Clin Chem Lab Med 2012;50(5):xxxxxx 2012 by Walter de Gruyter Berlin Boston. DOI 10.

1515/cclm-2011-0150

Uric acid biorhythm, a feature of long-term variation in a clinical laboratory database

Mauricio Pacheco de Andrade1,2, Rosario D.C. Hirata1, Fabiano Sandrini3, Alvaro Largura3 and Mario Hiroyuki Hirata1,*
Departamento de Anlises Clnicas e Toxicolgicas, Faculdade de Cincias Farmacuticas, Universidade de So Paulo, So Paulo, SP, Brazil 2 Nefroclinica de Foz de Iguau, Foz de Iguau, PR, Brazil 3 Instituto de Investigao Cientca do Paran, Cascavel, PR, Brazil
1

Introduction
Chronobiology is opening a new understanding of biological systems regulation. The biological time and its oscillations have been proposed to have inuence on hormonal and metabolic status in physiological and pathological conditions (1). Studies of rhythms help to understand the biological behavior of endogenous compounds and the interpretation of analytical results for clinical diagnosis and therapeutics monitoring purposes (2, 3). The chronobiological analysis of biomarkers has also been proposed as a process to evaluate analytical variation in laboratory medicine (2, 3). Circadian and/or circannual rhythms are suggested to inuence intra-individual variations and dynamic reference ranges of several analytes (4). Rhythm behavior has been found in biomarkers of several physiological systems, such as vascular, endocrine, gastrointestinal and immune (57). However, seasonal variations of these markers are not usually considered in the interpretation of the laboratory data for a clinical decision. Uric acid, the nal product of purine metabolism, is considered a useful biomarker for evaluation and management of gout, nephrolithiasis, hypertension, metabolic syndrome and other clinical conditions (811). It has been shown that uric acid has a biological rhythm that can be associated with gout, nephrolythiasis and other clinical conditions (1215). However, the seasonal rhythmicity of the uric acid values was not always demonstrated (16, 17). The long-term biorhythm of serum uric acid was evaluated in a large sample of a clinical laboratory database by spectral analysis and the inuence of the gender and age on uric acid variability was investigated.

Abstract
Background: The biorhythm of serum uric acid was evaluated in a large sample of a clinical laboratory database by spectral analysis and the inuence of the gender and age on uric acid variability. Methods: Serum uric acid values were extracted from a large database of a clinical laboratory from May 2000 to August 2006. Outlier values were excluded from the analysis and the remaining data (n = 73,925) were grouped by gender and age ranges. Rhythm components were obtained by the Lomb Scargle method and Cosinor analysis. Results: Serum uric acid was higher in men than in women older than 13 years (p < 0.05). Compared with 012 year group, uric acid increased in men but not in women older than 13 years (p < 0.05). Circannual (12 months) and transyear (17 months) rhythm components were detected, but they were signicant only in adult individuals ( > 26 years, p < 0.05). Cosinor analysis showed that midline estimating statistic of rhythm (MESOR) values were higher in men (range: 353368 mol/L) than in women (range: 240278 mol/L; p < 0.05), independent of the age and rhythm component. The extent of predictable change within a cycle, approximated by the double amplitude, represented up to 20% of the corresponding MESOR. Conclusions: Serum uric acid biorhythm is dependent on gender and age and it may have relevant inuence on preanalytical variability of clinical laboratory results. Keywords: biorhythm; laboratory data; uric acid; variability.

Materials and methods

Data sampling
Serum uric acid data were extracted from a clinical laboratory database settled in the Southern region of Brazil (Laboratorio Alvaro, Foz do Iguau, PR, Brazil). All uric acid results collected from May 2000 to August 2006 (76 months) were used, including those with abnormal values, therefore no exclusion criteria based on clinical status of the individuals were used. Body mass index (BMI) or sex steroid hormones were not evaluated in this sample.

