Abstract
Objective
This cross-sectional study investigates the association between the serum uric acid-to-creatinine (UA/Cr) ratio and gallstone risk using NHANES 2017–2020 data, while exploring modifying effects of demographic and metabolic factors.
Methods
A total of 5450 adult participants were included after excluding individuals with missing gallstone diagnoses or incomplete UA/Cr data. UA/Cr was calculated as uric acid (mg/dL)/creatinine (mg/dL). Gallstone diagnosis relied on self-reported questionnaires. Weighted logistic regression models (unadjusted, partially adjusted, fully adjusted) assessed associations, with covariates including demographic (age, sex, race/ethnicity, education), lifestyle (smoking, alcohol use), and metabolic factors (BMI, hypertension, total bilirubin, diabetes). A restricted cubic spline analysis was further employed to visualize potential nonlinear relationships. Additionally, subgroup analyses were conducted to evaluate the association between the UA/Cr and gallstone risk across various subgroups.
Results
Gallstone prevalence was 9.85% (537/5450), with higher UA/Cr in affected individuals (7.29 vs. 6.16, p = 0.034). Fully adjusted models demonstrated a 17% increased gallstone risk per UA/Cr unit (Odds ratio (OR) = 1.17, 95% confidence interval: 1.09–1.38, p = 0.021). The highest UA/Cr quartile (≥7.234) showed a 41% elevated risk (OR = 1.41, p = 0.017). Restricted cubic spline analysis revealed a non-linear dose–response relationship (inflection point: UA/Cr = 6.4). Subgroup analyses identified stronger associations in females (OR = 1.23, p = 0.012), obese individuals (OR = 1.24, p = 0.016), and divorced participants (OR = 1.21, p = 0.009).
Conclusions
Elevated UA/Cr ratio was independently associated with an increased risk of gallstone disease in this nationally representative sample. Future prospective and mechanistic studies are warranted to clarify the temporal relationship and the underlying pathways linking purine metabolism to biliary pathology.
Introduction
Gallstone disease is a prevalent biliary disorder that poses considerable public health and economic burdens worldwide. 1 Epidemiological studies have identified a range of risk factors—including advanced age, female sex, obesity, and hypertension—that contribute to its pathogenesis.2,3 Despite these known associations, the underlying metabolic mechanisms that predispose individuals to gallstone formation remain only partially elucidated.
Serum uric acid, a byproduct of purine metabolism, has garnered attention as a biomarker for several metabolic and cardiovascular conditions.4,5 However, considering that serum creatinine is a well-established indicator of renal function, the uric acid-to-creatinine (UA/Cr) ratio may offer a more nuanced reflection of metabolic dysregulation by adjusting uric acid levels according to renal clearance. 6 This ratio has been hypothesized to mirror systemic oxidative stress and inflammation—factors that are increasingly recognized in the pathophysiology of gallstone disease—yet its role as a potential predictor for gallstone risk has not been thoroughly investigated.
Leveraging data from the National Health and Nutrition Examination Survey (NHANES) 2017–2020, our study aims to clarify the association between the UA/Cr ratio and gallstone disease in a nationally representative cohort. Through comprehensive multivariable adjustments and subgroup analyses, we seek to determine whether an elevated UA/Cr ratio independently correlates with an increased risk of gallstones, and to explore the modifying effects of factors such as gender, body mass index, and marital status. Establishing this link could enhance our understanding of gallstone pathogenesis and aid in the development of more effective risk stratification and preventive strategies in clinical practice.
Methods
Study population
This cross-sectional analysis utilized data from the National Health and Nutrition Examination Survey (NHANES 2017–2020), a nationally representative program conducted by the National Center for Health Statistics (NCHS) to assess population health and nutritional status. This cross-sectional study included 5450 adult participants from NHANES 2017–2020. Figure 1 details the participant selection process from the NHANES 2017–2020 cohort. Exclusion criteria included: (1) incomplete gallstone diagnosis records (n = 6350), and (2) missing primary exposure data and covariate data (n = 3760). The final analytical sample comprised 5450 adults. The NCHS Research Ethics Review Board approved the study protocol, with written informed consent obtained from all participants prior to data collection. This study was conducted in accordance with the ethical principles of the Helsinki Declaration of 1975 as revised in 2024 and approved by the Ethics Committee of Lishui District People's Hospital (Approval No.: 2024048; Date of approval: 15 September 2024). All participant data were de-identified prior to analysis. Direct identifiers were removed, and indirect identifiers were aggregated or generalized to prevent re-identification. Only anonymized datasets were accessible to the research team during the study. The reporting of this study conforms to STROBE guidelines. 7
Flow chart of sample selection from NHANES 2017–2020.
