiving allopurinol (Fig. 8D) with concomitant higher mitochondrial aconitase activity (Fig. 8E) and lower cytoplasmic citrate release (Fig. 8F). As mentioned in the Introduction, NAFLD is strongly associated with hyperuricemia (13–22), but one potential explanation could be because many patients with hyperuricemia have obesity and metabolic syndrome. One potential way to determine whether hyperuricemia may predict NAFLD independent of obesity is to examine the hemodialysis population, as hyperuricemia is common even when obesity is absent.
Metabolic syndrome represents a collection of abnormalities that includes fatty liver, and it currently affects one-third of the United States population and has become a major health concern worldwide. Fructose intake, primarily from added sugars in soft drinks, can induce fatty liver in animals and is epidemiologically associated with nonalcoholic fatty liver disease in humans. Fructose is considered lipogenic due to its ability to generate triglycerides as a direct consequence of the metabolism of the fructose molecule. Here, we show that fructose also stimulates triglyceride synthesis via a purine-degrading pathway that is triggered from the rapid phosphorylation of fructose by fructokinase. Generated AMP enters into the purine degradation pathway through the activation of AMP deaminase resulting in uric acid production and the generation of mitochondrial oxidants. Mitochondrial oxidative stress results in the inhibition of aconitase in the Krebs cycle, resulting in the accumulation of citrate and the stimulation of ATP citrate lyase and fatty-acid synthase leading to de novo lipogeneis. These studies provide new insights into the pathogenesis of hepatic fat accumulation under normal and diseased states.

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Original articleRelationship between uric acid and hepatic steatosis among KoreansRelation entre hyperuricémie et stéatose hépatique chez les coréens

Abstract

Aim

Methods

Results

Conclusion

Résumé

Objectifs

Méthodes

Résultats

Conclusion

Introduction

Section snippets

Study subjects

Results

Discussion

Conflicts of interest

Am J Cardiol

Fatty liver and uric acid levels predict incident coronary heart disease but not stroke among atomic bomb survivors in Nagasaki

Hypertens Res

Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients

Diabetes

Serum uric acid and cardiovascular mortality: the NHANES I epidemiologic follow-up study, 1971–1992

JAMA

Uric acid and cardiovascular risk

N Engl J Med

Insulin resistance and C-reactive protein as independent risk factors for nonalcoholic fatty liver disease in non-obese Asian men

J Gastroenterol Hepatol

Prevalence and risk factors of nonalcoholic fatty liver disease in an adult population of Taiwan: metabolic significance of nonalcoholic fatty liver disease in non-obese adults

J Clin Gastroenterol

Ultrasound scanning in the detection of hepatic fibrosis and hepatic steatosis

BMJ

Original article
Relationship between uric acid and hepatic steatosis among KoreansRelation entre hyperuricémie et stéatose hépatique chez les coréens