*Corresponding author: Mario Hiroyuki Hirata, Universidade de So Paulo, Faculdade de Cincias Farmacuticas, Av. Prof. Lineu Prestes, 580, B.17, 05508-900, So Paulo, SP, Brazil Phone: +55 11 3091-3660, Fax: +55 11 3813-2197, E-mail: mhhirata@usp.br Received March 11, 2011; accepted January 27, 2012

Uric acid analysis

Blood samples were collected in the morning (7 a.m. to 9 a.m.), after overnight fasting, using Vacutainer SSTTM tube (Becton Dickinson and Company, New Jersey, USA). Serum was separated within 1 h and immediately used for uric acid analysis. Serum uric acid was

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Pacheco de Andrade et al.: Uric acid biorhythm and laboratory data variability

determined by routine enzymatic method using the Dimension RXL System (Dade Behring, Newark, USA), following the manufacturer recommendation and laboratory protocols. Blood sampling procedures and analytical method were not modied during the study. The within-run and between-day CVs were lower than 10%. The performance of the analytical process was evaluated by a quality control system provided by two Brazilian external quality control programs (PNCQ and PELM, Brazil).

Rhythm analysis
Uric acid database entries were inspected for outlier detection and extraction using the interquartile range method, considering outliers 0.7% of the most extreme values (18). Data were grouped according to gender and age ranges (012, 1325, 2650 and more than 50 years old) based on the sample size. Next, transverse series were formed by averaging all results in a particular group collected in a given month for rhythm analysis (19, 20). There was no signicant trend detectable in all groups (data not shown). Data sampling and pretreatment were conducted using AlRef software (Laboratory Alvaro, Cascavel, PR, Brazil). The mean values of spectral analysis and prospection of candidates for rhythm components were analyzed by Lomb Scargle method. The two most frequent components among the groups were selected for further analysis by Cosinor method in order to conrm signicance of the rhythm (21). Cosinor parameters were used to obtain the midline estimating statistic of rhythm (MESOR), amplitude (measure of one half of distance between peak and though of rhythm), acrophase (time at which peak occurs), and signicance of rhythm (p). Estimation of 95% condence intervals (CI) of periods of all gender and age range groups was conducted by using non-linear least square analysis (2224). Periodograms and Cosinor analyses were performed using the El Temps software gently provided by Professor Antoni Diez-Noguera, PhD (Facultat de Farmacia, Universitat de Barcelona, Barcelona, Spain).

abnormal distribution (data not shown) and were excluded from the analysis. As shown in Table 2, two major components with circannual/near transyear (12.113.4 months) and transyear (15.2 17.8 months) periods were detected for gender and age range groups. Results from Cosinor analysis of each selected period were grouped by gender and age ranges (Figure 2). All Cosinor analyses were signicant (p < 0.05) for both circannual/near transyear and transyear periods (Table 3). Mean MESOR values were signicantly higher in men than in women (p < 0.05) independently of the age range. Mean amplitude values ranged from 8 to 12 mol/L for circannual/near transyear rhythm and from 7 to 14 mol/L for transyear rhythm (Table 3). The overall variability accounted for a given cycle (i.e., the double amplitude) was below 10% of the MESOR means, except for the group of women with 2650 years for transyear rhythm. In Table 4, results for 95% condence limits are shown. There are two main ndings: rst, the model assumes the presence of a single yearly component, validated for three of the four groups. The estimated period tends to be longer than 1 year but the 95% CI overlaps 1 year, except for men older than 50 years. This component is detected either with statistical signicance (the lower limit of the CI of the amplitude is positive) or with borderline statistical signicance (lower limit of amplitudes CI slightly negative; lower limit of 1parameter CI of amplitude is positive but is not shown). The transyear component is also invariably validated with statistical or borderline statistical signicance. It has an amplitude similar or even slightly larger than the amplitude of the circannual component.

Statistical analysis
Uric acid and rhythm (acrophase, amplitude and MESOR) data values of age and gender groups were compared by two-way ANOVA with contrasts. Statistical analyses were carried out using Statistica 6.0 (Statsoft, Tulsa, USA). Signicance level was considered p < 0.05.

Discussion
In this sample, uric acid values were higher in male individuals than females, and rose in elderly, as have been previously
Table 1 Mean values of serum uric acid extracted from the laboratory database. Groups Total Total 322 102 (73,925) 296 121 (1073) 300 102 (2893) 316 102 (31,966) 331 100 (37,993) Men 361 94 (42,648) 296 133 (410) 346 99 (1534) < 0.05 359 98 (19,906) < 0.05 366 96 (20,798) < 0.05 Women 270 87 (31,277) 295 114 (663) 247 80 (1359) < 0.05 245 77 (12,060) > 0.05 288 89 (17,195) < 0.05 p-Valuesa < 0.05 > 0.05 < 0.05 < 0.05 < 0.05

