https://orcid.org/0000-0001-8038-3870
Figures
Abstract
Objective
Obesity and disorders of lipid metabolism are key factors in gallstone formation. The cardiometabolic index (CMI) is a new marker combining obesity indicators (WHtR) and lipid levels (TG/HDL-C). The aim of this study was to investigate whether CMI is associated with the prevalence of gallstone disease (GSD) in adults.
Methods
This study was a cross-sectional study by cohort data from the National Health and Nutrition Examination Survey (NHANES) January 2017-March 2020 cycle. Using sample-weighted multivariate logistic regression analysis, sample weighted restricted cubic spline (RCS), the receiver operating characteristic (ROC) and subgroup analysis to assist us with gaining insight into the association between CMI and GSD.
Results
Among the 2825 included participants, 307 of them were patients with GSD. In a model adjusting for multiple covariates, each unit increase in CMI increased the odds of GSD by 16% (OR = 1.16; 95% CI = 1.04-1.30; P = 0.015). Compared to participants with the lowest CMI, those with the highest index had a significantly increased risk of GSD (OR = 2.52; 95% CI = 1.45-4.36; P = 0.006). The sample-weighted multivariable adjusted RCS revealed a nonlinear relationship between CMI and GSD. ROC analysis revealed that CMI had a high predictive effect on the diagnosis of GSD (AUC = 0.680). Subgroup analysis suggested the influence of gender differences on the relationship between CMI and GSD.
Conclusions
The present study found that elevated CMI significantly increased the risk of GSD and emphasized the non-linear relationship between both. These results suggest that CMI could be a potential marker for early screening and intervention of GSD, thus providing guidance for future clinical management of GSD.
Citation: Xiong Z, Sun Q, Huang J, Li F (2025) Non-linear association of cardiometabolic index with gallstone disease in US adults: A cross-sectional study. PLoS One 20(8): e0328415. https://doi.org/10.1371/journal.pone.0328415
Editor: Qian Wu, The First Affiliated Hospital of Soochow University, CHINA
Received: October 18, 2024; Accepted: June 30, 2025; Published: August 1, 2025
Copyright: © 2025 Xiong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All data used for analysis in the study are available from https://figshare.com, DOI: https://10.6084/m9.figshare.28323725.
Funding: This work was supported by the Fund of Changzhou Medical Center, Nanjing Medical University (CMCC202209 and CMCM202310). The funder of this work is Jin Huang, who participated in the Data curation and Formal Analysis of this study.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Gallstone disease (GSD) as one of the most common digestive disorders, it is present in populations all over the world [1,2]. The prevalence and incidence of GSD have been reported to be approximately 15% and 0.6% per year, respectively. The prevalence of gallstones increases with age, and it is more prevalent among women than among men [3–5]. Gallstones can be located anywhere in the biliary system and are mainly categorized as cholecystolithiasis, calculus of extrahepatic bile duct and hepatolithiasis [1]. Most patients with GSD are asymptomatic, but when gallstones enter the bile ducts and cause obstruction, the patient experiences typical biliary colic, mostly accompanied by nausea and vomiting [4]. Approximately 1% to 4% of symptomatic patients with GSD develop serious complications, such as acute cholecystitis, gallstone pancreatitis, Mirizzi syndrome, and gallstone ileus [6–8]. In addition, long-term stimulation by gallstones and inflammation may increase the risk of gallbladder cancer incidence [9,10]. In the U.S., more than 800,000 cholecystectomies are performed each year, costing nearly $6.5 billion annually, making GSD a major global health concern [11]. Therefore, it is crucial to find accurate and reliable clinical indicators in order to provide new insights for early screening and intervention of GSD.
