CLINICAL TRIAL REPORT

Is Hyperuricemia the Missing Piece in the MetabolicSyndrome Puzzle?

Zohreh Soltani & Efrain Reisin

Published online: 29 January 2012# Springer Science+Business Media, LLC 2012

Hara S, Tsuji H, Ohmoto Y, Amakawa K, Hsieh SD, AraseY, Nakajima H. High serum uric acid level and low urinepH as predictors of metabolic syndrome: a retrospectivecohort study in a Japanese urban population. Metabo-lism. 2011 Aug 22. [Epub ahead of print]. doi:10.1016/j.metabol.2011.06.026.

Rating: • Of importance

Keywords Uric acid ⋅ Low urine pH ⋅ Metabolic syndrome ⋅Hyperuricemia ⋅ Clinical trials ⋅ Diagnostic criteria

Introduction: Levels of serum uric acid (SUA) are oftenincreased in patients with metabolic syndrome (MetS), butnone of the proposed sets of diagnostic criteria include SUAlevels in the definition of MetS. A recent study has demon-strated that SUA level is an independent predictor of nonal-coholic fatty liver disease, which is a common characteristicof MetS [1]. Furthermore, it was reported that other featuresof MetS—insulin resistance and obesity—are associatedwith excessively low urinary pH. It is conceivable that lowurinary pH also may be associated with MetS. The mecha-nistic relationship between insulin resistance and high SUA(with or without low urinary pH) is unclear.

Aims: This study, conducted in Japan at the Center ofHealth Management, Okinaka Memorial Institute, andOsaka Medical Center, was designed to determine whether

hyperuricemia, acidic urine, or their combination is associ-ated with MetS development.

Methods: Study 1: Clinical data for 69,094 individuals whoreceived routine health checkups between January 1985 andDecember 2005 were examined for the study. All subjects’medical records included complete measurements of MetS-related factors. MetS was defined as a body mass index(BMI) of 25 kg/m2 or higher (the cutoff point in the Japa-nese diagnostic criteria for obesity) in addition to two ormore of the following criteria: (1) systolic blood pressure(SBP) of at least 130 mm Hg, diastolic blood pressure(DBP) of at least 85 mm Hg, or both; (2) triglyceride (TG)level of at least 150 mg/dL, high-density lipoprotein choles-terol (HDLC) less than 40 mg/dL, or both; and (3) fastingblood glucose (FBG) of at least 110 mg/dL.

Based on their SUA level, the subjects were divided intosex-specific quartiles (Table 1), and the corresponding rela-tionships with age, BMI, SBP, DBP, TG, HDLC, FBG, andprevalence of MetS were analyzed. The subjects also werecross-classified into four groups according to their combi-nation of SUA level and urine pH: that is, low SUA(<5.9 mg/dL for men, <4.3 mg/dL for women) with eitherlow urine pH (<6.0) or high urine pH (≥6.0), and high SUA(≥5.9 mg/dL for men, ≥4.3 mg/dL for women) with eitherlow or high urine pH; the MetS prevalence was comparedacross these four groups.

Study 2: A total of 5,617 subjects from the study 1population who had at least five checkups over a 5-yearperiod and a BMI lower than 25 kg/m2 at their first checkupwere chosen for the analysis of MetS risk factors. Accordingto their SUA level and urine pH at the first checkup, thesubjects were classified into quartiles, and then the 5-yearcumulative MetS incidence was analyzed for each group.The analysis was conducted to show whether high SUA

Z. Soltani : E. Reisin (*)Section of Nephrology and Hypertension, Louisiana StateUniversity Health Science Center,1542 Tulane Ave,New Orleans, LA 70113, USAe-mail: ereisi@lsuhsc.edu

Curr Hypertens Rep (2012) 14:97–99DOI 10.1007/s11906-012-0249-8

level and low urine pH are risk factors for the developmentof MetS.

Statistical Analysis

Study 1: The MetS prevalence was calculated for eachquartile of SUA or urine pH for men and women. Analysisof the relationship between MetS prevalence and stratifiedSUA or urine pH was performed with the Cochran-Armitage trend test. A value of P<0.05 was consideredsignificant. To evaluate the association of the combinationof SUA and urine pH with MetS prevalence, the subjectswere cross-classified into four groups and MetS prevalencewas calculated for each group. Based on the Tukey method,multiple comparisons were performed for pair-wise compar-isons. Logistic regression analysis was also used to assessthe relationship between these groups and MetS status.

Study 2: The subjects were classified into quartilesaccording to SUA level and urine pH, and the Kaplan-Meier method was used to estimate the cumulative MetSincidence for each group. The Cox proportional hazardmodel was also used to analyze the risk of developing MetSwithout and with adjustment for age, BMI, SBP, DBP, TG,HDLC, FBG, and the year of the first checkup. To elucidatethe influence of high SUA and low urine pH on the devel-opment of MetS, Cox proportional hazard analysis and thelikelihood ratio test were performed on the four models asfollows:

& Model 0: Age, BMI, SBP, HDLC, TG, FBG, and theyear of the first checkup were included as explanatoryvariables

& Model 1: Model 0 + SUA& Model 2: Model 0 + urine pH& Model 3: Model 0 + SUA + urine pH.