Results
In this study, 73,925 valid data entries for uric acid were extracted from the database. Fifty-eight percent of data were obtained from men (n = 42,648) and 42% from women (n = 31,277) (Table 1). The mean value of uric acid monthly, in mol/L, was higher in men (361 94) than in women (270 87; p < 0.05). This difference was not found in the youngest age group (012 years). Serum uric acid was higher in men with more than 13 years (p < 0.05), compared with the youngest group. However, women with 1350 years presented reduced uric acid compared with the youngest group. The spectral analysis of the data grouped according to the gender and age groups (over 13 years) are presented in Figure 1. Data from the youngest age group (012 years) had

0 12 years 13 25 years pb 26 50 years pb > 50 years pb

Number of individuals in parentheses. Results are shown as mean SD, in mol/L, and compared by two-way ANOVA for gender (a) and the youngest age group (b).

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Pacheco de Andrade et al.: Uric acid biorhythm and laboratory data variability

5 4

10.412.8

16.4

21.4 5 4

23

12.8

17.6

3 P 2 1 0 10 Months 20 30

13-25 y 3 P 2 1 0 10 Months 8.4 13.4 17.4 24.2 12 8 6 26-50 y P 4 2 0 10 Months 10.2 13 17 23.6 20 15 10 5.2 7.4 20 30 10 Months 12.4 16.8 20 30 15.2 20 28.4 20 30 >50 y P 5 0 10 Months Women 20 30 10 Months Men 20 30

8 6 P 4 2 0 8 6 P 4 2 0

Figure 1 Spectral analysis obtained by Lomb Scargle method. Each peak represents a possible rhythm component (in months) for uric acid values for gender and age range groups.

Table 2 Groups

Rhythm components of serum uric acid. Rhythms, months Women Men Women Men Women Men 10.4, 12.8, 16.4, 21.4 2.0, 3.0, 12.8, 17.8 8.4, 13.4, 17.4, 24.2 12.1, 15.2, 20, 28.4 10.2, 13.1, 17.0, 23.6 5.2, 7.4, 12.5, 16.8

13 25 years 26 50 years > 50 years

Common circannual and transyear rhythms are indicated in bold.

reported (2528). This increasing trend holds from a very young age for males but not for females, with a drop between 13 and 50 years of age (Table 1). There is no single cause for this difference, and some authors suggest that increased levels may occur by different mechanisms, such as differences in

BMI and sex steroid status (2931). No further analysis, such as BMI or sex steroid hormones, were conducted in order to evaluate their inuence on uric acid values. The Cosinor analysis based in Fourier periodogram is usually applied to detect low-frequency rhythm behaviors (19, 20). In the present work, this method was useful to demonstrate the inuence of age and gender on long period variability of serum uric acid. We have demonstrated two signicant rhythmic components in groups of both genders older than 26 years old: the transyear having a period clearly longer than 1.0 year, and another component that, at this time, cannot be distinguished from a 1.0-year synchronized rhythm. Transyear component were signicantly found in all four groups, and periods range from 15.2 to 17.8 months. It has been shown some ndings related to transyear rhythms of around 17 months (1.4 years), some related to cardiac death

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Pacheco de Andrade et al.: Uric acid biorhythm and laboratory data variability

Circannual Women
330 0.25 300 60 300

Transyear 26-50 years

0 degrees 30 330 0.25 60
300 0.25 60 300 0.25 60

>50 years
0 degrees 30

Women
330

26-50 years
0 degrees 30 330

>50 years
0 degrees 30

270

90

270

90

270

90

270

90

240

120

240

120

240

120

240

120

210 180

150

210 180

150
210 180 150 210 180 150

Period T=13.4 months Men

330 0.25 300 60 300

Period T=13.1 months >50 years

0 degrees 330 0.25 60
300

Period T=17.4 months Men 26-50 years

0 degrees 330 30

Period T=17.0 months >50 years

0 degrees 330 30

26-50 years
0 degrees 30

30

0.25

60

300

0.1

60

270

90

270

90

270

90

270

90

240

120

240

120

240

120

240

120

210 180

150

210 180

150

210 180

150

210 180

150

Period T=12.1 months

Period T=12.5 months

Period T=15.2 months

Period T=16.8 months

Figure 2 Cosinor studies for gender and age groups. Main rhythm components: circannual and transyear according to age ranges and statistics of the Cosinor functions are presented.