According to previous studies, risk factors for GSD include age, female gender, pregnancy, unhealthy lifestyle, and inflammatory diet [12–14]. one of the key factors contributing to the formation of gallstones is obesity [5]. It is always known that visceral fat plays a supporting, stabilizing and protective role for the internal organs of the body [15]. However, excessive accumulation of visceral fat can lead to metabolic disorders related to obesity, such as insulin resistance, glucose intolerance and dyslipidemia, which undoubtedly increase the risk of gallstone disease [16–18]. Multiple studies have clearly demonstrated that obesity significantly increases the risk of gallstones and have emphasized the important role of novel anthropometric indices in the prevention of gallstones [19,20]. In addition, disorders of lipid metabolism in the body also promote the gallstones formation. Triglyceride (TG), as the lipid component of blood lipids, is an important product of lipid metabolism, and an increase in serum TG can induce a variety of metabolism-related diseases. However, high-density lipoprotein cholesterol (HDL-C) transports cholesterol from surrounding tissues, which is then converted to bile acids or excreted directly from the intestine via bile [21]. Normally, cholesterol, lecithin, and bile salts in bile work together to stabilize the bile. As TG increases or HDL decreases, cholesterol becomes supersaturated, causing cholesterol crystals to precipitate to form stones [22]. Studies have shown that serum HDL levels are inversely and linearly related to risk of gallstone. However, the risk of gallstones increases with increasing serum TG levels [23]. Although many studies have suggested a strong association between obesity and lipid metabolism and GSD, there is still a lack of reliable clinical indicators to manage the occurrence of gallstones.
The cardiometabolic Index (CMI) is a new index calculated from waist-to-height ratio (WHtR), triglycerides, and high-density lipoprotein cholesterol [24]. In contrast to previous body roundness index (BRI) and lipid accumulation product (LAP) indicators, CMI provides a more complete picture of the body’s metabolic state through an individual’s degree of obesity and lipid levels and has been found to have better predictive potential in some studies [25–27]. As the study evolved, researchers found that CMI could not only assess heart health status it could also be used to predict the presence and severity of metabolic syndrome in adult obese patients [28]. Furthermore, elevated CMI has been demonstrated to be significantly associated with insulin resistance and type 2 diabetes [29]. Based on the above findings, it is considered that metabolic syndrome (MetS) and insulin resistance are thought to be associated with an increased risk of gallstones [30,31]. Therefore, the present study hypothesized that metabolic abnormalities reflected by changes in CMI may influence the occurrence of gallstones. This study, with data from the National Health and Nutrition Examination Survey (NHANES), illustrates the relationship between CMI and GSD in U.S. adults for the first time, ultimately providing additional guidance on the clinical management of GSD and offering important insights for future research.
Methods
Study population and research design
The NHANES program was committed to collecting comprehensive data regarding the health and nutrition status of the American population, as well as relevant health behavior information. It covered demographics, dietary, examination, laboratory, and questionnaire data. Visit http://www.cdc.gov/nhanes to access more information about NHANES.
There were 15,560 participants enrolled in this study between January 2017 and March 2020, of whom 9232 were adults aged ≥ 20. However, 5,483 participants lacking CMI data and 6 participants lacking GSD data were excluded. Moreover, 918 participants were excluded because they did not have data on education status, poverty to income ratio (PIR), body mass index (BMI), smoking, alcohol consumption, hypertension, diabetes, cancer, and coronary heart disease (CHD). Fig 1 illustrated the flowchart of the screening process of the present study.
NHANES: National Health and Nutrition Examination Survey; CMI: cardiometabolic index.
Cardiometabolic index
Reference to previously published study [24], information on fasting TG and HDL in CMI was obtained from laboratory data, and information on waist circumference (WC) and height was obtained from measurement data. The specific calculations are as follows:
Assessment of gallstone
Questionnaires from the NHANES data were used for the diagnosis of gallstones. The questionnaire, “Have you been told by a doctor or other health professional that you have gallstones?” was used to indicate the presence of gallstones when the participant answered “yes”.
