Gout comorbidities: results from the Korean National Health and Nutrition Examination Survey

Abstract

Objectives

Gout is associated with several comorbidities. This study aimed to evaluate the prevalence of comorbidities in the Korean adult population with gout and investigated the association of gout with these comorbidities.

Methods

Data from 15,935 (weighted n = 39,049,167) participants aged 19 years and older in the Korean National Health and Nutrition Examination Survey from 2019 to 2021 were used for analysis. Weighted prevalence and odds ratios (OR) of comorbidities in individuals with gout were compared to a non-gout population.

Results

The weighted prevalence of gout was 2.1% (weighted n = 808,778). Among individuals with gout, 66.5% had metabolic syndrome, 54.9% had hypertension, 41.2% had hypercholesterolemia, 19.1% had diabetes, 13.5% had chronic kidney disease (CKD), 4.1% had myocardial infarction or angina, 3.8% had stroke, and 2.8% had rheumatoid arthritis (RA). After adjusting for socioeconomic and lifestyle characteristics, gout was independently associated with the increased prevalence of metabolic syndrome (male OR = 2.0, 95% confidence interval (CI): 1.5–2.8; female OR = 3.7, 95% CI: 1.5–9.2), hypercholesterolemia (male OR = 1.9, 95% CI: 1.4–2.5; female OR = 3.1, 95% CI: 1.3–7.5), CKD (male OR = 4.5, 95% CI: 2.7–7.3; female OR = 11.5, 95% CI: 4.1–32.1), and RA (male OR = 2.8, 95% CI: 1.1–7.1; female OR = 3.1, 95% CI: 1.1–8.7) compared to the non-gout population.

Conclusions

Gout was associated with several comorbidities, including RA, in both males and females. These results suggest that the prevention and treatment of comorbidities at the individual level, carried out by clinicians, and knowledge of these comorbidities would help guide health policies for the Korean population.

Introduction

Gout is the most common type of inflammatory arthritis in adults [1]. Gout is characterized as an arthritic condition that occurs due to the accumulation of monosodium urate crystals in the joints, resulting from the prolonged elevation of uric acid levels [2]. Various factors, including dietary and lifestyle choices, medications, and kidney function, can influence the levels of uric acid in the bloodstream [3]. Apart from the significant pain it causes, gout is also linked to a variety of comorbidities, including cardiovascular disease, kidney disease, metabolic syndrome, and diabetes [4, 5]. In certain instances, such as chronic kidney disease (CKD), it is evident that the coexisting condition plays a role in advancing gout [6]. Conversely, gout or hyperuricemia alone plays a part in the development of comorbidities associated with gout [7]. Population-based epidemiologic studies found that the prevalence and incidence of gout is increasing worldwide [8,9,10]. As the prevalence of gout increases, gout and comorbidities accompanying gout can have a significant adverse impact on public health. Therefore, understanding the patterns of comorbid conditions in gout is crucial.

According to the National Health and Nutrition Examination Survey 2007–2008 in the United States, gout was associated with an increased prevalence of hypertension, CKD, obesity, diabetes, nephrolithiasis, myocardial infarction, heart failure, and stroke compared to those without gout [11]. The multicenter study disclosed an association between gout and metabolic syndrome, highlighting obesity and dyslipidemia as the primary factors linked to this syndrome in the study participants [12]. The prevalence of metabolic syndrome in patients with gout was approximately 50% in a tertiary hospital study [13]. However, few studies have been conducted on comorbidities in Korean patients with gout using large-scale data.

This study aimed to evaluate the prevalence of comorbidities in the Korean adult population with gout and investigated the association of gout with these comorbidities using data from the Korean National Health and Nutrition Examination Survey (KNHANES).

Methods

This cross-sectional study utilized comorbidity and laboratory data collected during the 2019–2021 KNHANES. This nationwide survey, conducted periodically by the Korea Centers for Disease Control and Prevention, aims to assess the health and nutritional status of the Korean population [14].

