Relationship between Hyperuricemia and Body Fat Distribution

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1 ORIGINAL ARTICLE Relationship between Hyperuricemia and Body Fat Distribution Miho Hikita 1, Iwao Ohno 1, Yutaka Mori 2, Kimiyoshi Ichida 1, Takuo Yokose 3 and Tatsuo Hosoya 1 Abstract Objective We investigated the relationship between serum uric acid (SUA) and body fat area, serum lipid level, insulin resistance, and metabolic syndrome in Japanese men. Method We studied 508 Japanese man industrial workers who underwent an annual medical examination and agreed to participate in the CT scanning examination. Body fat area was measured at the umbilical level. Metabolic syndrome was defined by the presence of visceral fat Accumulation ( 100 cm 2 ) accompanied by two or more disorders; dislipidemia, hypertension, and hyperglycemia. Results SUA was positively correlated with visceral fat area, subcutaneous fat area, serum total cholesterol level, serum triglyceride level, the Homeostasis Model Assessment index, and was negatively correlated with the high-density lipoprotein cholesterol level. In multiple regression analysis, the most influential factor for SUA was visceral fat area (p=0.0027), followed by the serum triglyceride level (p=0.0245). We clarified a higher SUA in the metabolic syndrome group as compared with the non-metabolic syndrome group: 6.67± 1.14 mg, 6.09±1.14 mg, respectively (p<0.0001). The median SUA was elevated with increasing metabolic syndrome factors (p<0.0001). Conclusion The present study indicated that SUA is related to visceral fat accumulation. Patients with metabolic syndrome revealed a higher SUA. Key words: uric acid, metabolic syndrome, visceral fat obesity () Introduction Many previous reports have shown the relationship between obesity and lifestyle-related disease. Matsuzawa et al showed that visceral fat obesity caused the clustering of lifestyle-related diseases, leading to various vascular diseases, so they proposed the term visceral fat syndrome for this condition (1-3). The term metabolic syndrome was proposed by the World Health Organization (WHO) in 1999 (4). The criteria for the diagnosis of metabolic syndrome were defined by WHO (4), the National Cholesterol Education Program (ATP III) (5), and the International Diabetes Federation (IDF) (6), and the Japanese criteria was published in 2005 (7). In a previous study, we showed that hyperuricemia is closely related to obesity and the degree of body fat accumulation (8). We also reported that patients with hyperuricemia are complicated with various lifestyle-related diseases, and patients who have many lifestyle-related diseases show a higher SUA (9). There are various hypotheses as to why obesity causes hyperuricemia: for instance, accelerated uric acid production coupled with the synthesis of triglyceride (10), underexcretion of uric acid into the urine caused by the effect of insulin on the urinary tubular tract (11-13). Several epidemiological reports showed a significant relationship between SUA and cardiovascular and cerebrovascular disease. In particular, in patients with hypertension, SUA was defined as an independent risk factor for cardiovascular Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Division of Diabetes and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo and Matsushita Tokyo Healthcare Center, Tokyo Received for publication January 23, 2007; Accepted for publication May 2, 2007 Correspondence to Dr. Miho Hikita, miho-h@yc4.so-net.ne.jp 1353