Covariables
Several covariates were also included in this study for statistical analysis, as they may be potential confounding factors affecting the relationship between CMI and GSD. Confounding factors that were included age, gender, race, education level, PIR, and BMI. Smoking more than 100 cigarettes during one’s lifetime was identified as smoking status. Ever have 4/5 or more drinks every day was identified as drinking status. The results for total cholesterol (TC) were obtained from laboratory data. Definition of physical activity, hypertension, diabetes, cancer, and CHD were obtained from questionnaires or clinical diagnosis.
Statistical analysis
To ensure the reliability of the population estimates, this study processed the data according to sample weight recommended by NHANES. In the analysis of continuous variables, the researchers used the weighted mean and standard deviation (SD), and in the analysis of categorical variables, they used the weighted percentages. CMI was grouped into quartiles based on the characteristics of continuous variables. The Kruskal-Wallis H-test or chi-square test was applied to compare the differences between quartile groupings of CMI. Weighted multivariate logistic regression models were constructed to evaluate the relationship between CMI and GSD using the odds ratio (OR) and 95% confidence interval (CI). Logistic regression is a generalized linear model used for addressing classification problems, and it can intuitively reflect the impact of changes in CMI on the risk of GSD. The crude model (Model 1) was not adjusted. Age, sex, and race were accounted for in Model 2. Based on Model 2, Model 3 had adjustments for education level, PIR, physical activity, smoking status, drinking status, TC, hypertension, diabetes mellitus, cancer, and CHD. The adjustment did not account for BMI, as it had a substantial impact on exposure. Additionally, we further analyzed the nonlinear relationship between CMI and the prevalence of GSD using restricted cubic splines (RCS), generalized additive models (GAM), and smooth curve fitting. RCS is a method used for modeling nonlinear relationships; it segments the values of the independent variable and employs cubic spline functions within each interval for modeling. Therefore, RCS can effectively capture the complex relationship between CMI and GSD. Subsequently, the receiver operating characteristic (ROC) curve was used to calculate the area under curve (AUC) value to assess the diagnostic value of the CMI index for GSD. Finally, subgroup analyses were conducted to test for interactions between CMI and specific covariates. Statistical significance was determined at a threshold of P < 0.05 during the statistical analysis. The statistical analyses conducted in this study were conducted using R version 4.3.1.
Results
Baseline characteristics
After screening, the analysis encompassed a total of 2,825 participants. Table 1 presents the baseline characteristics of the study population by CMI quartiles. As indicated in the table, there were significant differences in CMI quartiles by age, gender, race, education level, PIR, BMI, hypertension, diabetes, and TC (P < 0.05). The increase in CMI was associated with an increase in the proportion of Mexican Americans, an increase in the proportion less than high school, and a decrease in annual household income. It is noteworthy that in the highest quartile there is a higher proportion of males than females (62.16% vs. 37.8%), with the proportion of males showing an upward trend in the quartiles, while the opposite is true for females. As CMI increased, BMI of the participants also increased. In addition, the prevalence of hypertension and diabetes also increased with increasing CMI. A significant correlation between CMI quartiles and gallstone prevalence without adjustment for covariates (P = 0.030).
Association between the CMI index and GSD
To provide insight into the potential link between CMI and GSD, the sample-weighted multivariate logistic regression models were constructed (Fig 2) (S1 Table). As shown in this table, when CMI was analyzed as a continuous variable, the prevalence of GSD was significantly correlated with CMI. (OR = 1.16; 95% CI = 1.04–1.30; P = 0.015) under model 3, which considered all relevant covariates. This suggested that for every unit increase in CMI, the odds of GSD increased by 16%. Next, CMI was further categorized into quartiles to describe the correlation. In model 3, Participants in the highest quartile (Q4) of CMI increased the risk of developing GSD by 152% (OR = 2.52; 95% CI = 1.45–4.36; P = 0.006) compared to those in the lowest quartile (Q1), and this positive correlation remains significant in both Model 1 and Model 2 species. Furthermore, the results of trend analysis for all three models were statistically significant (P for trend < 0.05). This indicated that as CMI increases, the prevalence of GSD is higher. Finally, the sample-weighted multivariable adjusted RCS revealed a statistically significant nonlinear relationship between CMI and GSD (P nonlinear = 0.0121) (Fig 3). Additionally, generalized additive models and smooth curve fitting showed a nonlinear relationship between CMI and OAB (log-likelihood ratio test P value < 0.001) (Table 2).
