Hyperuricemia may have an important role in metabolic syndrome, cardiovascular diseases and stroke. Elevated serum
uric acid concentration has been shown to be the strong predictor of cardiovascular mortality in several recently
published studies. Our aim was to determine the prevalence of hyperuricemia in general Croatian population and to investigate
the association of serum uric acid with glucose and lipids. This was a retrospective cross-sectional study on
6,476 consecutive adults. Prevalence of hyperuricemia was 13.9% in general population and it was significantly higher
in males, than in females (26% vs. 6%; p<0.001). Median uric acid concentration was higher in males than in females
(343 vs. 238 mmol/L; p<0.001). Age, glucose and lipid parameters did not correlate with uric acid. In hyperuricemic subjects,
increased concentrations of glucose (33.1% vs. 13.1%; p<0.001), triglycerides (46.9% vs. 17.6%; p<0.001), total cholesterol
(69.6% vs. 51.9%; p<0.001), LDL-cholesterol (64.5% vs. 46.4%; p<0.001) and decreased concentration of HDL-
-cholesterol (24.3% vs. 13.0%; p<0.001) were more prevalent than in subjects with normal serum concentrations of uric
acid. Hyperuricemia is highly prevalent in Croatian general population and it aggregates with hyperglycemia and dyslipidemia

Ana-Maria Šimundić

Marinko Bilušić

Nora Nikolac

Sanja Kačkov

HRČAK - Portal of Croatian Scientific and Professional Journals

Coll. Antropol. 35 (2011) 4: 1055–1059Original scientific paperThe Association of Uric Acid with Glucoseand Lipids in General Population: CroatianCross-Sectional StudySanja Ka~kov1, Ana-Maria [imundi}2, Nora Nikolac2 and Marinko Bilu{i}11 Bonifarm Policlinic, Medical Biochemistry Laboratory, Zagreb, Croatia2 University of Zagreb, »Sestre milosrdnice« University Hospital Center, Department of Chemistry, Zagreb, CroatiaA B S T R A C THyperuricemia may have an important role in metabolic syndrome, cardiovascular diseases and stroke. Elevated se-rum uric acid concentration has been shown to be the strong predictor of cardiovascular mortality in several recentlypublished studies. Our aim was to determine the prevalence of hyperuricemia in general Croatian population and to in-vestigate the association of serum uric acid with glucose and lipids. This was a retrospective cross-sectional study on6,476 consecutive adults. Prevalence of hyperuricemia was 13.9% in general population and it was significantly higherin males, than in females (26% vs. 6%; p<0.001). Median uric acid concentration was higher in males than in females(343 vs. 238 mmol/L; p<0.001). Age, glucose and lipid parameters did not correlate with uric acid. In hyperuricemic sub-jects, increased concentrations of glucose (33.1% vs. 13.1%; p<0.001), triglycerides (46.9% vs. 17.6%; p<0.001), total cho-lesterol (69.6% vs. 51.9%; p<0.001), LDL-cholesterol (64.5% vs. 46.4%; p<0.001) and decreased concentration of HDL--cholesterol (24.3% vs. 13.0%; p<0.001) were more prevalent than in subjects with normal serum concentrations of uricacid. Hyperuricemia is highly prevalent in Croatian general population and it aggregates with hyperglycemia and dysli-pidemia.Key words: uric acid, metabolic syndrome, lipids, hyperuricemiaIntroductionThe concentration of serum uric acid is controlled bymany factors, including genetics, insulin resistance, re-nal function, obesity, diet and alcohol consumption1,2.Elevation of the serum uric acid level (i.e. hyperuri-cemia) more frequently occurs in males and overweightpersons and its prevalence varies in different popula-tions3. It has been reported that hyperuricemia mayhave an important role in several pathological condi-tions such as metabolic syndrome, cardiovascular dis-eases (CVD), chronic kidney disease, stroke, maternalcomplications in pre-eclampsia4–7. Elevated serum uricacid has been shown to be the strong predictor of cardio-vascular mortality in several recently published stu-dies8–10, whereas some other publications were not ableto confirm these findings11.Hyperuricemia has also been associated with certainmetabolic abnormalities, such as impaired glucose me-tabolism and dyslipidemia and several investigatorshave studied this association12,13. However, these associ-ations are not yet fully understood and results are stillinconsistent.We have, therefore, undertaken this study with theaim to: (i) determine the prevalence of hyperuricemia ingeneral Croatian population and (ii) investigate the asso-ciation of serum uric acid with glucose and lipid concen-tration.Materials and MethodsPatientsThis was a retrospective cross-sectional study on pa-tient laboratory results retrieved from the laboratory in-formation system (LIS). The study included laboratory1055Received for publication July 28, 2010results for 6,476 consecutive adults referred to medicalbiochemistry laboratory of Policlinic Bonifarm for rou-tine blood testing, mainly as a part of the routine peri-odic health check-up between June 2007 and February2009.Policlinic Bonifarm is policlinic specialized in phar-macology and toxicology and medical biochemistry labo-ratory. Total