Study population

Participants were selected using the proportional allocation and systematic sampling method with multistage stratification to create a representative Korean population [15]. Although individual participants do not typically represent the entire Korean population, this survey provides representative estimates of the non-institutionalized Korean civilian population by utilizing sample weights. These weights were adjusted to address factors such as discrepancies in household and population counts between the time of sample design and the survey, unequal sampling rates, and non-response errors in the survey. This adjustment was made to enhance the representativeness and precision of health-related behaviors, the prevalence of chronic diseases, and associated estimations for the target population, which was the Korean population.

A total of 22,559 participants in the 2019–2021 KNHANES dataset were initially considered. Among them, a group of 18,691 individuals aged 19 and above was chosen for the study. The analysis excluded 2,756 participants due to missing data related to gout diagnosis or demographic variables. Finally, a total of 15,935 individuals (weighted n = 39,049,167) were included for analysis. This study received approval from the Institutional Review Board of Soonchunhyang University Hospital (IRB No. 2023-04-002).

Data collection

Standardized interviews were conducted individually by a professional investigator using a well-established questionnaire that encompassed demographic and socioeconomic characteristics to gather data on demographic variables.

Assessment of gout

Gout was defined in the questionnaire as “Gout diagnosed by a physician (yes/no)” through a standardized interview. The specific question asked was, “Has a physician diagnosed you with gout?”

Assessment of comorbidities

The KNHANES dataset encompasses a wealth of information on the association between gout and various diseases across diverse categories, including well-studied conditions like cardiovascular disease and kidney disorders, as well as relatively understudied ones such as allergic conditions, rheumatoid arthritis, cancers, and depression. Recognizing this breadth, our analysis extended beyond comorbidities traditionally associated with gout, such as cardiovascular and kidney diseases, to encompass a wide range of conditions included in the KNHANES survey. We aimed to explore the association between gout and a comprehensive array of diseases, beyond the commonly investigated ones.

The following comorbidities were defined in the same way as the gout diagnosis. Information was collected on comorbidities, including stroke, myocardial infarction or angina, osteoarthritis, rheumatoid arthritis (RA), osteoporosis, pulmonary tuberculosis, asthma, thyroid disease, thyroid cancer, depression, atopic dermatitis, allergic rhinitis, sinusitis, otitis media, cataract, and chronic hepatitis B that were diagnosed by a physician. Hypertension was defined as having a systolic blood pressure of 140 mmHg or higher or a diastolic blood pressure of 90 mmHg or higher. Individuals taking antihypertensive medication were also categorized within this group. Diabetes was defined as having a fasting blood glucose level of 126 mg/dL or higher, receiving a diagnosis of diabetes from a physician, using hypoglycemic drugs or insulin injections, or having an HbA1c level of 6.5% or higher. Hypercholesterolemia was defined as having a total cholesterol level greater than 240 mg/dL or using cholesterol-lowering drugs. Metabolic syndrome was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III (ATP III) definition [16]. Current ATP III criteria were used to define metabolic syndrome if any three of the following five traits were present: (1) central obesity (waist circumference ≥ 90 cm in Asian men or ≥ 80 cm in Asian women), (2) hypertriglyceridemia (a fasting serum triglyceride level ≥ 150 mg/dL or drug treatment for elevated triglycerides), (3) decreased high-density lipoprotein (HDL) cholesterol levels (serum HDL cholesterol <40 mg/dL in men or <50 mg/dL in women or drug treatment for low HDL cholesterol), (4) elevated blood pressure (BP) (systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg or drug treatment for elevated BP), and (5) hyperglycemia (fasting plasma glucose levels ≥ 100 mg/dL or drug treatment for elevated blood glucose). CKD was defined as an estimated glomerular filtration rate (eGFR) of < 60. The eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) study equation: eGFR (mL/min/1.73 m²) = 175 − (serum creatinine) − 1.154 − (age) − 0.203 − (0.742 if female) [17]. Blood samples were collected in the morning after a minimum 8-hour fasting period. The samples were promptly refrigerated and transported in cold storage to the central testing facility.

