Introduction
Hyperuricemia is a purine metabolic disorder characterized by excessive production and/or reduced excretion of uric acid (UA) by the kidneys. It can be triggered by various underlying conditions, including metabolic syndrome, acute and chronic kidney diseases (CKDs), and certain tumors [1]. Environmental factors such as certain medications, dehydration, and a purine-rich diet can also contribute to hyperuricemia development [2]. Moreover, hyperuricemia has significant implications for the prognosis of chronic diseases such as CKD and cardiovascular disease [1,3,4].
The global prevalence of hyperuricemia is steadily increasing, and reports indicate an upward trend in adults, children, and adolescents, including preschool-aged children [5]. To address this global health problem, modifiable risk factors including food and nutrition must be identified, and dietary habits should be rectified [2]. Although numerous studies have predominantly focused on adults, research in the context of children and adolescents remains relatively limited [6]. Thus, utilizing data from the Korean National Health and Nutrition Examination Survey (KNHANES), this study aimed to investigate the occurrence of hyperuricemia among Korean children and adolescents. In addition to known risk factors, the study sought to explore dietary factors associated with hyperuricemia in this population.
Methods
Study population
The data analyzed in this study was sourced from the eighth KNHANES conducted between 2019 and 2021. Among the total 22,559 participants included in the 3 years, individuals aged ≤18 years for whom serum UA (SUA) levels could be measured were eligible for this study. Laboratory tests, including SUA, were conducted on individuals aged ≥10 years [7], those aged >18 or <10 years were excluded, resulting in the exclusion of 20,640 participants. Subsequently, among the 1,919 children and adolescents aged 10 to 18 years, the study also excluded those with missing nutrient factor data, including sodium, protein, fat, total energy, and sugar intake (n = 327), and those with extreme energy intake deviating significantly from age and sex norms (n = 15) as described in a previous study [8]: for boys aged 10 to 11 years, extreme energy intakes were defined as energy intake <1,673 kJ/day (400 kcal/day) or >23,848 kJ/day (5,700 kcal/day), and for boys aged 12 to 18 years, <2,510 kJ/day (600 kcal/day) or >33,890 kJ/day (8,100 kcal/day). Similarly, for girls aged 10 to 11 years, extreme energy intakes were considered for energy intake <1,569 kJ/day (375 kcal/day) or >21,338 kJ/day (5,100 kcal/day), and for girls aged 12 to 18 years, <2,092 kJ/day (500 kcal/day) or >25,104 kJ/day (6,000 kcal/day). In addition, cases with incomplete laboratory or anthropometric examination data (n = 309) were excluded. Finally, 1,268 individuals were included in the present study.
Informed consent was obtained from all participants or their parents (Fig. 1). The survey was approved by the Institutional Review Board of the Centers for Disease Control and Prevention in Korea (No. 2018-01-03-C-A, 2018-01-03-2C-A, and 2018-01-03-5C-A).
Measurements and categorization of nutrient factors
Dietary intake data were collected by the trained survey team via 24-hour recall interviews. Nutrient intake values, including total calories (kcal/day) and total protein, fat, sugar (g/day), and sodium (mg/day), were calculated by converting food intake data into nutrient intake. This was achieved using several databases, including the food composition table, 10th edition, employed in the KNHANES [9]. Because higher food intake is associated with a tendency for higher nutrient intake, the relative energy intake (%) was calculated from each nutrient in relation to the total daily energy intake for the three nutrients (protein, fat, and sugar). Total protein, fat, and sugar intake values were expressed both as absolute intake (g/day) and relative intake (%, intake calories/total energy intake calories) [10,11]. Dietary sodium intake was expressed both as absolute intake (mg/day) and dietary sodium density (dietary Na intake [mg]/1,000 kcal) [8]. Based on these values, each nutrient intake value was classified into tertiles (low-, intermediate-, and high-intake groups) [8].