number of samples admitted to the labora-tory is 11,000 per year and the total yearly number ofanalyses is about 75,000.MethodsFollowing data were retrieved from the LIS for everyindividual: age, gender, concentration of glucose, triglyc-erides, total cholesterol, HDL-cholesterol, LDL-choles-terol and uric acid.For all patients venous blood sampling was done inthe morning, after an overnight fast. All laboratory testswere done immediately after sampling.All biochemical parameters were measured by stan-dard enzymatic methods on analyzer Cobas Integra 400plus (Roche Diagnostics, Mannheim, Germany).LDL-cholesterol was calculated using Friedwald equa-tion. When triglyceride concentration was above 3 mmol/L,LDL-cholesterol was measured by direct method on Co-bas Integra 400 plus (Roche Diagnostics, Mannheim,German).Statistical analysisCategorical data are presented as counts and percent-ages. Normality was tested using Kolmogorov-Smirnovtest. All distributions were non-Gaussian. Median andinterquartile range (IQR) were used to describe the data.Data were categorized into two subgroups: with (a) nor-mal and (b) increased (decreased for HDL) concentra-tions of measured parameters. Cut-off values used forgrouping were 5.5 mmol/L for glucose, 5.0 mmol/L forcholesterol, 1.7 mmol/L for triglycerides, 3.0 mmol/L forLDL cholesterol and 1.0 mmol/L and 1.2 mmol/L forHDL cholesterol for males and females respectively. Tho-se values were chosen according to the recommendedATP III criteria14. Value for HDL in females was slightlymodified according to national recommended value (Cro-atian Chamber of Medical Biochemists). As a cut-offvalue used for categorizing subjects respective to the con-centration of uric acid, we used the upper limit of refer-ence interval (URL) (403 mmol/L for males and 337mmol/L for females).The c2-test was used for comparing categorical vari-ables and Mann-Whitney rank sum test for assessing dif-ferences between numerical variables. Spearman rankcorrelation analysis was used to assess the associationbetween variables (uric acid, age, glucose, lipid parame-ters). The level of statistical significance was set at 0.001,due to the large sample size.Statistical analysis was performed by using MedCalc10.1.2.0 (Frank Schoonjans, Mariakerke, Belgium).ResultsThe study included 6,476 patients. Patient demo-graphic characteristics and biochemical parameters arepresented in Table 1.Hyperuricemia prevalence was 13.9% in general pop-ulation and it was significantly higher in males, than infemales (26% vs. 6%; p<0.001). Furthermore, medianuric acid concentration, although within the referenceinterval, was higher in males than in females (343 vs. 238mmol/L; p<0.001).We have tested possible correlations of uric acid withage, glucose and lipid parameters. As of our result, age,glucose and lipid parameters did not correlate with uricacid in studied population (data not shown). Correlationwas not present even when we analyzed the relationshipof uric acid with age, glucose and lipids within the uricacid quartile subgroups (data not shown).Study subjects with hyperuricemia were found tohave higher prevalence of increased concentrations ofglucose (33.1% vs. 13.1%; p<0.001), triglycerides (46.9%vs. 17.6%; p<0.001), total cholesterol (69.6% vs. 51.9%;p<0.001), LDL-cholesterol (64.5% vs. 46.4%; p<0.001)and decreased value HDL-cholesterol (24.3% vs. 13.0%;p<0.001) compared to subjects with serum uric acid lev-els within the reference interval (Table 2).S. Ka~kov et al.: Uric acid, Glucose and Lipids in General Population, Coll. Antropol. 35 (2011) 4: 1055–10591056TABLE 1PATIENT DEMOGRAPHIC CHARACTERISTICS AND BIOCHEMICAL PARAMETERSMale, N=2,827 Female, N=3,598 pAge, years* 43 (34–52) 41 (33–50) <0.001Uric acid, mmol/L* 343 (300–391) 238 (204–276) <0.001Hyperuricemia, N (%) 1.683 (26%) 389 (6%) <0.001Glucose, mmol/L* 5.1 (4.8–5.5) 4.7 (4.5–5.1) <0.001Cholesterol, mmol/L* 5.3 (4.6–6.1) 5.0 (4.4–5.8) <0.001HDL-cholesterol, mmol/L* 1.3 (1.1–1.5) 1.7 (1.4–2.0) <0.001LDL-cholesterol, mmol/L* 2.8 (2.3–3.5) 3.3 (2.6–3.9) <0.001Triglycerides, mmol/L* 1.4 (0.9–2.0) 0.9 (0.7–1.3) <0.001*Data are presented as median and interquartile rangeDiscussionThe prevalence of hyperuricemia in this study was13.9% in general population and it was significantlymore prevalent in males, than in females. Age, glucoseand lipid parameters did not correlate with uric acid con-centration in studied population. However, hyperurice-mic subjects more often had increased concentrations ofglucose, triglycerides, total cholesterol, LDL-cholesterol.HDL-cholesterol concentrations were more often decrea-sed in our subjects with elevated uric acid concentration.Eventhough the prevalence of hyperuricemia and itsassociation with various biochemical parameters has beenstudied by many authors, the results are controversialand not yet conclusive. The overall prevalence of hyper-uricemia in one recently published study on 132 subjectsfrom western Turkey was 12.1%3. The cut-off values foruric acid in this study were >420 mmol/L for males and>360 mmol/L for females, what was comparable to