Assessment of confounders

Socioeconomic and lifestyle characteristics were assessed as potential confounders in the relationship between gout and comorbidities. Socioeconomic factors, such as age, income, education, and marital status, were considered, alongside lifestyle characteristics including alcohol consumption, smoking habits, and body mass index (BMI). These information were collected through the KNHANES questionnaire. Heavy alcohol drinking was defined as consuming alcohol more than two times per week in the year preceding the interview.

Statistical analysis

Descriptive statistics were used to identify the characteristics of the study population. Clinical comparisons were performed using t-tests, and the Mann–Whitney U-test was performed for continuous variables, as appropriate. Chi-square tests were used for categorical variables. Logistic regression analysis for each sex individually was performed to investigate the association between gout and comorbidities. Firstly, the crude analysis, without adjustment, was carried out, and then the multivariate analysis was done, adjusting for socioeconomic factors (age, income, education, marital status) and lifestyle characteristics (alcohol consumption, smoking, and BMI).

Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each comorbidity. P-values were corrected by Bonferroni’s method for multiple testing. Statistical analyses were performed using SAS (SAS version 9.4; SAS Institute, Cary, NC, USA). All P-values were two-sided, and P < 0.05 was considered statistically significant.

Results

Demographic and frequency of comorbidities in individuals with gout

The average age of the total study population was 47.5 years, with 50.2% being male. The weighted prevalence of gout was determined to be 2.1% (weighted n = 808,778). Among participants with gout, 66.5% had metabolic syndrome, 54.9% had hypertension, 41.2% had hypercholesterolemia, 19.1% had diabetes, 17.2% had cataracts, 14.7% had allergic rhinitis, 13.5% had CKD, 9.3% had osteoarthritis, 5.7% had pulmonary tuberculosis, 4.1% had myocardial infarction or angina, 3.8% had stroke, and 2.8% had RA.

Demographic and clinical characteristics based on the presence or absence of gout for both males and females are presented in Table 1. The mean age of both males and females with gout was higher than that of the non-gout population. In males, alcohol consumption was more frequent in the gout population than in the non-gout population, while in females, there was no significance in alcohol consumption between those with and without gout. The prevalence of comorbidities, including hypertension, diabetes, hypercholesterolemia, metabolic syndrome, CKD, osteoarthritis, rheumatoid arthritis, and cataracts, was higher in both males and females with gout compared to the individuals without gout. The prevalence of stroke was higher in males with gout compared to those without gout, whereas in the female group, there was no significant difference.

Table 1 Demographic and clinical characteristics according to the presence or absence of gout, stratified by sex

Logistic regression analyses for comorbidities based on the presence of gout

Univariable and multivariable logistic regression analyses for comorbidities based on the presence of gout in both males and females are presented in Table 2. After adjusting for socioeconomic and lifestyle characteristics, gout was found to be independently associated with an increased prevalence of metabolic syndrome (male OR = 2.0, 95% CI: 1.5–2.8; female OR = 3.7, 95% CI: 1.5–9.2), hypercholesterolemia (male OR = 1.9, 95% CI: 1.4–2.5; female OR = 3.1, 95% CI: 1.3–7.5), CKD (male OR = 4.5, 95% CI: 2.7–7.3; female OR = 11.5, 95% CI: 4.1–32.1), and RA (male OR = 2.8, 95% CI: 1.1–7.1; female OR = 3.1, 95% CI: 1.1–8.7) compared to the non-gout population. The prevalence of hypertension was significantly associated with gout in males, whereas no significant association was observed in females (male OR = 2.4, 95% CI: 1.7–3.3; female OR = 1.4, 95% CI: 0.7–2.7).