Model 1: unadjusted. Model 2: age, sex and race were adjusted. Model 3: age, sex, race, education level, PIR, smoking status, drinking status, physical activity, total cholesterol, hypertension, diabetes, cancer, and coronary heart disease were adjusted. CMI: cardiometabolic index; OR: odds ratio; 95% CI: 95% confidence interval.
Diagnostic value of CMI index for GSD
ROC curves were further plotted to assess the diagnostic value of CMI and its components for GSD. As shown in Fig 4 in diagnosing GSD, CMI has the highest accuracy with an AUC of 0.680. The other indices with diagnostic values in descending order were WHtR (AUC = 0.646) and TG/HDL (AUC = 0.570).
Subgroup analysis
Completely adjusted multivariate logistic regression analyses were used for each subgroup to assess that the association between CMI and GSD was robust across age, sex, education level, smoking, alcohol consumption, hypertension, diabetes, cancer, and CHD stratification. As shown in S2 Table and Fig 5, the positive correlation between CMI and gallstones was robust in all subgroups (P for interaction > 0.05) except in the gender subgroup (P for interaction = 0.015).
Note: All covariates (as in Model 3) were adjusted except the stratification variable itself. CMI: cardiometabolic index; OR: odds ratio; 95% CI: 95% confidence interval.
Discussion
Through cross-sectional analysis of NHANES data, we discovered that the prevalence of GSD was substantially and positively correlated with CMI. In the fully adjusted model, the risk of GSD increased by 152% for each unit increase in CMI, as indicated by the results of this study. In all three models, A trend test produced significant significance, indicating a dose-response relationship between CMI and GSD. Also, the RCS confirmed there is a nonlinear association between the two. Moreover, the ROC analysis highlighted the promising diagnostic value of CMI in the diagnosis of GSD. Subgroup analysis and interaction testing demonstrated that the association between CMI and GSD was steady in age, education level, smoking, alcohol consumption, hypertension, diabetes, cancer, and CHD. In summary, CMI may be regarded as an effective tool for screening high-risk groups for GSD, which is important for early intervention and personalized treatment of GSD.
The CMI, as an indicator to assess the degree of obesity and lipid levels in an individual, was thought to provide a better insight into the body’s metabolic status. In previous studies, obesity resulted disorders of lipid metabolism and excessive accumulation of cholesterol, which were important mechanisms for gallstone formation [21,32]. As a result, obesity is universally acknowledged as a concrete risk factor for gallstones. Furthermore, a study from a health check-up cohort of Chinese adult emphasized that obesity promoted gallstones development by investigating the association between metabolically health obesity (MHO) and gallstones [12]. Several anthropometric measures reflecting obesity, such as BMI, WC, and WHtR, have been demonstrated to be independently linked to the occurrence of gallstones [33]. Furthermore, the triglyceride glucose-waist height ratio (TyG-WHtR) was superior to triglyceride glucose-body index mass (TyG-BMI) and triglyceride glucose-waist circumference (TyG-WC) in identifying gallstone risk in a new indicator for assessing insulin resistance [34]. Similarly, obesity affects cholesterol metabolism, which is a key part of gallstone formation. Some serum lipid markers have been shown to be important factors in gallstone risk. Based on a multicenter study and meta-analysis, Zhang et al. found that both low HDL cholesterol levels and high TG levels were risk factors for gallstone [23]. In addition, multivariate Mendelian randomization analysis also revealed that serum TG was an independent risk factor to gallstones, and lowering TG also lower the risk of gallstones [35].