All analyses were performed using SAS 9.1 (SAS Institute,Cary, NC).

Results: Study 1: The MetS prevalence was 9.3% in menand 2.6% in women. The prevalence of MetS increasedsignificantly with increases in SUA in both men and women(P<0.001). In addition, the MetS prevalence increased sig-nificantly with decreases in urine pH (increased urine acid-ity) in men. Among the combinations of SUA and urine pH,the group with high SUA and low urine pH had a signifi-cantly higher prevalence of MetS than those with low SUAand high urine pH (P<0.05). Trend tests in both men andwomen identified a positive correlation between SUA andsome laboratory data (BMI, SBP, DBP, and TG), whereas aninverse correlation was observed for urine pH and HDLC.

Study 2: The top quartile of SUA levels was associatedwith higher MetS development during the 5-year period inmen (P00.023). For urine pH, the bottom quartile (acidicurine) was also associated with higher MetS development inmen (P00.025). A likelihood ratio test confirmed that highSUA and low urine pH act synergistically in the developmentof MetS in men. The risk for developingMetS was elevated inthose with a higher SUA level and lower urine pH.

Discussion: In this study by Hara et al., the prevalence ofMetS was lower in women than men. The authors demon-strated a positive correlation between SUA level and theprevalence of MetS in men and women and a negativerelationship between urine pH and MetS in men in thisretrospective cohort study. The study also suggested thatthe subjects (both men and women) with high SUA hadsignificantly higher BMI, SBP, DBP, and TG.

The combination of high SUA and low urine pH wassignificantly associated with higher MetS prevalence thanthe combination of low SUA and high urine pH.

In addition, the data also showed that high SUA level andlow urine pH in men increased the risk of developing MetS,and the multiple Cox regression analysis revealed that highSUA level is an independent risk factor for MetS in men. Alikelihood ratio test confirmed that high SUA and low urinepH act synergistically in the development of MetS. In con-clusion, high SUA, low urine pH, and their combination arepredictive risk factors for MetS development.

Comment

MetS is a disease entity characterized by a clustering of met-abolic and cardiovascular atherosclerotic risk factors, includingdisturbances of glucose and insulin metabolism, hypertension,dyslipidemia, and central obesity [2]. The presence of thismodern epidemic is strongly associated with the developmentof many serious conditions, such as cardiovascular disease,diabetes mellitus, chronic kidney disease, and hypertension[3–6]. The principal underlying pathophysiologic abnormalityis insulin resistance, which is associated mainly with

Table 1 Sex-specificquartiles for serum uricacid and urine pH

Quartile Serum uricacid (mg/dL)

Urine pH

Men

Q1 ≤5.1 ≤5

Q2 5.2–5.8 5.5

Q3 5.9–6.6 6.0

Q4 ≥6.7 ≥6.5

Women

Q1 ≤3.6 ≤5

Q2 3.7–4.1 5.5

Q3 4.2–4.7 6.0

Q4 ≥4.8 ≥6.5

98 Curr Hypertens Rep (2012) 14:97–99

abdominal obesity. Although a number of studies have foundthat SUA levels are increased in individuals with MetS [7–9],none of the proposed diagnostic criteria include SUA levels inthe definition of MetS.

The key question is whether the hyperuricemia has acausal role in this syndrome. Most authorities have viewedelevated uric acid as a secondary phenomenon, but recentexperiments have challenged this point of view. Moreover,Maalouf et al. evaluated the relationship between MetS andurine pH and reported an inverse relationship between urinepH and insulin resistance, which is a central feature of MetS[10]. Recently, a 5-year follow-up study has shown that thecumulative incidence of chronic kidney disease in type 2diabetic patients with hyperuricemia is significantly higherthan in those without hyperuricemia [11].

The paper by Hara et al. reports the first longitudinal cohortstudy on the relationships between SUA, urine pH, and thedevelopment of MetS. This paper has not only shown theevidence of hyperuricemia in MetS but also has demonstratedthat high SUA and acidic urine are risk factors in MetSdevelopment. Data from this study also have shown that uricacid may not just be an innocent bystander in MetS; it isinterrelated with the metabolic disarrangements of MetS.

The authors failed to show a definitive conclusion on theimpact of high SUA on the development of MetS in women.This result was probably due to the low statistical powerafforded by the small population of women and their lowerincidence of MetS compared with the incidence in the men.

In summary, the study by Hara et al. showed that hyper-uricemia and acidic urine act synergistically in the develop-ment of MetS. More studies are needed to show the exactmechanisms responsible for high SUA and low urine PH inpatients with MetS and to determine whether including SUAconcentration and urine PH in the MetS definition wouldimprove its power to predict cardiovascular disease riskindependently of other associated features.

Disclosure

No potential conflict of interest relevant to this article wasreported.

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