Clinical and laboratory evaluation
Information on sex, age, height, weight, and blood pressure (BP) was collected. Body mass index (BMI; kg/m2) was calculated using body weight and height measurements. BMI status was categorized into the following three groups by sex- and age-specific percentiles: normal (BMI <85th percentiles), overweight (BMI ≥85th to <95th percentile), and obesity (BMI ≥95th percentile) [12]. Height, weight, and BMI were converted to z-scores using the 2017 Korean National Growth Charts [13]. BP was measured using a mercury sphygmomanometer after resting for 5 minutes in a sitting position, and the average of the last two values was used for the analysis. The BP status was categorized into three groups (normal, elevated BP, and hypertension) based on the sex-, age-, and height-specific percentiles [14]. Hypertension was defined as an average systolic or diastolic BP ≥95th percentile or 130/80 mmHg (whichever is lower) for children aged 10 to 12 years and ≥130/80 mmHg for children aged 13 to 18 years, respectively. Elevated BP was defined as BP percentile ≥90th to <95th percentile or 120/80 mmHg to <95th percentile for children aged 10 to 12 years and as BP levels ranging from 120/80 to 129/80 mmHg for adolescents aged ≥13 years.
SUA was measured through the uricase method using a Labospect 008AS (Hitachi). Hyperuricemia was defined as SUA levels exceeding 6.6 mg/dL in individuals aged 10 to 11 years (both sexes) and exceeding 7.7 mg/dL in male and 5.7 mg/dL in female aged 12 to 18 years [15]. Serum creatinine was measured through the kinetic colorimetric assay using Cobas (Roche). An estimated glomerular filtration rate (eGFR; mL/min/1.73 m2) was calculated to measure kidney function using the revised Schwartz formula: 0.413 × height (in cm)/serum creatinine (mg/dL). Decreased kidney function was indicated by eGFR <90 mL/min/1.73 m2 [16]. A hemoglobin A1c (HbA1c) level (≥5.7%) indicated an abnormal blood glucose status in children and adolescents [17].
Statistical analysis
Continuous variables are presented as medians (interquartile range), whereas categorical variables are presented as number (%) for each group. Student t test or chi-square test was performed as appropriate to compare each group. Multiple logistic regression analysis was performed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for hyperuricemia. For multiple logistic regression analysis, the covariates used for adjustment were the BMI status, age, sex, BP status, HbA1c, and eGFR. All statistical analyses were conducted using Rex version 3.6.3 (Rex Soft Inc.) and R version 4.2.3 (R Foundation for Statistical Computing). A p-value <0.05 was considered significant.
Results
Clinical characteristics of the study participants
Table 1 presents the clinical characteristics of 1,268 participants according to the presence or absence of hyperuricemia. Among the study participants, 150 (11.8%) had hyperuricemia. The median age of the entire study population was 13 years, with male comprising 55.9%. When participants were categorized into three age groups, 38.5% (n = 488) were aged 10 to 12 years, 33.1% (n = 420) were aged 13 to 15 years, and 28.4% (n = 360) were aged 16 to 18 years. Among those with hyperuricemia, the median age was 14 years, and male accounted for 60.7%. No significant sex differences were found between the hyperuricemia and non-hyperuricemic groups. However, the hyperuricemia group was significantly older (p = 0.001) and had a higher proportion of participants aged 13 to 15 years compared to the non-hyperuricemic group (p = 0.002). In the overall population, 10.3% were overweight, and 16.7% were obese. Among those in the hyperuricemia group, 41.3% were obese compared with 13.4% in the non-hyperuricemic group, indicating a significantly higher BMI among participants with hyperuricemia (p < 0.001). Despite the trend toward a higher prevalence of hypertension in the hyperuricemia group (14% for hyperuricemia vs. 8.5% for non-hyperuricemia), the difference did not reach significance. In the entire cohort, 24.2% (n = 307) of individuals had decreased kidney function (eGFR <90 mL/min/1.73 m2). Among them, 4.7% (n = 59) had an eGFR <75 mL/min/1.73 m2, while 19.6% (n = 248) had an eGFR between 75 and 90 mL/min/1.73 m2. The hyperuricemia group had a significantly higher proportion of subjects with decreased kidney function (35.3%) compared to the non-hyperuricemia group (22.7%) (p = 0.001), as well as a higher proportion of subjects with eGFR <75 mL/min/1.73 m2 (p = 0.001). Among all participants, the prevalence of abnormal HbA1c was 14.8%, with the hyperuricemia group exhibiting a higher rate of 24.0% (p = 0.001). In addition, the hyperuricemia group showed higher levels of hemoglobin (p = 0.02), aspartate aminotransferase (p = 0.004), alanine aminotransferase (p < 0.001) and total cholesterol (p = 0.002). However, no significant differences were observed in total energy intake and dietary intake, including sodium, protein, fat, and sugar, between the two groups.