To date, the association of CMI with metabolism-related diseases had been elaborated in numerous literatures. On the one hand, CMI was pointed out to have better predictive potential in identifying MetS in U.S. adults [28]. On the other hand, higher CMI was associated with an increased prevalence of NAFLD and exacerbation of liver fibrosis [36]. However, there were no research that explored the association between CMI and GSD. Therefore, the prospective association between CMI and GSD was first disclosed in this study using NHANES data. The present study, the sample-weighted multivariate logistic regression models suggested a significant positive association between CMI and the risk of developing GSD and demonstrated a nonlinear relationship. These findings are beneficial for identifying asymptomatic GSD patients in clinical practice. Given that waist-to-height ratio and lipid profiling are routine examinations, CMI is far more accessible compared to abdominal ultrasound. Therefore, CMI can serve as a novel and convenient indicator for GSD prevalence and may assist clinicians in determining whether patients should undergo abdominal ultrasound screening in the future. Additionally, interaction tests revealed that the association between CMI and gallstones exhibited statistically significant variations across subgroups stratified by age, sex, alcohol consumption, smoking status, hypertension, diabetes mellitus, cancer, and CHD. The findings highlight that a higher CMI is associated with an elevated prevalence of GSD in females. This may be attributed to higher estrogen levels in women, which promote cholesterol deposition and influence gallstone formation. In animal experiments, GPER antagonists prevented estrogen-induced cholesterol stone formation in female mice [37]. Based on the results of an epidemiologic survey, estrogen therapy in menopausal women significantly increases the risk of symptomatic gallstones and cholecystectomy [38]. However, the clinical relevance of identifying emergent GSD using the CMI is extended by acknowledging the significant relationship between GSD and CVD, probably due to common causal pathways, as established through meta-analysis and meta-regression [39]. In conclusion, all these reports further prove the credibility of the findings of this research.
Regarding the potential mechanism between CMI and GSD, we first hypothesized that it could be attributed to inflammation and oxidative stress. Adipose tissue secretes a diverse array of inflammatory factors in addition to its function as an energy storage and organ protection, such as IL-1β, TL-6 and TNF-α[40]. These inflammatory factors can lead to gallstone formation by directly affecting the contractile function of gallbladder epithelial cells [41]. Furthermore, reactive oxygen species (ROS) produced during the inflammatory process mediate gallbladder epithelial cell damage, thereby promoting cholecystitis and gallstones [42]. Second, immune cell infiltration may also be the mechanism by which lipid accumulation leads to GSD. Adipose tissue contains a large number of immune cells who are able to regulate adipocyte function by secreting a variety of factors under physiological and pathological conditions [40]. Accumulation of adipose tissue macrophages (ATM) has been reported to affect cholesterol metabolism in obese states [43,44]. Besides, the researchers found that inhibiting the formation of neutrophil extracellular traps (NETs) was effective in suppressing crystal aggregation in bile [45,46]. Third, adipose tissue induced insulin resistance is similarly a key factor for stone formation. In the liver, insulin resistance promotes cholesterol secretion through ABCG5/8 induced aberrant expression of FOXO1 [47]. The above studies provided further strong evidence that CMI has a positive correlation with an elevated risk of GSD in terms of pathological mechanisms.
This investigation boasts numerous noteworthy advantages: first, this research considered the sample-weighted design from the NHANES database, which is nationally representative. Second, covariates that could potentially influence the relationship between CMI and GSD were appropriately adjusted to ensure the accuracy of the results. Third, subgroup analysis of the population was conducted in this study and further validated the stability of the results. However, we accept that the current study is subject to certain inherent limitations. First, the causative relationship between CMI and GSD could not be ascertained since this investigation was predominantly founded on a cross-sectional study. Second, due to the limitations of the NHANES database, we were unable to include all potential confounding factors that may influence the relationship between CMI and GSD, such as dietary habits and genetic predisposition. Lastly, we must emphasize that the outcome variable and some covariates in this study are based on self-reported data, which may introduce recall bias. Therefore, the findings of this study require validation through longitudinal research.