Data collection
The data of UA/Cr ratio was designed as an exposure variable and was calculated as uric acid (mg/dl) / creatinine (mg/dl). The diagnosis of gallstones was primarily determined through a self-reported questionnaire rather than ultrasound imaging, with participants responding to the question “ Have you ever been told you have gallstones?” This self-reported occurrence of gallstones served as the primary outcome measure in the study. To account for potential confounding factors that might influence the relationship between the UA/Cr ratio and gallstone risk, multivariate regression models were employed, incorporating relevant covariates. Covariates in our study included: age (years), gender (male/female), race (categorized as Mexican American, non-Hispanic black, non-Hispanic white, other Hispanic and other race), education level (categorized as 9–11th grade, College graduate or above, High school graduate, Less than 9th grade, Some college), poverty-to-income ratio (PIR), marital status, diabetes, alcohol consumption, smoke, BMI, hypertension, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), and total bilirubin.
Statistical analysis
All analyses were conducted using a complex sampling framework to account for the multi-stage, stratified design of NHANES 2017–2020 and to ensure nationally representative estimates. Weighted logistic regression models were applied to examine the association between serum UA/Cr ratio and gallstone disease. In Model 1, no covariates were adjusted; Model 2 controlled for key demographic factors (age, sex, race/ethnicity, education level, and marital status); and Model 3 further included socioeconomic (family PIR) and metabolic/lifestyle factors (BMI, creatinine, uric acid, total bilirubin, LDL, HDL, TG, hypertension, alcohol use, and smoking). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. A restricted cubic splinem (RCS) analysis was performed to visualize potential non-linear trends, with knots selected based on percentiles of the UA/Cr distribution. RCS was analyzed by placing 4 knots at the following UA/Cr percentiles:5th (3.2), 35th (4.8), 65th (6.1), and 95th (9.1).This default configuration balances flexibility and stability, avoiding overfitting while capturing non-linear trends.
Subgroup analyses (e.g. stratified by sex, BMI category) and interaction tests were conducted to explore effect modification. Statistical significance was set at a two-sided p-value <0.05. Statistical analyses were performed using R 4.2.2 software.
Results
Baseline characteristics of participants
The final analytical cohort comprised 5450 participants from NHANES 2017–2020, including 537 (9.85%) individuals with gallstones. Baseline characteristics revealed significant disparities between groups (Table 1). Gallstone patients exhibited higher proportions of females (69.09% vs 46.47%, p < 0.001) and individuals aged >60 years (54.19% vs 33.36%, p < 0.001). Metabolic parameters showed elevated total bilirubin (8.36 vs 7.86 μmol/L, p = 0.020), uric acid (6.34 vs 5.40 mg/dL, p = 0.039), and UA/Cr ratio (7.29 vs 6.16, p = 0.034), along with significantly higher LDL cholesterol (130.0 vs 118.0 mg/dL; p < 0.001) and lower HDL cholesterol (50.0 vs 52.0 mg/dL; p = 0.003), while TG levels showed no significant difference (108.9 vs 105.0 mg/dL; p = 0.12) in the gallstone group. Comorbidity profiles indicated higher prevalence of obesity (52.89% vs 37.51%, p < 0.001) and hypertension (51.21% vs 36.23%, p < 0.001) among gallstone patients.
The characteristics of the study participants.
Notes Median ± SE for continuous variables and % for categorical variables. BMI: body mass index; PIR: poverty-to-income ratio; UA/Cr: uric acid-to-creatinine ratio. LDL: low-density lipoprotein; HDL: high-density lipoprotein; TG:triglyceride. p < 0.05 was considered statistically significant.