events in Czech Republic, and other related to different geophysical phenomena, as discussed by Halberg et al. (32). Also, Akioka et al. have described a 17-month periodicity of sunspot activity (33). Moreover, this rhythm was described previously, on a different sampling (34). These results are

suggestive that other components besides the circannual rhythm inuence the variability of the uric acid data. The second rhythmic component, showing estimated periods close to 1 year was tested by non-linear least squares in order to check circannuality suspect, to obtain 95% condence

Table 3

Cosinor analysis for circannual and transyear rhythms. Parameter estimates at a trial period of 12 months MESOR, mol/L Amplitude, mol/L Acrophase, degrees p-Values Best tting period, months

Rhythm component

Circannual/near transyear 26 50 years Women Men > 50 years Women Men Transyear 26 50 years Women Men > 50 years Women Men

244 (240 249) 357 (353 361) 275 (272 278) 366 (363 368)

12 (3 21) 10 (3 16) 8 (3 14) 9 (5 13)

95.4 (49.2 141.6) 238.8 (197.1280.0) 121.7 (83.4 160.2) 194.6 (166.5 222.6)

0.0042 0.0010 0.0008 < 0.0001

13.4 12.1 13.1 12.5

244 (240 249) 357 (354 361) 275 (272 278) 365 (363 368)

14 (6 22) 10 (3 16) 8 (3 13) 7 (2 11)

74.1 (36.9 110.3) 263.5 (193.1280.2) 92.5 (52.8 131.7) 109.3 (63.8 154.6)

0.0003 0.0022 0.0009 0.0030

17.4 15.2 17.0 16.8

Results are presented as mean (range). MESOR values were compared by two-way ANOVA (p-values indicate differences between gender groups. No difference was found between age ranges). MESOR, midline estimating statistic of rhythm. p-Values came from linear least squares analysis, not corrected for multiple testing. Parameter estimates were derived and comparisons were performed at the same common period of 12 months.
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Pacheco de Andrade et al.: Uric acid biorhythm and laboratory data variability

Table 4

Rhythmic estimated parameters by Non-linear Least Square Analysis. Period Months Years (95% CI) Amplitude, mol/L (95% CI)

Model: Trial period = 8766 h (1 year) 26 50 years Women Men > 50 years Women Men Model: Trial period = 12,272 h (1.4 years) 26 50 years Women Men > 50 years Women Men Model: Trial period = 15,780 h (1.8 years) 26 50 years Women Men > 50 years Women Men All (pooled normalized data) 1 year All (pooled normalized data) 1.4 years CI, condence interval.

13.9 12.7 12.2 13.0

1.157 1.056 1.016 1.085

0.927 0.948 0.917 1.009

1.386 1.164 1.114 1.160

5.95 7.73 6.54 7.73

1.78 0.59 1.78

17.84 13.68 14.28

18.3 15.9 17.7 17.0

1.521 1.328 1.475 1.418

1.328 1.181 1.260 1.272

1.714 1.476 1.690 1.565

11.90 9.52 5.95 7.73

0.00 0.00 1.19 1.19

23.79 19.03 13.68 13.68

25.3 20.9 24.6 23.0 12.9 17.4

2.107 1.740 2.053 1.920 1.073 1.454

1.840 1.180 1.754 1.442 1.002 1.331

2.375 2.027 2.352 2.397 1.143 1.577

15.46 8.33 8.33 4.16 122.53 136.21

3.57 1.19 1.19 2.38 27.36 43.42

27.36 17.84 15.46 11.30 217.70 229.00

limits for periods. The estimated period tends to be longer than 1 year but the 95% CI overlaps 1 year, except for men older than 50 years (in this group, lower limit was 1.009) (Table 4). This component is detected either with statistical signicance (the lower limit of the CI of the amplitude is positive) or with borderline statistical signicance (lower limit of amplitudes CI slightly negative; lower limit of 1-parameter CI of amplitude is positive but is not shown in Table). This difference could be a range of circannual rhythm, as described by Cugini as 12 2 months (35), therefore we considered 13 months as a circannual rhythm. Halberg et al. have established a different range for circanuality, limited between 0.9 and 1.1 years (10.8 and 13.2 months, respectively) (32). Similar circannual rhythms have been found in other clinical conditions (22, 36, 37). The brevity of the series may account for the difculty of reaching statistical signicance in all groups, in terms of dene circanuality. When each rhythmic components is tted separately, they both can be demonstarted with statistical signicance, the CIs of their periods being well separated, indicating that there are indeed two separate components. Again, the period estimate of the circannual component is slightly longer than 1 year, but the CI of the period is either very nearly 1 year or overlapping it. This means that while it may be a near-transyear, a longer series would be needed to prove it. Letellier and Desjarlais have also reported a serum uric acid rhythmicity, with peak in summer, in a homogeneous group