Conclusions
In summary, the current investigation revealed that the higher CMI was strongly associated with higher prevalence of GSD and confirmed a nonlinear relationship between the two. Subgroup analyses indicate that the association varies between the genders. These findings may help physicians to screen for people at risk of GSD and highlight the importance of taking gender differences into account when delivering personalized interventions for accurate gallstone prevention.
Supporting information
S1 Table. Association between CMI and gallstone disease (GSD) in NHANES 2017–2020, weighted.
https://doi.org/10.1371/journal.pone.0328415.s001
(DOCX)
S2 Table. Subgroup analysis between CMI and gallstone disease (GSD).
https://doi.org/10.1371/journal.pone.0328415.s002
(DOCX)
References
- 1. Lammert F, Gurusamy K, Ko CW, Miquel J-F, Méndez-Sánchez N, Portincasa P, et al. Gallstones. Nat Rev Dis Primers. 2016;2:16024. pmid:27121416
- 2. Wang X, Yu W, Jiang G, Li H, Li S, Xie L, et al. Global Epidemiology of Gallstones in the 21st Century: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2024;22(8):1586–95. pmid:38382725
- 3. Stinton LM, Myers RP, Shaffer EA. Epidemiology of gallstones. Gastroenterol Clin North Am. 2010;39(2):157–69, vii. pmid:20478480
- 4. Shabanzadeh DM. Incidence of gallstone disease and complications. Curr Opin Gastroenterol. 2018;34(2):81–9. pmid:29256915
- 5. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut Liver. 2012;6(2):172–87. pmid:22570746
- 6. Alemi F, Seiser N, Ayloo S. Gallstone Disease: Cholecystitis, Mirizzi Syndrome, Bouveret Syndrome, Gallstone Ileus. Surg Clin North Am. 2019;99(2):231–44. pmid:30846032
- 7. Gallaher JR, Charles A. Acute Cholecystitis: A Review. JAMA. 2022;327(10):965–75. pmid:35258527
- 8. Roberts SE, Morrison-Rees S, John A, Williams JG, Brown TH, Samuel DG. The incidence and aetiology of acute pancreatitis across Europe. Pancreatology. 2017;17(2):155–65. pmid:28159463
- 9. Ryu S, Chang Y, Yun KE, Jung H-S, Shin JH, Shin H. Gallstones and the Risk of Gallbladder Cancer Mortality: A Cohort Study. Am J Gastroenterol. 2016;111(10):1476–87. pmid:27575712
- 10. Zhang J, Liang D, Xu L, Liu Y, Jiang S, Han X, et al. Associations between novel anthropometric indices and the prevalence of gallstones among 6,848 adults: a cross-sectional study. Front Nutr. 2024;11:1428488. pmid:39104753
- 11. Sandler RS, Everhart JE, Donowitz M, Adams E, Cronin K, Goodman C, et al. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122(5):1500–11. pmid:11984534
- 12. Man S, Gao Y, Lv J, Tong M, Yin J, Wang B, et al. Metabolically healthy obesity was significantly associated with increased risk of gallstones. Eur J Endocrinol. 2022;186(2):275–83. pmid:34889778
- 13. Lin I-C, Yang Y-W, Wu M-F, Yeh Y-H, Liou J-C, Lin Y-L, et al. The association of metabolic syndrome and its factors with gallstone disease. BMC Fam Pract. 2014;15:138. pmid:25070766
- 14. Tsai C-J, Leitzmann MF, Willett WC, Giovannucci EL. Macronutrients and insulin resistance in cholesterol gallstone disease. Am J Gastroenterol. 2008;103(11):2932–9. pmid:18853969
- 15. Kolb H. Obese visceral fat tissue inflammation: from protective to detrimental?. BMC Med. 2022;20(1):494. pmid:36575472