Association of hyperuricemia with the four dietary factors
The cutoff values for each nutrient intake tertile (low-, intermediate-, and high-intake groups) are shown in Table 2. To assess the risk of hyperuricemia based on nutrient intake, a model adjusted for age, BMI, sex, BP, HbA1c, and eGFR values was used. The multivariate adjusted ORs (95% CI) for hyperuricemia according to tertile values for relative intake (expressed as a percentage of intake calories/total energy intake calories) of total protein, fat, and sugar, as well as dietary sodium density (dietary sodium intake in mg per 1,000 kcal), are presented in Fig. 2.
No significant increases in hyperuricemia risk with high intake of protein, fat, and sodium were observed. However, regarding sugar intake, the high-intake group had a significantly increased risk of hyperuricemia compared with the low-intake group (OR, 1.79; 95% CI, 1.13–2.85; p = 0.01), whereas the intermediate-intake group had no significant increase in the risk of hyperuricemia compared with the low-intake group (OR, 1.45; 95% CI, 0.92–2.31; p = 0.11).
Association of hyperuricemia with other clinical and laboratory variables
The multivariate ORs (95% CI) for hyperuricemia according to other potential risk variables (age, sex, overweight/obesity, high BP, high HbA1c, or decreased kidney function status) used for the adjusted model besides sugar intake are presented in Fig. 3. The risk of hyperuricemia did not significantly increase according to sex or hypertension status. However, age of 13 to 15 years, decreased kidney function, high HbA1c, and high BMI were associated with an increased risk of hyperuricemia. When participants aged 10 to 18 years were classified into three groups based on age, those aged 13 to 15 years had significantly higher ORs for hyperuricemia than those aged 10 to 12 years (youngest age group) with an OR of 2.02 (95% CI, 1.29–3.20; p = 0.001), whereas participants aged 16 to 18 years (oldest age group) did not exhibit a significantly higher occurrence rate (OR, 1.29; 95% CI, 0.75–2.23). Individuals with higher HbA1c had a 1.6 times higher risk of hyperuricemia compared to those with normal HbA1c (p = 0.04). Additionally, the risk of hyperuricemia increased as kidney function declined. Compared to individuals with an eGFR ≥90 mL/min/1.73 m2, those with an eGFR between 75 and 90 mL/min/1.73 m2 had a 1.63 times higher risk of hyperuricemia (p = 0.047), while those with an eGFR <75 mL/min/1.73 m2 had a 3.42 times higher risk (95% CI, 1.01–2.50; p = 0.002). The strongest positive correlation was found between BMI status and risk of hyperuricemia among the adjusted variables. Compared with the normal BMI group, the ORs of the overweight and obesity groups were 3.0 (95% CI, 1.74–5.04; p < 0.001) and 5.5 (95% CI, 3.63–8.36; p < 0.001), respectively.
Discussion
This study reveals a hyperuricemia prevalence of 11.8% among the general population of Korean children and adolescents from 2019 to 2021. The prevalence of hyperuricemia in the general children and adolescent population varies widely, ranging from <10% to >30%, due to differences in age, sex, criteria for hyperuricemia, and race across studies [5,18]. In a previous study targeting Korean children and adolescents, the 2-year prevalence of hyperuricemia (2016–2017) was 9.4% [15]. Applying the same criteria for participants’ age (10–18 years) and definition of hyperuricemia in the present study conducted over 3 years (2019–2021), the prevalence of hyperuricemia increased to 11.8%. This trend is consistent with the results of a previous study conducted in other countries. Studies in other Asian countries such as China and Japan have also reported an increasing prevalence of hyperuricemia among children and adolescents, indicating it is a significant global public health problem [19]. Therefore, the risk factors of hyperuricemia, particularly modifiable factors, must be corrected to promote public health.