cut-offvalues used in our study. Males had significantly higheruric acid concentrations than females (330±80 vs. 260±70mmol/L, respectively; p=0.05). This gender dependentdifference in uric acid concentrations may probably beexplained by gonadal hormones15.Lippi et al.12 have investigated the association be-tween uric acid, fasting plasma glucose and triglyceridesin the general population. The overall prevalence ofhyperuricemia in 10,181 randomly selected individualswas 3.8%. It should be noted that cut-off values for uricacid were much higher than the ones used in our study(uric acid cut-off values were 506 mmol/L and 416mmol/L, for males and females, respectively). This mightexplain the observed large difference between the preva-lence in our and Italian population. The major finding ofthe study by Lippi et al. was that hypertriglyceridemic(triglycerides >1.7 mmol/L) and hyperglycemic (fastingplasma glucose >6.1 mmol/L) adults had increased prev-alence of elevated serum uric acid concentrations, com-pared to subjects having normal lipid and glucose con-centrations (11% vs. 3%, respectively; p=0.018). Theauthors conclude that this association raises the possibilityof a potential pathogenic overlap between these states.Hjortnaes et al.16 have investigated the association be-tween serum uric acid and components of metabolic syn-drome in patients with manifest vascular disease. Theyobserved higher average concentrations of serum uricacid in patients with, than in patients without metabolicsyndrome (360±80 mmol/L vs. 329±90 mmol/L). Further-more, their observation was that the patients who hadmore components of metabolic syndrome present, hadalso higher concentration of serum uric acid.Rathmann17 and his colleagues have published the re-sults of the Cardia study with the 10-year follow-up on1,249 male and 1,362 female young subjects. During thefollow-up, they observed the significant increase of themean serum uric acid concentration (p<0.01). They alsoobserved a significant independent association of bodymass index (BMI) and triglycerides with serum uric acid.In the study published by Liou et al.18, uric acid aggre-gated with BMI, waist circumference (WC), glucose, logvalue of triglycerides, and HDL cholesterol. However,their conclusion was that metabolic syndrome is not as-sociated with hyperuricemia.In one recently published cross-sectional study on2,085 Taiwanese men and 1,557 women19, hyperuricemiawas significantly associated with increased risk for hy-pertriglyceridemia, low high-density lipoprotein choles-terol level, and high blood pressure in men and women.However, contrary to our results, the uric acid levelswere inversely associated with hyperglycemia in Taiwan-ese men. In one other similar study on 470 subjects, whowere also from Taiwan, serum uric acid was significantlyrelated to risk factors of metabolic syndrome, with theexception of blood glucose which did not correlate withuric acid20. It may be that there are some racial and eth-nic differences in metabolic interactions of the compo-nents of lipid and glucose metabolism. Furthermore, theobserved difference in the association between glucoseand uric acid may also be at least partially due to largeS. Ka~kov et al.: Uric acid, Glucose and Lipids in General Population, Coll. Antropol. 35 (2011) 4: 1055–10591057TABLE 2PREVALENCE OF SUBJECTS WITH HYPERGLYCEMIA AND DYSLIPIDEMIA RESPECTIVE TO THE URIC ACID CONCENTRATIONUric acid within referenceinterval N=5,671 (87.8%)Uric acid aboveURL N=787 (12.2%)pGlucose >5.5 mmol/LN=457 (15.6%)746 (13.1%) 261 (33.1%) <0.001Cholesterol >5.0 mmol/LN=3,500 (54.0%)2,947 (51.9%) 553 (69.6%) <0.001Triglycerides >1.7 mmol/LN=1,374 (21.2%)1,001 (17.6%) 373 (46.9%) <0.001LDL cholesterol >3.0 mmol/LN=3,151 (48.7%)2,638 (46.4%) 513 (64.5%) <0.001HDL cholesterol 1.0 (M) mmol/LHDL cholesterol 1.2 (F) mmol/LN=929 (14.3%)736 (13.0%) 193 (24.3%) <0.001URL – upper limit of reference intervaldifferences in diet and lifestyle between Western civiliza-tions and Asian subjects21.So, although not confirmed by all, uric acid was mo-stly found to aggregate with disturbed metabolism of glu-cose and lipids. Uric acid is known to correlate with insu-lin resistance. The mechanism of this phenomenon is notfully understood. It has been postulated that insulinprobably decreases the clearance of uric acid in the renalproximal tubule, resulting in a subsequent increase in se-rum uric acid levels in healthy individuals and asymp-tomatic hyperuricemic subjects22.As such, the measurement of uric acid might be advis-able to those at increased risk of CVD23. However, thereis a continuing debate about the relevance of the in-creased serum uric acid concentration and its role as anindependent cardiovascular risk factor. The predictivevalue of uric acid concentration for cerebrovascular andcardiovascular mortality has been studied in several lar-ge prospective studies. In the prospective cohort study on1,423 middle-aged Finnish men initially without CVD,published by Niskanen et al., serum uric acid was astrong predictor of cardiovascular mortality, independ-ent of variables