Association between uric acid-to-creatinine and gallstone disease
Weighted logistic regression analyses demonstrated a robust positive association between the UA/Cr ratio and gallstone risk (Table 2). In the unadjusted model (Model 1), each one unit increase in UA/Cr was associated with a 32% increased risk of gallstones (OR = 1.32, 95% CI: 1.21–1.45, p < 0.001). After adjustment for demographic factors (Model 2), the association remained significant (OR = 1.25, 95% CI: 1.10–1.36, p < 0.001), and in the fully adjusted model (Model 3), each unit increment in the UA/Cr ratio corresponded to a 17% elevated risk (OR = 1.17, 95% CI: 1.09–1.38, p = 0.021). Categorical analyses by quartiles of UA/Cr corroborated these findings. Using the lowest quartile (Q1: UA/Cr < 5.081) as the reference, the highest quartile (Q4: UA/Cr ≥ 7.234) was associated with a 41% increased risk of gallstone disease (OR = 1.41, 95% CI: 1.24–1.84, p = 0.017), while the third quartile (Q3: UA/Cr between 6.071 and 7.234) also showed a significant association (OR = 1.31, 95% CI: 1.08–1.72, p = 0.032). A significant trend across quartiles (p for trend < 0.001) and a restricted cubic spline analysis indicating a non-linear relationship—with an inflection point at a UA/Cr value of 6.4 and a 95% CI delineated by a shaded region—reinforce the dose-dependent relationship between increasing UA/Cr levels and gallstone risk (Figure 2). This restricted cubic spline plot demonstrates a non-linear dose–response relationship between UA/Cr and gallstone risk, with a critical inflection point at UA/Cr = 6.4. Below this threshold, the association is minimal, but beyond 6.4, each unit increase in UA/Cr corresponds to a steep rise in gallstone risk (OR = 1.29 per unit). Clinically, this identifies UA/Cr = 6.4 as a potential biomarker threshold for risk stratification, enabling targeted screening in high-risk populations (e.g. obese or female subgroups). The findings suggest that monitoring and managing elevated UA/Cr levels above this threshold could inform preventive strategies for gallstone-related morbidity.
The association between UA/Cr and gallstones. RCS shows a non-linear relationship between UA/Cr and gallstone. The fitted regression line is a solid yellow line; the black solid line indicates the position where the OR is equal to 1; the UA/Cr value marked by the pink vertical line represents an inflection point at 6.4; the shaded area indicates the 95% CI; UA/Cr: uric acid-to-creatinine ratio; OR: odds ratio; CI: confidence interval; RCS: restricted cubic splinem.
The association between UA/Cr and gallstones by weighted logistic regression.
Notes Model1: No adjustment for covariates was made. Model 2: Partially adjustment was made for gender, age, race, education level and marital status. Model 3: Fully adjustment was made for gender, age, race, education level, marital status, family PIR, BMI, creatinine, uric acid, total bilirubin, LDL, HDL, TG, hypertension, alcohol consumption, smoke and diabetes. OR: odds ratio. UA/Cr: uric acid-to-creatinine ratio. LDL: low-density lipoprotein; HDL: high-density lipoprotein; TG:triglyceride; PIR: poverty-to-income ratio; OR: adds ratio; CI: confidence interval. p < 0.05 was considered statistically significant.
Subgroup analysis
Subgroup analyses identified differential effects by BMI (p for interaction = 0.021) with the strongest association observed in obese individuals (OR = 1.24, 95% CI: 0.88–1.41, p = 0.016). Gender significantly modified the relationship (p for interaction = 0.006), showing a stronger association in females (OR = 1.23, 95% CI: 0.97–1.39, p = 0.012) compared to males. Notably, marital status also demonstrated a significant interaction (p for interaction =0.015); specifically, analyses indicated that divorced individuals had a heightened risk of gallstone disease with each unit increase in the UA/Cr ratio (OR = 1.21, 95% CI: 0.92–1.51, p = 0.009). In contrast, no significant interactions were observed for age, race, education, hypertension, alcohol use, or smoking status (all p for interaction > 0.05). The UA/Cr-gallstone association remained robust across all sensitivity analyses. While our subgroup analyses identified differential effects by sex, BMI, and marital status, these results should be interpreted cautiously due to the risk of Type I errors from multiple comparisons (Table 3). The consistency of findings in high-risk subgroups (e.g. females, obese individuals) with prior biological evidence, however, suggests these interactions are less likely to be spurious.
The results of subgroup analyses.
OR: odds ratio; CI: confidence interval.