Table 2 ORs (95% CI) for comorbidities among participants with gout compared to non-gout participants

Discussion

We evaluated the comorbidities of patients with gout using the nationwide KNHANES conducted by the Korean government. Frequently associated comorbidities in patients with gout included metabolic syndrome, hypertension, hypercholesterolemia, diabetes, CKD, and RA, listed in descending order. Following adjustment for socioeconomic and lifestyle factors, gout demonstrated an independent association with a metabolic syndrome, hypercholesterolemia, CKD, and RA in males and females compared to individuals without gout. Additionally, the presence of gout was significantly linked to hypertension in male participants.

In nationwide study in Taiwan, hypercholesterolemia (OR 1.63), hypertension (OR 2.00), renal insufficiency (OR 2.06) were the common comorbidities of gout [18]. Hyperlipidemia (59.7%) and hypertension (53.7%) were common comorbidities of gout in Japan [19]. Hypertension and obesity are common comorbidities in Western countries. In USA, frequently associated comorbidities in gout was hypertension (74%), chronic kidney disease (71%), obesity (53%), and diabetes (26%) [11]. In UK, obesity (27.7%), hypertension (17.5%), myocardial infarction (7.4%), and heart failure (7.1%) [20]. In Germany, diabetes (25.9%) was most common comorbidities in gout, followed by hypertension (18.5%), and heart failure (10.5%) [20].

Metabolic syndrome is increased among gout patients compared to the general population [12, 13, 21]. We previously reported that hyperuricemia was associated with an increased prevalence of metabolic syndrome in both males and females [22]. Hyperuricemia was also associated with the number of metabolic syndrome components [22]. Several studies demonstrated a relationship between elevated uric acid levels and insulin resistance [23, 24]. As serum insulin diminishes the renal excretion of uric acid, uric acid levels could increase as a result of hyperinsulinemia in metabolic syndrome [25].

Hypertension is associated with a 2 to 3 folds increase the risk of gout [26, 27]. Meta-analysis of 25 studies showed that hyperuricemia can modestly increase the risk of hypertension with a dose-dependent relationship [28]. Although there is a clear relationship between gout and hypertension, there remains insufficient evidence elucidating how gout precipitates the hypertension. Several studies might provide evidence for uric acid-induced hypertension [29]. Uric acid directly simulates the vascular smooth muscle proliferation and induces renal arteriolopathy, leading to hypertension in experimental rat model [30]. Serum uric acid was strongly associated with the risk allele (T) of the rs734553 polymorphism of the glucose transporter 9 gene, and individuals with risk allele showed higher systolic blood pressure than control group [31]. Allopurinol use was independently associated with fall in both systolic and diastolic blood pressure after allopurinol initiation [32].

The association between gout and hypercholesterolemia was not fully understood. Previous studies shown that hypercholesterolemia is associated with increased risk of gout [33,34,35]. In nationwide, population-based cohort study in Taiwan, overall incidence risk of hyperlipidemia in gout patients was 2.55 fold compared to that in non-gout population [36]. Higher baseline serum uric acid levels and increased serum uric acid levels over 5 years is an independent risk factor for developing high LDL cholesterol [37]. Serum uric acid might play a part in promoting lipogenesis while inhibiting fatty acid oxidation [38, 39]. Wu et al. reported that uric acid lowering therapy decreased serum cholesterol levels in patients with gout who did not receive lipid lowering therapy [40]. Uric acid lowering medications are proposed to have an effect on decreasing the expression of lipogenesis-related genes [36].