commonly associated with gout or themetabolic syndrome8. Elevated concentrations of uricacid were also associated with increased mortality in oneAustrian cohort of 83,683 subjects10. However, one pro-spective cohort study on 22,698 Korean men, aged 30 to77 years, with a 9-year of follow-up found that elevatedserum uric acid was not an independent risk of cardio-vascular mortality11. It is therefore clear that we stillneed some well designed prospective trials and moni-tored therapeutic interventions to further improve ourunderstanding of the risk factors for metabolic syndromeand cardiovascular mortality24.Despite of the very intense research on this field,there is still much controversy on the role and signifi-cance of uric acid and its relation to some biological pa-rameters. Such controversy may be due to the differentcut-off used to define hyperuricemia, small sized studiesand some ethnical differences, comorbidity and other dif-ferences in studied populations.The present study has some limitations. The studypopulation of outpatient adults from laboratory may notbe completely representative sample of general popula-tion. Anthropometric measures, like BMI and some otherimportant data on the comorbidity (like hypertension,cardiovascular disease, etc.), therapy, diet and other envi-ronmental factors would be very useful to further ex-plore these complex associations. Unfortunately, none ofthe additional clinical information was available on thislarge cohort of outpatients.ConclusionHyperuricemia is highly prevalent in Croatian gen-eral population and it aggregates with hyperglycemiaand dyslipidemia. Males are more often hyperuricemicthan females.R E F E R E N C E S1. BLEYER AJ, HART TC, Adv Chronic Kidney Dis, 13 (2006) 124. —2. TANIGUCHI A, KAMATANI N, Curr Opin Rheumatol, 20 (2008) 192.— 3. SARI I, AKAR S, PAKOZ B, SISMAN AR, GURLER O, BIRLIK M,ONEN F, AKKOC N, Rheumatol Int, 29 (2009) 869. — 4. CHOI HK, FORDES, Am J Med, 120 (2007) 442. — 5. KOOPMANS CM, VAN PAMPUSMG, GROEN H, AARNOUDSE JG, VAN DEN BERG PP, MOL BW, Eur JObstet Gynecol Reprod Biol, 146 (2009) 8. — 6. KIM SY, GUEVARA JP,KIM KM, CHOI HK, HEITJAN DF, ALBERT DA, Arthritis Rheum, 61(2009) 885. — 7. BERGAMINI C, CICOIRA M, ROSSI A, VASSANELLIC, Eur J Heart Fail, 11 (2009) 444. — 8. NISKANEN LK, LAAKSONENDE, NYYSSÖNEN K, ALFTHAN G, LAKKA HM, LAKKA TA, SALONENJT, Arch Intern Med, 164 (2004) 1546. — 9. IOACHIMESCU AG, BRE-NNAN DM, HOAR BM, HAZEN SL, HOOGWERF BJ, Arthritis Rheum,58 (2008) 623. — 10. STRASAK A, RUTTMANN E, BRANT L, KELLE-HER C, KLENK J, CONCIN H, DIEM G, PFEIFFER K, ULMER H, ANDVHM&PP STUDY GROUP, Clin Chem, 54 (2008) 273. — 11. JEE SH,LEE SY, KIM MT, Eur J Cardiovasc Prev Rehabil, 11 (2004) 185. — 12.LIPPI G, MONTAGNANA M, TARGHER G, SALVAGNO GL, GUIDI GC,Biochem Med, 18 (2008) 37. — 13. LIN KP, J Nurs Res, 17 (2009) 286. —14. EXPERT PANEL ON DETECTION, EVALUATION AND TREAT-MENT OF HIGH BLOOD CHOLESTEROL IN ADULTS, JAMA, 285(2001) 2486. — 15. GHEI M, MIHAILESCU M, LEVINSON D, Curr Rheu-matol Rep, 4 (2002) 270. — 16. HJORTNAES J, ALGRA A, OLIJHOEK J,HUISMAN ET AL, J Rheumatol, 34 (9) (2007) 1882. — 17. RATHMANNW, HAASTERT B, ICKS A, GIANI G, ROSEMAN JM, Eur J Epidemiol,22 (2007) 439. — 18. LIOU TL, LIN MW, HSIAO LC, TSAI TT, CHANWL, HO LT, HWU CM, J Chin Med Assoc, 69 (2006) 104. — 19. LIU PW,CHANG TY, CHEN JD, Metabolism, 59 (6) (2010) 802. — 20. LIN JD,CHIOU WK, CHANG HY, LIU FH, WENG HF, Metabolism, 56 (2007)751. — 21. EGUSA G, WATANABE H, OHSHITA K, FUJIKAWA R,YAMANE K, OKUBO M, KOHNO N, J Atheroscler Thromb, 9 (2002)299. — 22. RATHMANN W, FUNKHOUSER E, DYER AR, ROSEMANJM, Annals Epidemiol, 8 (1998) 250. — 23. LIPPI G, MONTAGNANAM, SALVAGNO GL, TARGHER G, GUIDI GC, Clin Cardiol, 33 (2)(2010) 76. — 24. BLATON VH, KORITA I, BULO A, Biochem Med, 18(2008) 14.S. Ka~kovBonifarm Policlinic, Medical Biochemistry Laboratory, Laginjina 16, 10000 Zagreb, Croatiae-mail: skackov@bonifarm.hrS. Ka~kov et al.: Uric acid, Glucose and Lipids in General Population, Coll. Antropol. 35 (2011) 4: 1055–10591058POVEZANOST MOKRA]NE KISELINE S GLUKOZOM I LIPIDIMA U OP]OJ POPULACIJI:PRESJE^NO ISTRA@IVANJE U HRVATSKOJS A @ E T A KHiperuricemija mo`e imati zna~ajnu ulogu u metaboli~kom sindromu, kardiovaskularnim bolestima i mo`danomudaru. Novija istra`ivanja su pokazala da koncentracija mokra}ne kiseline u serumu mo`e biti sna`an prediktor kar-diovaskularne smrtnosti. Cilj ovog istra`ivanja bio je utvrditi prevalenciju hiperuricemije u op}oj populaciji u Hrvatskoji ispitati povezanost koncentracije mokra}ne kiseline s koncentracijama glukoze i lipida. Ovo retrospektivno presje~noistra`ivanje provedeno je na 6,476 uzastopnih odraslih ispitanika. Prevalencija hiperuricemije je bila 13,9% u op}ojpopulaciji. Hiperuricemija je bila u~estalija u mu{karaca, nego u `ena (26% prema 6%; p<0,001), a medijan koncen-tracije mokra}ne kiseline je bio vi{i u mu{karaca nego u `ena (343 prema 238 mmol/L; p<0,001). Dob, koncentracijaglukoze i lipidnih parametara nisu bili povezani s koncentracijom mokra}ne kiseline. Ispitanici s hiperuricemijom imalisu povi{enu koncentraciju glukoze (16,5% prema 6,8%; p<0,001), triglicerida (46,9% prema 17,6%; p<0,001), ukupnogkolesterola (69,6% prema 51,9%; p<0,001), LDL-kolesterola (64,5% prema 46,4%; p<0,001) i sni`enu koncentracijuHDL-kolesterola (24,3% prema 13,0%; p<0,001) ~e{}e nego ispitanici s normalnom koncentracijom mokra}ne kiselineu serumu. Hiperuricemija ima visoku prevalenciju i povezana je s hiperglikemijom i dislipidemijom u op}oj populaciji uHrvatskoj.S. Ka~kov et al.: Uric acid, Glucose and Lipids in General Population, Coll. Antropol. 35 (2011) 4: 1055–10591059