2 Table1. PatientCharacteristicsbyQuartileofSerum UricAcidLevel disease. In the National Health and Nutrition Survey (NHANES I study), SUA was an independent risk factor for cardiovascular disease in both men and women (14). There are several cohort study reports in Japan on the relationship between SUA and the risk factors for diseases such like cardiovascular diseases, other cardiogenic diseases, cerebrovascular disease, renal failure, hepatogenic diseases, cancer, and mortality. In a cohort study of industrial workers, Tomita et al reported that hyperuricemia raises the incidence of these diseases and mortality (15), and Hakoda et al reported that SUA is an independent risk factor for cardiovascular disease in women, and for total mortality in both men and women (16). On the basis of such evidence, SUA is suggested to be a significant risk marker in the Japanese criteria. In the present study, we investigated the relationship between SUA and body fat area and metabolic syndrome. We used the visceral fat area determined by CT scanning to assess visceral fat obesity, because we think it is useful for comparison with other races and reflects visceral fat accumulation more precisely. Subjects Subjects and Methods A total of 508 man Japanese industrial workers (24-68 years) who underwent an annual medical examination and agreed to participate in CT scanning examination were enrolled in this study. Method of measurement of body fat distribution The visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by computed tomographic scanning at the umbilical level (17) (CT-W550, HITACHI, Japan). Measurement of each parameter SUA was measured enzymatically using uricase peroxidase. The serum total cholesterol level (TC), serum triglyceride level (TG) and serum high-density lipoprotein cholesterol level (HDL-C) were also measured enzymatically. Fasting plasma glucose was measured using the glucose oxidase method, and immunoreactive insulin (IRI) was measured by radioimmunoassay. Homeostasis Model Assessment (HOMA) was used for the assessment of insulin resistance. The HOMA index was calculated as FPG (mg/dl) IRI (μu/ml)/405, according to the method of Matthews et al (18). Diagnosis of metabolic syndrome In the present study, we used modified Japanese criteria; metabolic syndrome was defined as I (visceral fat obesity) and the presence of two or more conditions in criteria II. IDF criteria recommend that waist circumference should be defined using ethnicity specific values. The Japanese criteria requires a waist circumference measurement of 85 cm in men, and 90 cm in women as the diagnostic level. It also recommends that it is better to examine the body fat area using CT scanning, with a diagnostic level of 100 cm 2 in both men and women. Therefore, we used the visceral fat area determined by CT scan examination at the umbilical level. I Visceral fat area 100 cm 2 II 1 TG 150 mg/dl and/or HDL-C < 40 mg/dl 2 Systolic blood pressure 130 mmhg and/or diastolic blood pressure 85 mmhg 3 Fasting blood glucose 110 mg/dl Statistical analysis The correlation between the two variables was assessed using Pearson s correlation test. Differences between the two groups were assessed with the Mann-Whitney U test and those among multiple groups were assessed with Sheffe s F test and analysis of variance. The correlation between the complication number of metabolic syndrome components and SUA level was assessed by Spearman s correlation coefficient by rank. P<0.05 was considered statistically significant in all analyses. All analyses were performed with the StatView for Windows version 5.0 software program. Results The characteristics of subjects are shown in Table 1. The subjects mean age was 47.5 years old (24-68 years). Their mean BMI was 24.9 kg/m 2. All subjects were classified into quartiles by SUA (Quartile 1 (Q1): SUA 5.3 mg/dl, n= 119; Quartile 2 (Q2): SUA mg/dl, n=132; Quartile 3 (Q3): SUA mg/dl, n=133; Quartile 4 (Q4 ): SUA 1354

3 Figure1. Relationshipbetweentheserum uricacidlevel andvisceralfatarea. 7.1 mg/dl, n=124. No significant differences of mean age were seen in any quartile. Higher quartiles showed higher BMI, and a significant difference was seen between Q2 and Q4 (p<0.001). We investigated the relationship between SUA and VFA. A significant correlation between SUA and VFA was seen (r=0.303, P<0.001); furthermore, a higher quartile of SUA showed a higher VFA (Fig. 1). A significant correlation was also seen between SUA and SFA (r=0.252, p<0.001) (Fig. 2); however, in the quartile analysis, a significant difference was only seen between Q4 and the other quartiles (Fig. 2). These results showed that the body fat area, especially VFA, was significantly related to SUA. In the study of serum lipid and SUA, a significant correlation was seen between SUA and TC (r=0.158, p<0.001) and TG (r=0.189, p<0.001), and a negative correlation was seen between SUA and HDL (r=-0.019, p<0.001) (data not shown). These results suggested that serum lipids, and in particular TG, are significantly related to SUA. A significant correlation was also seen between SUA and HOMA index (r=0.152, p<0.001) (data not shown). This indicates a significant relationship between SUA and insulin resistance. Figure2. Relationshipbetweentheserum uricacidlevel andsubcutaneousfatarea. To examine the most influential parameters on SUA, multiple regression analysis was carried out. As shown in Table 2, the contributing factors to SUA were VFA (p= ), followed by TG (p=0.0245). Furthermore, we investigated the difference of serum uric acid in two groups: Metabolic syndrome group (MS: n=130) and non-metabolic syndrome group (NMS: n=372). In this study, mean SUA was significantly higher than that in the NMS group (6.67±1.14 mg, 6.09±1.14 mg, for each, p< ) (Fig. 3). In Spearman s rank correlation coefficient analysis, the median SUA was elevated with increasing metabolic syndrome characteristics (p <0.0001) (Fig. 4). Discussion Upper-body obesity is considered to be a risk factor for coronary artery disease. Matsuzawa et al showed that visceral fat obesity (VFO) cause many lifestyle-related diseases based on insulin resistance, and accelerated the development of atherosclerotic diseases, as termed visceral fat obesity syndrome (1-3). 1355