of men and women aged 3039 years, but not in younger groups (38). It is likely that the lack of uric acid rhythmicity in adolescent and young adults is not inuenced by hormonal rhythms during sexual maturity (3941). Gallerani et al. found circannual distribution in clinical presentation of uric acid unbalance (gout attacks), in an Italian population, with peak of cases in summer (April for northern hemisphere) (17). However, Schlesinger et al. found that acute gout crisis manifestations are more frequent in spring (12). The difference between those ndings could be explained by the near-transyear rhythmic component. Uric acid and other laboratory biomarkers have also shown to have signicant circannual rhythms with little amplitudes in chronic hemodialysis patients that were attributed to seasonal variations in food intake (4, 12, 42, 43). These differences in seasonality of clinical manifestations of hyperuricemia may be partially explained by the inuence of dietary factors, physical activity or level of exposition to sunlight (12, 42, 43). However, there is no consensus to some extension due to difculties in isolating the specic factors for the study. The environmental factors that inuence serum uric acid variability may have a relevant role on serum uric acid management of gout-susceptible individuals to prevent crisis and improve their dietary orientation and pharmacological therapy. The conditions that favor hyperuricemia may be also relevant to monitor individuals with increased risk for nephrolythiasisor even in chronic dialysis patients.

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Pacheco de Andrade et al.: Uric acid biorhythm and laboratory data variability

Dalpino et al. did not nd a circannual rhythm in uric acid values from a hospital sample of Brazilian population (44). These differences may be due to the methods used for data sampling and analysis. In our study, uric acid data were sampled from a routine laboratory, which is likely to have lesser variation of analyte results than that from hospital units. Moreover, we have excluded the outlier values preventing their inuence on data analysis. Differences in seasonality of clinical manifestations of uricemia are somehow hard to evaluate in terms of isolated causes, and there is no consensus, to a some extension due to the methodological difculties on isolation of specic factors (12, 17). Circannual variations in biological phenomena may be attributable to many factors. Yanai et al. proposed food intake as the main cause for biochemical variations in hemodialysis patients (4). Johnsson purpose that circannuality must be mediated in terms of sunlight activation and/or temperature variation (45). Gallerani et al. state that some variations observed for gout and pseudogout attacks can be explained by various causes, alone or in combination (17). Dincer and colleagues list some physiological, pharmacological and clinical causes for elevations on serum uric acid levels, some of them may present seasonal fashion as, e.g., variation on some foods availability, sunlight exposure and physical activity (30). The results from this large sample of a clinical laboratory database conrmed that serum uric acid has a long-term biorhythm. It has been suggested that quantitative measurements of time structure in laboratory data may have an important contribution mainly when amplitudes in rhythms are high enough to affect decisions in clinical practice (46, 47). According to Ricos et al., variations over 18% in uric acid levels could be considered as signicant in clinical settings (48). When double of mean amplitudes are expressed as percentage of mean MESORs, we found that highest percentage was 11.4% (group of women with 2650 years). However, clinical signicance of this variability remains to be elucidated. It is noteworthy that analysis of long-term biological rhythms of laboratory data are a difcult and complex task, including data collection and processing during at least 1 year (49). In addition, laboratory personnel should have the expertise to use and interpret the results generated by the software system, in order to detect the components of considerable rhythmic variation (50). In conclusion, we found two independent serum uric acid rhythm components, a transyear and a circannual/near-transyear. These rhythm patterns may have relevant inuence on pre-analytical variability of clinical laboratory results, whose effects may present clinical relevance. Awareness of these variations should be taken into account in the interpretation of laboratory results.

Conict of interest statement

Authors conict of interest disclosure: The authors stated that there are no conicts of interest regarding the publication of this article. Research funding: None declared. Employment or leadership: None declared. Honorarium: None declared.

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Acknowledgments
We thank Laboratorio Alvaro (Cascavel, PR, Brazil) for granting the access to the database and technical support. MHH and RDCH are recipients of a fellowship from CNPq, Brazil.

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