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The Association of Uric Acid with Glucose and Lipids in General Population: Croatian Cross-Sectional Study

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Coll. Antropol. 35 (2011) 4: 1055–1059Original scientific paperThe Association of Uric Acid with Glucoseand Lipids in General Population: CroatianCross-Sectional StudySanja Ka~kov1, Ana-Maria [imundi}2, Nora Nikolac2 and Marinko Bilu{i}11 Bonifarm Policlinic, Medical Biochemistry Laboratory, Zagreb, Croatia2 University of Zagreb, »Sestre milosrdnice« University Hospital Center, Department of Chemistry, Zagreb, CroatiaA B S T R A C THyperuricemia may have an important role in metabolic syndrome, cardiovascular diseases and stroke. Elevated se-rum uric acid concentration has been shown to be the strong predictor of cardiovascular mortality in several recentlypublished studies. Our aim was to determine the prevalence of hyperuricemia in general Croatian population and to in-vestigate the association of serum uric acid with glucose and lipids. This was a retrospective cross-sectional study on6,476 consecutive adults. Prevalence of hyperuricemia was 13.9% in general population and it was significantly higherin males, than in females (26% vs. 6%; p<0.001). Median uric acid concentration was higher in males than in females(343 vs. 238 mmol/L; p<0.001). Age, glucose and lipid parameters did not correlate with uric acid. In hyperuricemic sub-jects, increased concentrations of glucose (33.1% vs. 13.1%; p<0.001), triglycerides (46.9% vs. 17.6%; p<0.001), total cho-lesterol (69.6% vs. 51.9%; p<0.001), LDL-cholesterol (64.5% vs. 46.4%; p<0.001) and decreased concentration of HDL--cholesterol (24.3% vs. 13.0%; p<0.001) were more prevalent than in subjects with normal serum concentrations of uricacid. Hyperuricemia is highly prevalent in Croatian general population and it aggregates with hyperglycemia and dysli-pidemia.Key words: uric acid, metabolic syndrome, lipids, hyperuricemiaIntroductionThe concentration of serum uric acid is controlled bymany factors, including genetics, insulin resistance, re-nal function, obesity, diet and alcohol consumption1,2.Elevation of the serum uric acid level (i.e. hyperuri-cemia) more frequently occurs in males and overweightpersons and its prevalence varies in different popula-tions3. It has been reported that hyperuricemia mayhave an important role in several pathological condi-tions such as metabolic syndrome, cardiovascular dis-eases (CVD), chronic kidney disease, stroke, maternalcomplications in pre-eclampsia4–7. Elevated serum uricacid has been shown to be the strong predictor of cardio-vascular mortality in several recently published stu-dies8–10, whereas some other publications were not ableto confirm these findings11.Hyperuricemia has also been associated with certainmetabolic abnormalities, such as impaired glucose me-tabolism and dyslipidemia and several investigatorshave studied this association12,13. However, these associ-ations are not yet fully understood and results are stillinconsistent.We have, therefore, undertaken this study with theaim to: (i) determine the prevalence of hyperuricemia ingeneral Croatian population and (ii) investigate the asso-ciation of serum uric acid with glucose and lipid concen-tration.Materials and MethodsPatientsThis was a retrospective cross-sectional study on pa-tient laboratory results retrieved from the laboratory in-formation system (LIS). The study included laboratory1055Received for publication July 28, 2010results for 6,476 consecutive adults referred to medicalbiochemistry laboratory of Policlinic Bonifarm for rou-tine blood testing, mainly as a part of the routine peri-odic health check-up between June 2007 and February2009.Policlinic Bonifarm is policlinic specialized in phar-macology and toxicology and medical biochemistry labo-ratory. Total number of samples admitted to the labora-tory is 11,000 per year and the total yearly number ofanalyses is about 75,000.MethodsFollowing data were retrieved from the LIS for everyindividual: age, gender, concentration of glucose, triglyc-erides, total cholesterol, HDL-cholesterol, LDL-choles-terol and uric acid.For all patients venous blood sampling was done inthe morning, after an overnight fast. All laboratory testswere done immediately after sampling.All biochemical parameters were measured by stan-dard enzymatic methods on analyzer Cobas Integra 400plus (Roche Diagnostics, Mannheim, Germany).LDL-cholesterol was calculated using Friedwald equa-tion. When triglyceride