- 16. Bensussen A, Torres-Magallanes JA, Roces de Álvarez-Buylla E. Molecular tracking of insulin resistance and inflammation development on visceral adipose tissue. Front Immunol. 2023;14:1014778. pmid:37026009
- 17. He M, Wang J, Liang Q, Li M, Guo H, Wang Y, et al. Time-restricted eating with or without low-carbohydrate diet reduces visceral fat and improves metabolic syndrome: A randomized trial. Cell Rep Med. 2022;3(10):100777. pmid:36220069
- 18. Miazgowski T, Taszarek A, Miazgowski B. Visceral fat, cardiometabolic risk factors, and nocturnal blood pressure fall in young adults with primary hypertension. J Clin Hypertens (Greenwich). 2019;21(9):1406–14. pmid:31369205
- 19. Aune D, Norat T, Vatten LJ. Body mass index, abdominal fatness and the risk of gallbladder disease. Eur J Epidemiol. 2015;30(9):1009–19. pmid:26374741
- 20. Banim PJR, Luben RN, Bulluck H, Sharp SJ, Wareham NJ, Khaw K-T, et al. The aetiology of symptomatic gallstones quantification of the effects of obesity, alcohol and serum lipids on risk. Epidemiological and biomarker data from a UK prospective cohort study (EPIC-Norfolk). Eur J Gastroenterol Hepatol. 2011;23(8):733–40. pmid:21623190
- 21. Nussbaumerova B, Rosolova H. Obesity and Dyslipidemia. Curr Atheroscler Rep. 2023;25(12):947–55. pmid:37979064
- 22. Di Ciaula A, Garruti G, Frühbeck G, De Angelis M, de Bari O, Wang DQ-H, et al. The Role of Diet in the Pathogenesis of Cholesterol Gallstones. Curr Med Chem. 2019;26(19):3620–38. pmid:28554328
- 23. Zhang M, Mao M, Zhang C, Hu F, Cui P, Li G, et al. Blood lipid metabolism and the risk of gallstone disease: a multi-center study and meta-analysis. Lipids Health Dis. 2022;21(1):26. pmid:35236330
- 24. Wakabayashi I, Daimon T. The “cardiometabolic index” as a new marker determined by adiposity and blood lipids for discrimination of diabetes mellitus. Clin Chim Acta. 2015;438:274–8. pmid:25199852
- 25. Duan S, Yang D, Xia H, Ren Z, Chen J, Yao S. Cardiometabolic index: A new predictor for metabolic associated fatty liver disease in Chinese adults. Front Endocrinol (Lausanne). 2022;13:1004855. pmid:36187093
- 26. Ebrahimi M, Seyedi SA, Nabipoorashrafi SA, Rabizadeh S, Sarzaeim M, Yadegar A, et al. Lipid accumulation product (LAP) index for the diagnosis of nonalcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis. Lipids Health Dis. 2023;22(1):41. pmid:36922815
- 27. Wei C, Zhang G. Association between body roundness index (BRI) and gallstones: results of the 2017-2020 national health and nutrition examination survey (NHANES). BMC Gastroenterol. 2024;24(1):192. pmid:38840060
- 28. Tamini S, Bondesan A, Caroli D, Sartorio A. The Lipid Accumulation Product Index (LAP) and the Cardiometabolic Index (CMI) Are Useful for Predicting the Presence and Severity of Metabolic Syndrome in Adult Patients with Obesity. J Clin Med. 2024;13(10):2843. pmid:38792386
- 29. Song J, Li Y, Zhu J, Liang J, Xue S, Zhu Z. Non-linear associations of cardiometabolic index with insulin resistance, impaired fasting glucose, and type 2 diabetes among US adults: a cross-sectional study. Front Endocrinol (Lausanne). 2024;15:1341828. pmid:38410697
- 30. Zhu Q, Xing Y, Fu Y, Chen X, Guan L, Liao F, et al. Causal association between metabolic syndrome and cholelithiasis: a Mendelian randomization study. Front Endocrinol (Lausanne). 2023;14:1180903. pmid:37361524