4 Table2. MultipleRegresionAnalysisforEachParameterinRelationtoSe rum UricAcidLevel Figure3. Diferenceintheserum uricacidlevelinthepres enceofmetabolicsyndrome. Some investigators reported the relationship of body fat area and SUA. Matsuura et al. reported that patients with VFO (V/S ratio >0.4) show a higher urinary excretion of uric acid than those with subcutaneous fat obesity (SFO) (19); they therefore concluded that visceral fat accumulation is related to the overproduction of uric acid. Furthermore, Takahashi et al. reported that gout patients had a larger VFA than healthy subjects (20). They also reported that gout patients with the overproduction type had an increased VFA compared with the underexcretion type. In the present study, there were significant relations between SUA and both VFA and SFA; in particular, SUA was more closely related to VFA. Unfortunately, we did not examine the urinary uric acid level in the present study, and thus we could not assess the relationship between uric acid metabolism or the type of hyperuricemia and body fat area. It is considered that the accumulation of visceral fat leads to insulin resistance, and a plurality of lifestyle-related diseases based on insulin resistance. The mechanism as to why visceral fat accumulation causes insulin resistance is thought Figure4. Distributionoftheserum uricacidlevelaccord ingtothenumberofmetabolicsyndromecomponent. to result from direct injury to the insulin receptor system by excessive free fatty acid in the portal vein (2). Several past studies have shown that hyperinsulinemia or insulin resistance decreased urinary uric acid excretion by the effect of insulin on urinary tubules (12, 13, 21). It is known that uric acid and sodium have a co-transporter system in the kidney (22). Ferrannini et al reported that patients with essential hypertension show insulin resistance as determined by the glucose clamp test (23) DeFronzo showed that venous infusion of insulin decreases the urinary excretion of sodium (24). After these reports, Galvan et al showed that elevation of the plasma insulin level decreases both the urinary fractional excretion of sodium (FENa) and uric acid (FEua) (12). Furthermore, Ter Maaten et al showed a negative correlation between uric acid clearance and insulin resistance as determined by the glucose clamp method (13). These studies indicated that hyperinsulinemia or insulin resistance decreases 1356

5 the urinary excretion of uric acid and causes hyperuricemia. From these results, it is considered that altered renal handling of uric acid and sodium due to an insulin effect lead to the coexistence of hyperuricemia and hypertension in a clustering of lifestyle-related diseases. As a significant correlation between insulin resistance measured by the HOMA index, and SUA was also seen in the present study, our results support that insulin resistance causes hyperuricemia. Another reason why VFO causes hyperuricemia is as follows; in VFO patients, excessive free fatty acid in the portal vein accelerates the overproduction of very low-density lipoprotein that leads to hypertriglyceridemia. This also accelerates the de novo synthesis of ribose-5-phosphate to phosphoribosylpyrophosphate through the common metabolic pathway of NADP-NADPH, and as a result of this mechanism, uric acid production increases (10, 25). Tsutsumi et al reported that decreased activities of lipoprotein lipase and hepatic triglyceride lipase are seen in patients with gout (26). They considered that this might lead to a higher risk of coronary atherosclerotic diseases. In the present study, we concluded that the elevation of SUA is related to visceral fat accumulation and to the elevation of TG. In multiple regression analysis, the strongest correlation was seen between SUA and VFA (p=0.0027), followed by TG (p=0.0245). Other parameters, such as SFA, TC, the HOMA index, BMI andbpshowednosignificantcorrelationtosua. The criteria for the diagnosis of metabolic syndrome in Japan was defined in 2005 (7). In this criteria, SUA is not a diagnostic factor, because there is not enough evidence that it is an independent risk factor of cardiovascular disease, and they recommend that SUA should be used as a significant risk marker. Our results also suggest a relationship between SUA and metabolic syndrome. Recently, Kawamoto et al reported a significant relationship between SUA and metabolic syndrome in women (27). They also clarified that SUA was an independent risk factor for the incidence of carotid atherosclerosis, and concluded that SUA increases the risk of cardiovascular morbidity. By accumulation of clinical evidence, the significance of SUA in metabolic syndrome will become clearer. The improvement of insulin resistance might improve hyperuricemia and many lifestyle-related diseases, so we consider that treatment and education to decrease visceral fat accumulation is the most important for such patients. In conclusion, 1) SUA was positively correlated with VFA, SFA, TC, TG, and HOMA index, and negatively correlated with HDL; 2) In multiple regression analysis, the most influential factor for SUA was VFA; 3) SUA was significantly higher in the metabolic syndrome group than in the non-metabolic syndrome group; 4) SUA was elevated with increasing metabolic syndrome characteristics. To clarify these mechanisms, more advanced study should be conducted, such as a prospective cohort study or a study on uric acid metabolism in many subjects. References 1. Fujioka S, Matsuzawa Y, Tokunaga K, Tarui S. Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism 36: 54-59, Tarui S, Tokunaga K, Fujioka S, Matsuzawa Y. Visceral fat obesity: anthropological and patho-physiological aspects. Int J Obes 15: 1-8, Matsuzawa Y. Pathophysiology and molecular mechanisma of visceral fat syndrome: The Japanese experience. 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