concentration was above 3 mmol/L,LDL-cholesterol was measured by direct method on Co-bas Integra 400 plus (Roche Diagnostics, Mannheim,German).Statistical analysisCategorical data are presented as counts and percent-ages. Normality was tested using Kolmogorov-Smirnovtest. All distributions were non-Gaussian. Median andinterquartile range (IQR) were used to describe the data.Data were categorized into two subgroups: with (a) nor-mal and (b) increased (decreased for HDL) concentra-tions of measured parameters. Cut-off values used forgrouping were 5.5 mmol/L for glucose, 5.0 mmol/L forcholesterol, 1.7 mmol/L for triglycerides, 3.0 mmol/L forLDL cholesterol and 1.0 mmol/L and 1.2 mmol/L forHDL cholesterol for males and females respectively. Tho-se values were chosen according to the recommendedATP III criteria14. Value for HDL in females was slightlymodified according to national recommended value (Cro-atian Chamber of Medical Biochemists). As a cut-offvalue used for categorizing subjects respective to the con-centration of uric acid, we used the upper limit of refer-ence interval (URL) (403 mmol/L for males and 337mmol/L for females).The c2-test was used for comparing categorical vari-ables and Mann-Whitney rank sum test for assessing dif-ferences between numerical variables. Spearman rankcorrelation analysis was used to assess the associationbetween variables (uric acid, age, glucose, lipid parame-ters). The level of statistical significance was set at 0.001,due to the large sample size.Statistical analysis was performed by using MedCalc10.1.2.0 (Frank Schoonjans, Mariakerke, Belgium).ResultsThe study included 6,476 patients. Patient demo-graphic characteristics and biochemical parameters arepresented in Table 1.Hyperuricemia prevalence was 13.9% in general pop-ulation and it was significantly higher in males, than infemales (26% vs. 6%; p<0.001). Furthermore, medianuric acid concentration, although within the referenceinterval, was higher in males than in females (343 vs. 238mmol/L; p<0.001).We have tested possible correlations of uric acid withage, glucose and lipid parameters. As of our result, age,glucose and lipid parameters did not correlate with uricacid in studied population (data not shown). Correlationwas not present even when we analyzed the relationshipof uric acid with age, glucose and lipids within the uricacid quartile subgroups (data not shown).Study subjects with hyperuricemia were found tohave higher prevalence of increased concentrations ofglucose (33.1% vs. 13.1%; p<0.001), triglycerides (46.9%vs. 17.6%; p<0.001), total cholesterol (69.6% vs. 51.9%;p<0.001), LDL-cholesterol (64.5% vs. 46.4%; p<0.001)and decreased value HDL-cholesterol (24.3% vs. 13.0%;p<0.001) compared to subjects with serum uric acid lev-els within the reference interval (Table 2).S. Ka~kov et al.: Uric acid, Glucose and Lipids in General Population, Coll. Antropol. 35 (2011) 4: 1055–10591056TABLE 1PATIENT DEMOGRAPHIC CHARACTERISTICS AND BIOCHEMICAL PARAMETERSMale, N=2,827 Female, N=3,598 pAge, years* 43 (34–52) 41 (33–50) <0.001Uric acid, mmol/L* 343 (300–391) 238 (204–276) <0.001Hyperuricemia, N (%) 1.683 (26%) 389 (6%) <0.001Glucose, mmol/L* 5.1 (4.8–5.5) 4.7 (4.5–5.1) <0.001Cholesterol, mmol/L* 5.3 (4.6–6.1) 5.0 (4.4–5.8) <0.001HDL-cholesterol, mmol/L* 1.3 (1.1–1.5) 1.7 (1.4–2.0) <0.001LDL-cholesterol, mmol/L* 2.8 (2.3–3.5) 3.3 (2.6–3.9) <0.001Triglycerides, mmol/L* 1.4 (0.9–2.0) 0.9 (0.7–1.3) <0.001*Data are presented as median and interquartile rangeDiscussionThe prevalence of hyperuricemia in this study was13.9% in general population and it was significantlymore prevalent in males, than in females. Age, glucoseand lipid parameters did not correlate with uric acid con-centration in studied population. However, hyperurice-mic subjects more often had increased concentrations ofglucose, triglycerides, total cholesterol, LDL-cholesterol.HDL-cholesterol concentrations were more often decrea-sed in our subjects with elevated uric acid concentration.Eventhough the prevalence of hyperuricemia and itsassociation with various biochemical parameters has beenstudied by many authors, the results are controversialand not yet conclusive. The overall prevalence of hyper-uricemia in one recently published study on 132 subjectsfrom western Turkey was 12.1%3. The cut-off values foruric acid in this study were >420 mmol/L for males and>360 mmol/L for females, what was comparable to cut-offvalues used in our study. Males had significantly higheruric acid concentrations than females (330±80 vs. 260±70mmol/L, respectively; p=0.05). This gender dependentdifference in uric acid concentrations may probably beexplained by gonadal hormones15.Lippi et al.12 have investigated the association be-tween uric acid, fasting plasma glucose and triglyceridesin the general population. The overall prevalence ofhyperuricemia in 10,181 randomly selected individualswas 3.8%. It should be noted that cut-off values for uricacid were much higher than the ones used in our study(uric acid cut-off values were 506 mmol/L and 416mmol/L, for males and females, respectively). This mightexplain