In this study, the risk of hyperuricemia was approximately twice as high in adolescents aged 13 to 15 years compared with those aged 10 to 12 years. Generally, UA levels gradually increase during puberty, with a sharper rise observed in male up to midpuberty, followed by a plateau in both sexes during late puberty [20]. Although the reason why UA levels are higher in middle school-aged adolescents in the present study cannot be determined, environmental factors such as unfavorable dietary changes exacerbated during the coronavirus disease 2019 pandemic, in addition to sexual maturation and hormonal changes during puberty, may have had an effect on SUA levels during the middle school period [21,22]. Further follow-up may be necessary to investigate the trends in the prevalence of hyperuricemia and the need for screening for hyperuricemia risk among Korean adolescents of middle school age, considering other confounding factors such as physical activity, metabolic components such as abdominal obesity and hyperlipidemia, and additional nutritional influences that could contribute to the development of hyperuricemia.
In this study, obesity was the most powerful risk factor for hyperuricemia in Korean children and adolescents (OR, 5.5). Previous studies have also shown that obesity is significantly correlated with hyperuricemia and that weight loss lowers blood UA levels [23]. Studies have suggested that obesity causes hyperuricemia through several mechanisms including metabolic regulation, genomic and epigenetic modulation, and insulin resistance [24,25]. Obesity is steadily increasing in Korean children and adolescents; subsequently, the risk of hyperuricemia is further increasing [26]. Considering that being overweight or obese is an important risk factor for hyperuricemia and weight loss has the effect of lowering blood UA levels, screening for hyperuricemia and active lifestyle modification in children and adolescents who are overweight or obese, even if they are asymptomatic, may help in preventing hyperuricemia and correcting it early [23]. A recent study conducted in China among children and adolescents aged 2 to 17 years with obesity also indicated a significantly higher prevalence of hyperuricemia among children and adolescents who were obese, particularly those aged ≥12 years, than the younger age groups [27]. This underscores the need for screening for hyperuricemia in children aged ≥12 years and who are obese.
Our results demonstrated that elevated HbA1c levels increased the risk of hyperuricemia by 1.6 times. Among the 157 participants with elevated HbA1c, only four had levels ≥6.5%, with the majority being in a prediabetic state. The findings of our study on the association between prediabetes and hyperuricemia are consistent with previous studies. In a study of 4,633 individuals aged 20 to 81 years from the Korean general population, those with hyperuricemia had a higher prevalence of prediabetes compared to those with normal UA levels (OR, 1.51; p < 0.01). Furthermore, for each standard deviation increase in UA levels, the risk of prediabetes increased by approximately 114% in male (p = 0.05) and 116% in female (p = 0.01) [28]. Similarly, Choi and Ford [29] investigated the relationship between SUA levels and markers of glycemic control, including HbA1c, fasting glucose, serum C-peptide, and insulin resistance, using data from 14,664 participants aged 20 years and older in the U.S. National Health and Nutrition Examination Survey. They found that individuals with moderately elevated HbA1c levels had a higher risk of hyperuricemia, highlighting the potential role of UA as an indicator of impaired glucose metabolism and insulin resistance [29]. However, studies in children and adolescents remain extremely limited. Further research involving larger cohorts of Korean children and adolescents is necessary to explore the relationship between hyperuricemia and impaired glucose metabolism, as well as the underlying mechanisms.