Discussion
Our study revealed a significant, dose-dependent association between the serum UA/Cr ratio and gallstone disease using nationally representative data from NHANES 2017–2020. Specifically, we observed that every unit increase in the UA/Cr ratio corresponded to a 17% to 32% elevated risk of gallstones, even after comprehensive adjustments for demographic, socioeconomic, and metabolic factors. Categorical analyses by quartiles further underscored this relationship, with the highest quartile exhibiting a markedly greater risk. Subgroup analyses suggested that the association was particularly prominent among females, obese individuals, and those with divorced marital status. These findings support the hypothesis that disturbances in purine metabolism–as reflected in the UA/Cr ratio—may contribute to the pathogenesis of gallstone disease. While the 17% increased risk per unit UA/Cr is modest at the individual level, its population-level impact is substantial, particularly above the inflection point (UA/Cr = 6.4). This threshold may guide targeted screening and prevention efforts in high-risk subgroups, akin to interventions for other metabolic risk factors like obesity or diabetes.
The biological plausibility of our findings is supported by previous studies linking hyperuricemia to metabolic syndrome and inflammation,8,9 both of which are implicated in gallstone formation. Unlike isolated uric acid measures, the UA/Cr ratio accounts for variations in renal function, potentially offering a more stable and precise biomarker that mirrors systemic oxidative stress and inflammatory status.10,11 This integrated metric could thus serve both as an early indicator of metabolic dysregulation and as a risk stratification tool for gallstone disease.
In addition, emerging evidence indicates that an elevated UA/Cr ratio may directly influence bile composition and gallbladder motility through several molecular pathways.12–14 Specifically, increased serum uric acid levels have been shown to enhance the activation of inflammatory cascades–such as the NLRP3 inflammasome–resulting in the release of pro-inflammatory cytokines that disrupt hepatocellular lipid metabolism and alter bile acid profiles.15–17 This disruption may contribute to cholesterol supersaturation in bile, a key factor in gallstone formation. 18 Moreover, uric acid-induced oxidative stress might impair the expression and function of transporters involved in bile secretion, further exacerbating bile compositional changes.19–21 Beyond these systemic effects, the potential deposition of uric acid crystals within the biliary system could act as a nidus for gallstone nucleation, thereby compounding the risk.22–24 These mechanistic insights highlight the complex interplay between purine metabolism, renal function, and biliary physiology, and suggest that targeting these pathways may offer novel therapeutic avenues for the prevention and treatment of gallstone disease. The stronger UA/Cr-gallstone associations in females may reflect estrogen-mediated effects on both uric acid metabolism and bile cholesterol saturation. In obese individuals, chronic inflammation and metabolic dysfunction likely synergize to amplify UA/Cr's lithogenic role. Among divorced participants, psychosocial stressors (e.g. dietary shifts, reduced healthcare access) may compound biological risk pathways. These mechanisms, while speculative, align with prior work on metabolic-stress interactions and warrant further investigation.
However, several limitations should be considered. First, the cross-sectional design of NHANES precludes any causal inference; it remains unclear whether an elevated UA/Cr ratio is a cause or consequence of metabolic changes that lead to gallstones. Second, our analysis relied on a single-timepoint measurement, which may not capture long-term fluctuations in metabolic parameters. Additionally, although we adjusted for a wide range of potential confounders, the possibility of residual confounding cannot be entirely excluded. Finally, the accuracy of gallstone diagnosis depends on self-reported information and available clinical data, which may introduce measurement bias. Reliance on self-reported gallstone diagnoses introduces the possibility of recall bias, as participants may misremember prior diagnoses, potentially leading to outcome misclassification. Such bias could either inflate the observed association or underestimate it. To address these limitations, future studies could adopt prospective designs with objective diagnostic confirmation to minimize recall bias. Additionally, validation studies to assess the accuracy of self-reported gallstones in NHANES populations, coupled with longitudinal UA/Cr measurements, would strengthen causal interpretations. Our findings benefit from methodological strengths, including rigorous covariate adjustment, a nationally representative sample, and the identification of a clinically plausible UA/Cr threshold for gallstone risk stratification. These elements collectively enhance the reliability and generalizability of our conclusions.