the observed large difference between the preva-lence in our and Italian population. The major finding ofthe study by Lippi et al. was that hypertriglyceridemic(triglycerides >1.7 mmol/L) and hyperglycemic (fastingplasma glucose >6.1 mmol/L) adults had increased prev-alence of elevated serum uric acid concentrations, com-pared to subjects having normal lipid and glucose con-centrations (11% vs. 3%, respectively; p=0.018). Theauthors conclude that this association raises the possibilityof a potential pathogenic overlap between these states.Hjortnaes et al.16 have investigated the association be-tween serum uric acid and components of metabolic syn-drome in patients with manifest vascular disease. Theyobserved higher average concentrations of serum uricacid in patients with, than in patients without metabolicsyndrome (360±80 mmol/L vs. 329±90 mmol/L). Further-more, their observation was that the patients who hadmore components of metabolic syndrome present, hadalso higher concentration of serum uric acid.Rathmann17 and his colleagues have published the re-sults of the Cardia study with the 10-year follow-up on1,249 male and 1,362 female young subjects. During thefollow-up, they observed the significant increase of themean serum uric acid concentration (p<0.01). They alsoobserved a significant independent association of bodymass index (BMI) and triglycerides with serum uric acid.In the study published by Liou et al.18, uric acid aggre-gated with BMI, waist circumference (WC), glucose, logvalue of triglycerides, and HDL cholesterol. However,their conclusion was that metabolic syndrome is not as-sociated with hyperuricemia.In one recently published cross-sectional study on2,085 Taiwanese men and 1,557 women19, hyperuricemiawas significantly associated with increased risk for hy-pertriglyceridemia, low high-density lipoprotein choles-terol level, and high blood pressure in men and women.However, contrary to our results, the uric acid levelswere inversely associated with hyperglycemia in Taiwan-ese men. In one other similar study on 470 subjects, whowere also from Taiwan, serum uric acid was significantlyrelated to risk factors of metabolic syndrome, with theexception of blood glucose which did not correlate withuric acid20. It may be that there are some racial and eth-nic differences in metabolic interactions of the compo-nents of lipid and glucose metabolism. Furthermore, theobserved difference in the association between glucoseand uric acid may also be at least partially due to largeS. Ka~kov et al.: Uric acid, Glucose and Lipids in General Population, Coll. Antropol. 35 (2011) 4: 1055–10591057TABLE 2PREVALENCE OF SUBJECTS WITH HYPERGLYCEMIA AND DYSLIPIDEMIA RESPECTIVE TO THE URIC ACID CONCENTRATIONUric acid within referenceinterval N=5,671 (87.8%)Uric acid aboveURL N=787 (12.2%)pGlucose >5.5 mmol/LN=457 (15.6%)746 (13.1%) 261 (33.1%) <0.001Cholesterol >5.0 mmol/LN=3,500 (54.0%)2,947 (51.9%) 553 (69.6%) <0.001Triglycerides >1.7 mmol/LN=1,374 (21.2%)1,001 (17.6%) 373 (46.9%) <0.001LDL cholesterol >3.0 mmol/LN=3,151 (48.7%)2,638 (46.4%) 513 (64.5%) <0.001HDL cholesterol 1.0 (M) mmol/LHDL cholesterol 1.2 (F) mmol/LN=929 (14.3%)736 (13.0%) 193 (24.3%) <0.001URL – upper limit of reference intervaldifferences in diet and lifestyle between Western civiliza-tions and Asian subjects21.So, although not confirmed by all, uric acid was mo-stly found to aggregate with disturbed metabolism of glu-cose and lipids. Uric acid is known to correlate with insu-lin resistance. The mechanism of this phenomenon is notfully understood. It has been postulated that insulinprobably decreases the clearance of uric acid in the renalproximal tubule, resulting in a subsequent increase in se-rum uric acid levels in healthy individuals and asymp-tomatic hyperuricemic subjects22.As such, the measurement of uric acid might be advis-able to those at increased risk of CVD23. However, thereis a continuing debate about the relevance of the in-creased serum uric acid concentration and its role as anindependent cardiovascular risk factor. The predictivevalue of uric acid concentration for cerebrovascular andcardiovascular mortality has been studied in several lar-ge prospective studies. In the prospective cohort study on1,423 middle-aged Finnish men initially without CVD,published by Niskanen et al., serum uric acid was astrong predictor of cardiovascular mortality, independ-ent of variables commonly associated with gout or themetabolic syndrome8. Elevated concentrations of uricacid were also associated with increased mortality in oneAustrian cohort of 83,683 subjects10. However, one pro-spective cohort study on 22,698 Korean men, aged 30 to77 years, with a 9-year of follow-up found that elevatedserum uric acid was not an independent risk of cardio-vascular mortality11. It is therefore clear that we stillneed some well designed prospective trials and moni-tored therapeutic interventions to further improve ourunderstanding of the risk factors for metabolic syndromeand cardiovascular mortality24.Despite of the very intense research on this field,there is still