In the present study, decreased kidney function was significantly associated with hyperuricemia in Korean children and adolescents. Decreased kidney function leads to decreased renal excretion of UA, resulting in hyperuricemia. On the contrary, hyperuricemia can cause kidney injury through mechanisms such as the proliferation of vascular smooth muscle cells, endothelial dysfunction, impaired production of endothelial nitric oxide, and inflammation [30,31]. The relationship between kidney function and hyperuricemia has been demonstrated in several clinical studies. A large Italian multicenter cohort study (n = 26,971, 51% male, 62% with hypertension, and 12% with diabetes mellitus) showed that the lower the eGFR, the higher the prevalence of hyperuricemia. Individuals with eGFR <60 mL/min/1.73 m2 had a tenfold higher incidence of hyperuricemia than those with eGFR >90 mL/min/1.73 m2 [32]. In a single-center study investigating hyperuricemia and associated factors in Chinese children with CKD (n = 170), Xu et al. [33] reported that normal kidney function (eGFR >90 mL/min/1.73 m2) served as a protective factor against increased SUA levels in children. Recently, Li et al. [34] reported that hyperuricemia was associated with a rapid decline in kidney function, even in healthy adults with normal kidney function. They followed up the trends of eGFR in 2,802 individuals over 3 years and found high UA levels as an independent risk factor for a rapid decline in kidney function (eGFR > 5 mL/min/1.73 m2) in multifactorial logistic regression analysis (OR, 1.64; p < 0.001) [34]. However, few studies have elucidated the relationship between hyperuricemia and kidney function in the general pediatric population. This study focused on the general pediatric and adolescent population. However, it included 24.2% (n = 307) of children and adolescents with an eGFR <90 mL/min/1.73 m2. Among them, 19.6% (n = 248) had an eGFR between 75 and 90 mL/min/1.73 m2, 4.7% (n = 59) had an eGFR below 75 mL/min/1.73 m2, and one individual had an eGFR below 60 mL/min/1.73 m2. Based on the conclusion that eGFR between 75 and 90 mL/min/1.73 m2 had a 1.63 times higher risk of hyperuricemia (p = 0.047), even minimal decreases in kidney function can be a risk factor for hyperuricemia in children and adolescents without CKD. However, serum creatinine-based eGFR has limitations in assessing kidney function in children and adolescents due to significant changes in body composition. Therefore, longitudinal studies using more accurate kidney function assessments, such as serum creatinine-cystatin C-based eGFR, are needed to better understand the relationship between hyperuricemia and kidney function in the general pediatric and adolescent population.
This study also confirmed that higher sugar intake was an independent risk factor for hyperuricemia. Previous studies have extensively evaluated the associations between fructose (a type of sugar) and hyperuricemia [35]. However, the relationship between total sugar intake and hyperuricemia has not been extensively evaluated. Excessive sugar intake, particularly added sugar intake, was found to be detrimental to human health [36]. The Dietary Reference Intakes for Koreans recommends that total sugars, including both natural and added sugars, should be within 10% to 20% of total energy. Although the mean intake of total sugar for Koreans is within the recommended range, the intake among children, adolescents, and young adults tends to exceed these guidelines, implying the need for intervention [10]. A 1.79-fold increased risk of hyperuricemia was noted in Korean children and adolescents with high sugar intake compared with those with low intake. However, no significant association was found with intermediate intake. Based on the findings of this study, careful regulation of sugar intake in the diets of children and adolescents, regardless of sugar type, is essential. High sugar intake, defined as exceeding 15.23% of total energy intake, may contribute to pediatric hyperuricemia.
However, this study has certain limitations. First, given the cross-sectional design, the evidence for establishing a clear causality solely based on the findings may not be definitive. Therefore, the results of this study need to be validated in prospective studies. Second, the approach involved considering total dietary intake rather than detailed categorization of components such as animal proteins, unsaturated fatty acids, and fructose. Consequently, differences among these specific types of dietary intake could not be ascertained. Third, because the amounts of dietary intake were assessed using a single 24-hour recall, exclusive reliance on self-report data could introduce bias. Lastly, even though some important confounding factors were adjusted, residual confounders may remain such as physical activity, other dietary factors including micronutrients, and dietary habits.
Nevertheless, this study has several strengths. A nationwide dataset representative of the general pediatric and adolescent population was used, and SUA, creatinine, amounts of dietary intakes, and other values were measured consistently among all participants using the same method. Values of each dietary factor in addition to its absolute value were adjusted, which may improve the assessment methods for dietary intake in children and adolescents having variations in dietary pattern. Finally, data were adjusted for multiple confounding variables.
In conclusion, the results demonstrate that the increasing prevalence of hyperuricemia in Korean children and adolescents, and pubertal age, obesity, decreased kidney function, high HbA1c level, and high sugar intake are associated with the risk of hyperuricemia. Thus, even in children and adolescents without underlying conditions or symptoms, UA screening is necessary if they are obese or prediabetic state or have even minimal kidney function abnormalities. These findings underscore the importance of sugar intake regulation, early detection of prediabetic states, and renal health monitoring in preventing hyperuricemia among children and adolescents.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Download Citation
Print