While we adjusted for key sociodemographic, metabolic, and lifestyle confounders, unmeasured factors such as dietary patterns or medication use could contribute to residual confounding. Future studies with detailed longitudinal data on diet and pharmacotherapy may further clarify these relationships. While our findings highlight UA/Cr as a novel biomarker of gallstone risk, we recognize the indispensable role of cholesterol supersaturation and lipid dysregulation in gallstone pathophysiology. Cholesterol nucleation and bile acid metabolism remain central to stone formation, yet our results suggest UA/Cr may exert complementary effects through distinct mechanisms. Elevated uric acid levels are known to induce oxidative stress and endothelial dysfunction, which could impair gallbladder motility and promote cholesterol crystal aggregation—processes independent of classical lipid-centric pathways. Furthermore, preclinical studies suggest uric acid may directly modulate hepatic cholesterol transporters (e.g. ABCG5/8), potentially altering biliary cholesterol secretion. This bidirectional interplay between purine and lipid metabolism could explain why populations with metabolic syndrome—a condition characterized by concurrent hyperuricemia and dyslipidemia—exhibit disproportionately high gallstone prevalence. While our study did not directly measure bile composition or lipid subfractions, these mechanistic insights align with epidemiological observations and warrant further investigation into UA/Cr's role as both a biomarker and mediator of lithogenicity.
Our study identified divorced participants as a subgroup with elevated gallstone risk, a finding that may reflect the interplay of psychosocial stress and behavioral changes. Divorce is often associated with chronic psychological stress, which dysregulates the hypothalamic–pituitary–adrenal axis, leading to elevated cortisol levels. Cortisol excess is known to promote insulin resistance and dyslipidemia—both established risk factors for cholesterol gallstones. Additionally, divorce-related disruptions in social support networks may contribute to unhealthy dietary patterns and reduced healthcare utilization, delaying diagnosis of asymptomatic gallstones. Preclinical studies further suggest that chronic stress impairs gallbladder motility and bile acid secretion, potentially accelerating stone formation. While our data lack direct measures of stress biomarkers or dietary habits, these mechanisms align with epidemiological evidence linking marital transitions to metabolic dysfunction. Future studies should explore stress mitigation interventions as potential strategies to reduce gallstone risk in this vulnerable population. The sex disparity in gallstone risk observed here may partly reflect estrogen's dual role in cholesterol metabolism and gallbladder motility. Estrogen-driven biliary cholesterol hypersecretion and bile stasis could synergize with metabolic traits to amplify lithogenicity, particularly in premenopausal women. Future studies stratifying by menopausal status or exogenous estrogen exposure could clarify these interactions. Although the UA/Cr ratio is commonly used to normalize uric acid for variations in renal excretion, it is an indirect surrogate and may not fully capture underlying kidney function. Established metrics such as eGFR provide a more robust and comprehensive assessment of renal function. Impaired kidney function can influence both serum uric acid and creatinine levels, potentially confounding their ratio. In our study, the absence of direct eGFR adjustment is a limitation and may have influenced the association observed between UA/Cr and gallstone risk. Single-timepoint UA/Cr measurements may not reflect chronic uric acid levels, and unmeasured urate-lowering therapies could bias results by suppressing uric acid in treated individuals. Future studies should incorporate serial UA/Cr assessments and medication data to address these limitations. Ursidiol, commonly used for non-surgical management of gallstones, may influence bile composition and potentially affect uric acid excretion or metabolism. As medication history was not available in our dataset, we cannot rule out confounding by ursodiol use. Future studies should collect and adjust for ursodiol and other relevant medications to clarify their impact on the UA/Cr–gallstone association.
Despite these limitations, our study contributes to the growing body of literature linking metabolic biomarkers with biliary pathology. Future research should focus on prospective studies to verify the temporal relationship between the UA/Cr ratio and gallstone formation. Moreover, further mechanistic investigations are warranted to elucidate the molecular processes by which altered purine metabolism and renal function impact biliary cholesterol and bilirubin homeostasis, and thereby promote gallstone pathogenesis. Interventional studies aimed at modifying the UA/Cr ratio could additionally help determine whether such changes effectively reduce gallstone risk.
Conclusion
In conclusion, our cross-sectional analysis of NHANES data indicates that an elevated serum UA/Cr ratio is independently associated with an increased risk of gallstone disease. This finding not only strengthens the evidence linking metabolic dysregulation to gallstone pathogenesis but also positions the UA/Cr ratio as a promising biomarker for clinical risk stratification. Future research employing longitudinal study designs and experimental models is needed to confirm these associations and further elucidate the underlying mechanisms. Ultimately, targeted interventions addressing metabolic imbalances may prove beneficial in the prevention and management of gallstone disease.
Footnotes
Ethical considerations
Consent to participate
NHANES has obtained written informed consent from all participants.
Author contributions
Formal analysis done by YH; investigation done by YH; methodology done by SF; software done by SF; supervision done by CZ; visualization done by CZ; writing—original draft done by YH. All authors read and approved the final manuscript.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.