much controversy on the role and signifi-cance of uric acid and its relation to some biological pa-rameters. Such controversy may be due to the differentcut-off used to define hyperuricemia, small sized studiesand some ethnical differences, comorbidity and other dif-ferences in studied populations.The present study has some limitations. The studypopulation of outpatient adults from laboratory may notbe completely representative sample of general popula-tion. Anthropometric measures, like BMI and some otherimportant data on the comorbidity (like hypertension,cardiovascular disease, etc.), therapy, diet and other envi-ronmental factors would be very useful to further ex-plore these complex associations. Unfortunately, none ofthe additional clinical information was available on thislarge cohort of outpatients.ConclusionHyperuricemia is highly prevalent in Croatian gen-eral population and it aggregates with hyperglycemiaand dyslipidemia. Males are more often hyperuricemicthan females.R E F E R E N C E S1. BLEYER AJ, HART TC, Adv Chronic Kidney Dis, 13 (2006) 124. —2. TANIGUCHI A, KAMATANI N, Curr Opin Rheumatol, 20 (2008) 192.— 3. SARI I, AKAR S, PAKOZ B, SISMAN AR, GURLER O, BIRLIK M,ONEN F, AKKOCN, Rheumatol Int, 29 (2009) 869. — 4. CHOI HK, FORDES, Am J Med, 120 (2007) 442. — 5. KOOPMANS CM, VAN PAMPUSMG, GROENH, AARNOUDSE JG, VAN DEN BERG PP, MOL BW, Eur JObstet Gynecol Reprod Biol, 146 (2009) 8. — 6. KIM SY, GUEVARA JP,KIM KM, CHOI HK, HEITJAN DF, ALBERT DA, Arthritis Rheum, 61(2009) 885. — 7. BERGAMINI C, CICOIRA M, ROSSI A, VASSANELLIC, Eur J Heart Fail, 11 (2009) 444. — 8. NISKANEN LK, LAAKSONENDE, NYYSSÖNENK, ALFTHANG, LAKKAHM, LAKKA TA, SALONENJT, Arch Intern Med, 164 (2004) 1546. — 9. IOACHIMESCU AG, BRE-NNAN DM, HOAR BM, HAZEN SL, HOOGWERF BJ, Arthritis Rheum,58 (2008) 623. — 10. STRASAK A, RUTTMANN E, BRANT L, KELLE-HER C, KLENK J, CONCINH, DIEMG, PFEIFFER K, ULMERH, ANDVHM&PP STUDY GROUP, Clin Chem, 54 (2008) 273. — 11. JEE SH,LEE SY, KIM MT, Eur J Cardiovasc Prev Rehabil, 11 (2004) 185. — 12.LIPPI G, MONTAGNANAM, TARGHERG, SALVAGNOGL, GUIDI GC,Biochem Med, 18 (2008) 37. — 13. LIN KP, J Nurs Res, 17 (2009) 286. —14. EXPERT PANEL ON DETECTION, EVALUATION AND TREAT-MENT OF HIGH BLOOD CHOLESTEROL IN ADULTS, JAMA, 285(2001) 2486. — 15. GHEIM, MIHAILESCUM, LEVINSOND, Curr Rheu-matol Rep, 4 (2002) 270. — 16. HJORTNAES J, ALGRA A, OLIJHOEK J,HUISMAN ET AL, J Rheumatol, 34 (9) (2007) 1882. — 17. RATHMANNW, HAASTERT B, ICKS A, GIANI G, ROSEMAN JM, Eur J Epidemiol,22 (2007) 439. — 18. LIOU TL, LIN MW, HSIAO LC, TSAI TT, CHANWL, HO LT, HWU CM, J Chin Med Assoc, 69 (2006) 104. — 19. LIU PW,CHANG TY, CHEN JD, Metabolism, 59 (6) (2010) 802. — 20. LIN JD,CHIOU WK, CHANG HY, LIU FH, WENG HF, Metabolism, 56 (2007)751. — 21. EGUSA G, WATANABE H, OHSHITA K, FUJIKAWA R,YAMANE K, OKUBO M, KOHNO N, J Atheroscler Thromb, 9 (2002)299. — 22. RATHMANN W, FUNKHOUSER E, DYER AR, ROSEMANJM, Annals Epidemiol, 8 (1998) 250. — 23. LIPPI G, MONTAGNANAM, SALVAGNO GL, TARGHER G, GUIDI GC, Clin Cardiol, 33 (2)(2010) 76. — 24. BLATON VH, KORITA I, BULO A, Biochem Med, 18(2008) 14.S. Ka~kovBonifarm Policlinic, Medical Biochemistry Laboratory, Laginjina 16, 10000 Zagreb, Croatiae-mail: skackov@bonifarm.hrS. Ka~kov et al.: Uric acid, Glucose and Lipids in General Population, Coll. Antropol. 35 (2011) 4: 1055–10591058POVEZANOST MOKRA]NE KISELINE S GLUKOZOM I LIPIDIMA U OP]OJ POPULACIJI:PRESJE^NO ISTRA@IVANJE U HRVATSKOJS A @ E T A KHiperuricemija mo`e imati zna~ajnu ulogu u metaboli~kom sindromu, kardiovaskularnim bolestima i mo`danomudaru. Novija istra`ivanja su pokazala da koncentracija mokra}ne kiseline u serumu mo`e biti sna`an prediktor kar-diovaskularne smrtnosti. Cilj ovog istra`ivanja bio je utvrditi prevalenciju hiperuricemije u op}oj populaciji u Hrvatskoji ispitati povezanost koncentracije mokra}ne kiseline s koncentracijama glukoze i lipida. Ovo retrospektivno presje~noistra`ivanje provedeno je na 6,476 uzastopnih odraslih ispitanika. Prevalencija hiperuricemije je bila 13,9% u op}ojpopulaciji. Hiperuricemija je bila u~estalija u mu{karaca, nego u `ena (26% prema 6%; p<0,001), a medijan koncen-tracije mokra}ne kiseline je bio vi{i u mu{karaca nego u `ena (343 prema 238 mmol/L; p<0,001). Dob, koncentracijaglukoze i lipidnih parametara nisu bili povezani s koncentracijommokra}ne kiseline. Ispitanici s hiperuricemijom imalisu povi{enu koncentraciju glukoze (16,5% prema 6,8%; p<0,001), triglicerida (46,9% prema 17,6%; p<0,001), ukupnogkolesterola (69,6% prema 51,9%; p<0,001), LDL-kolesterola (64,5% prema 46,4%; p<0,001) i sni`enu koncentracijuHDL-kolesterola (24,3% prema 13,0%; p<0,001) ~e{}e nego ispitanici s normalnom koncentracijom mokra}ne kiselineu serumu. Hiperuricemija ima visoku prevalenciju i povezana je s hiperglikemijom i dislipidemijom u op}oj populaciji uHrvatskoj.S. Ka~kov et al.: Uric acid, Glucose and Lipids in General Population, Coll. Antropol. 35 (2011) 4: 1055–10591059

The Association of Uric Acid with Glucose and Lipids in General Population: Croatian Cross-Sectional Study

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