Chronic kidney disease is common in patients with gout. A meta-analysis of epidemiological studies reported that gout was associated with both CKD stage ≥ 3 (OR = 2.41, 95% CI: 1.86–3.11) and nephrolithiasis (OR = 1.77, 95% CI: 1.43–2.19) [41]. A diminished GFR poses a risk of premature tophi emergence, indicating that renal function could influence the severity of gout [42]. Conversely, the prevalence of gout is elevated in individuals diagnosed with CKD [43]. Kidney impairment may arise due to comorbid conditions, such as hypertension, diabetes, and the use of nonsteroidal anti-inflammatory drugs [44]. Hyperuricemia-mediated endothelial dysfunction and renovascular disease also cause renal impairment [45]. A previous meta-analysis study suggested that CKD patients with uric acid-lowering therapy tended to show superior eGFR preservation compared to patients without uric acid-lowering therapy [46]. Appropriately managing uric acid levels in patients with gout is speculated to contribute to the prevention of CKD [47].

The prevalence of RA was significantly higher in participants with gout compared to the non-gout population (2.8% vs. 1.4%, p = 0.033). Gout was independently associated with an increased prevalence of RA (male OR = 2.8, 95% CI: 1.1–7.1; female OR = 3.1, 95% CI: 1.1–8.7) compared to the non-gout population after adjusting for socioeconomic and lifestyle characteristics. In contrast, the prevalence of osteoarthritis was not significantly different between the gout and non-gout populations. In the literature, gout and RA occur in the same patients. However, it seems that the incidence is rare. To date, approximately 60 cases of concurrent RA and gout have been documented in the literature [48]. Jebakumar et al. reported that among 813 patients with RA, 22 developed gout, and the 25-year cumulative incidence of gout in patients with RA was 2.4%. Gout development was more common among patients diagnosed with RA in recent years (1995–2007) compared to those diagnosed in earlier years (1980–1994) [49]. In this study, older age, male sex, and obesity were risk factors for gout in patients with RA [49]. A single-center retrospective study showed that 13 patients met both classification criteria for RA and gout over a period of 13 years. All of the 13 patients had at least one comorbidity, such as hypertension, CKD, or obesity [48]. To the best of our knowledge, no analysis of the prevalence of RA in patients with gout has been performed. The reasons for the higher prevalence of RA in patients with gout compared to those without gout, as observed in the current study, are not definitively clear. Gout and RA are inflammatory arthritis conditions with different clinical and laboratory features. Despite their differences, RA and gout share clinical features, such as polyarticular involvement and subcutaneous nodules. Studies have suggested a potential close connection between uric acid and inflammatory responses. Elevated serum uric acid levels show a positive correlation with tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C-reactive protein (CRP) [50, 51]. Wang et al. reported that serum uric acid levels were significantly higher in patients with RA than in the healthy controls. Furthermore, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) were positively correlated with serum uric acid levels in patients with RA [52]. Additional studies incorporating more epidemiological data are needed to understand the relationship between gout and RA further.

When examining comorbidities among gout patients based on the presence of hyperuricemia (male, uric acid ≥ 7 mg/dL; female, uric acid ≥ 6 mg/dL), the prevalence of metabolic syndrome was higher in the hyperuricemia group in both males and females. However, there was no significant difference in multivariable analysis among gout-afflicted males with or without hyperuricemia (data were not shown). The limited number of female gout patients precluded multivariable analysis due to the small sample size. Furthermore, since uric acid was measured only once, there may have been limitations in determining whether uric acid control was achieved.

This study had several limitations. First, the determination of gout and RA relied on participant-provided information during interviews, lacking the application of specific classification criteria for these conditions. Second, an analysis was conducted to examine the association between gout and malignancy, but no significant correlation with gout was found. Due to the limited number of malignancy cases in both males and females, multivariable analysis was often unfeasible. Therefore, results were not provided for most malignancies, excluding thyroid cancer. Third, the cross-sectional design of this study precluded the establishment of causality. Despite the limitations, the current study provides comprehensive cross-sectional data on gout and comorbidities in Korean adult populations.

Conclusions

Gout was independently associated with several comorbidities, including metabolic syndrome, hypercholesterolemia, CKD, and RA in both males and females. These findings indicate the importance of healthcare professionals paying attention to underlying comorbidities in individuals with gout.