- 31. Cortés VA, Barrera F, Nervi F. Pathophysiological connections between gallstone disease, insulin resistance, and obesity. Obes Rev. 2020;21(4):e12983. pmid:31814283
- 32. Aron-Wisnewsky J, Warmbrunn MV, Nieuwdorp M, Clément K. Metabolism and Metabolic Disorders and the Microbiome: The Intestinal Microbiota Associated With Obesity, Lipid Metabolism, and Metabolic Health-Pathophysiology and Therapeutic Strategies. Gastroenterology. 2021;160(2):573–99. pmid:33253685
- 33. Lim J, Wirth J, Wu K, Giovannucci E, Kraft P, Turman C, et al. Obesity, Adiposity, and Risk of Symptomatic Gallstone Disease According to Genetic Susceptibility. Clin Gastroenterol Hepatol. 2022;20(5):e1083–120. pmid:34217876
- 34. Fu C, Li X, Wang Y, Chen J, Yang Y, Liu K. Association between triglyceride glucose index-related indices with gallstone disease among US adults. Lipids Health Dis. 2024;23(1):203. pmid:38937793
- 35. Chen L, Qiu W, Sun X, Gao M, Zhao Y, Li M, et al. Novel insights into causal effects of serum lipids and lipid-modifying targets on cholelithiasis. Gut. 2024;73(3):521–32. pmid:37945330
- 36. Yan L, Hu X, Wu S, Cui C, Zhao S. Association between the cardiometabolic index and NAFLD and fibrosis. Sci Rep. 2024;14(1):13194. pmid:38851771
- 37. DeLeon C, Wang HH, Gunn J, Wilhelm M, Cole A, Arnett S, et al. A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice. J Lipid Res. 2020;61(5):767–77. pmid:32127396
- 38. Jackson SS, Graubard BI, Gabbi C, Koshiol J. Association with menopausal hormone therapy and asymptomatic gallstones in US women in the third National Health and Nutrition Examination Study. Sci Rep. 2024;14(1):191. pmid:38168135
- 39. Hasan R, Allahbakhshi F, Shlyk AD, Allahbakhshi K. Gallstones as a predictor of elevated cardiovascular disease risk: A meta-analysis and meta-regression of over 7.4 million participants. PLoS One. 2025;20(3):e0314661. pmid:40106516
- 40. Kawai T, Autieri MV, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol. 2021;320(3):C375–91. pmid:33356944
- 41. Rege RV. Inflammatory cytokines alter human gallbladder epithelial cell absorption/secretion. J Gastrointest Surg. 2000;4(2):185–92. pmid:10675242
- 42. Koppisetti S, Jenigiri B, Terron MP, Tengattini S, Tamura H, Flores LJ, et al. Reactive oxygen species and the hypomotility of the gall bladder as targets for the treatment of gallstones with melatonin: a review. Dig Dis Sci. 2008;53(10):2592–603. pmid:18338264
- 43. Edgel KA, McMillen TS, Wei H, Pamir N, Houston BA, Caldwell MT, et al. Obesity and weight loss result in increased adipose tissue ABCG1 expression in db/db mice. Biochim Biophys Acta. 2012;1821(3):425–34. pmid:22179025
- 44. Wei H, Tarling EJ, McMillen TS, Tang C, LeBoeuf RC. ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction. J Lipid Res. 2015;56(12):2337–47. pmid:26489644
- 45. Muñoz LE, Boeltz S, Bilyy R, Schauer C, Mahajan A, Widulin N, et al. Neutrophil Extracellular Traps Initiate Gallstone Formation. Immunity. 2019;51(3):443-450.e4. pmid:31422870
- 46. Chen H, Wang J, Ji Q, Jiang Z. Sodium butyrate restricts neutrophils migration and NETs formation through reducing macrophage-derived CXCL16 in calculous cholecystitis. Heliyon. 2024;10(3):e25189. pmid:38322881
- 47. Biddinger SB, Haas JT, Yu BB, Bezy O, Jing E, Zhang W, et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med. 2008;14(7):778–82. pmid:18587407