Association Between Metabolic Dysfunction and Gallstone Disease in U.S. Adults: An Analysis of the National Health and Nutrition Examination Survey

Abstract

Objectives: Gallstones affect a significant proportion of U.S. adults and can cause serious complications. We aimed to investigate the association between gallstone disease and common metabolic disorders in a nationally representative sample in the United States.

Methods: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) collected from 2017 to 2020. We included 6164 participants meeting the eligibility criteria, which represented 171 407 370 participants. The associations between gallstone disease and six metabolic disorders were analyzed using multivariate logistic regression analyses, accounting for potential confounding factors. Subgroup analyses were conducted by age, gender, and race.

Results: Altogether 10.9% of participants had gallstone disease, with prevalence increasing with age (mean age with vs. without gallstones: 56.435 years vs. 46.896 years, p < 0.001) and a female predominance (75.1% vs. 24.9%, p < 0.001). Non-alcoholic fatty liver disease (NAFLD), obesity, hypertension, and diabetes mellitus were significantly associated with an increased risk of gallstone formation, with adjusted odds ratios (OR) of 1.523 (95% confidence interval [CI] 1.180–1.965, p = 0.002), 1.733 (95% CI 1.265–2.374, p = 0.001), 1.466 (95% CI 1.203–1.785, p = 0.001), and 1.522 (95% CI 1.165–1.989, p = 0.003), respectively. These associations were more pronounced in individuals under 60 years of age and in females. No significant associations were observed with hyperlipidemia or hyperuricemia.

Conclusions: Gallstone disease is significantly associated with obesity, NAFLD, diabetes mellitus, and hypertension, with stronger associations found in younger individuals and females. Sensitivity analyses confirmed the robustness of these findings.

Keywords

cholelithiasis / diabetes mellitus / hypertension / non-alcoholic fatty liver disease / obesity

References

[1] P. Portincasa, A. Moschetta, and G. Palasciano, “Cholesterol Gallstone Disease,” Lancet 368, no. 9531 (2006): 230-239.

[2] S. Sauerland and M. R. Langenbach, “Managing Symptomatic Gallstone Disease,” BMJ 383 (2023): 2624, https://doi.org/10.1136/bmj.p2624.

[3] F. Alemi, N. Seiser, and S. Ayloo, “Gallstone Disease: Cholecystitis, Mirizzi Syndrome, Bouveret Syndrome, Gallstone Ileus,” Surgical Clinics of North America 99, no. 2 (2019): 231-244.

[4] Y. Pang, J. Lv, C. Kartsonaki, et al., “Causal Effects of Gallstone Disease on Risk of Gastrointestinal Cancer in Chinese,” British Journal of Cancer 124, no. 11 (2021): 1864-1872.

[5] W. Y. Du, C. Yan, Y. K. Wang, et al., “Association Between Dietary Magnesium Intake and Gallstones: The Mediating Role of Atherogenic Index of Plasma,” Lipids in Health and Disease 23, no. 1 (2024): 82, https://doi.org/10.1186/s12944-024-02074-4.

[6] S. Yuan, D. Gill, E. L. Giovannucci, and S. C. Larsson, “Obesity, Type 2 Diabetes, Lifestyle Factors, and Risk of Gallstone Disease: A Mendelian Randomization Investigation,” Clinical Gastroenterology and Hepatology 20, no. 3 (2022): e529-e537.

[7] B. Ke, Y. Sun, X. Dai, Y. Gui, and S. Chen, “Relationship Between Weight-Adjusted Waist Circumference Index and Prevalence of Gallstones in U.S. Adults: A Study Based on the NHANES 2017-2020,” Frontiers in Endocrinology 14 (2023): 1276465, https://doi.org/10.3389/fendo.2023.1276465.

[8] K. Wortelboer, P. A. de Jonge, T. P. M. Scheithauer, et al., “Phage-Microbe Dynamics After Sterile Faecal Filtrate Transplantation in Individuals With Metabolic Syndrome: A Double-Blind, Randomised, Placebo-Controlled Clinical Trial Assessing Efficacy and Safety,” Nature Communications 14, no. 1 (2023): 5600, https://doi.org/10.1038/s41467-023-41329-z.

[9] C. W. Fwu, I. H. Schulman, J. M. Lawrence, et al., “Association of Obesity, Metabolic Syndrome, and Diabetes With Urinary Incontinence and Chronic Kidney Disease: Analysis of the National Health and Nutrition Examination Survey, 2003-2020,” Journal of Urology 211, no. 1 (2024): 124-133.

[10] S. H. Wen, X. Tang, T. Tang, and Z. R. Ye, “Association Between Weight-Adjusted-Waist Index and Gallstones: An Analysis of the National Health and Nutrition Examination Survey,” BMC Gastroenterology 24, no. 1 (2024): 40, https://doi.org/10.1186/s12876-024-03127-9.

[11] P. J. Eddowes, M. Sasso, M. Allison, et al., “Accuracy of FibroScan Controlled Attenuation Parameter and Liver Stiffness Measurement in Assessing Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease,” Gastroenterology 156, no. 6 (2019): 1717-1730.

[12] Z. M. Younossi, J. M. Paik, M. Stepanova, J. Ong, S. Alqahtani, and L. Henry, “Clinical Profiles and Mortality Rates Are Similar for Metabolic Dysfunction-Associated Steatotic Liver Disease and Non-Alcoholic Fatty Liver Disease,” Journal of Hepatology 80, no. 5 (2024): 694-701.

[13] L. Liu, L. Y. Xia, Y. J. Gao, X. H. Dong, R. G. Gong, and J. Xu, “Association between Obesity and Periodontitis in US Adults: NHANES 2011-2014,” Obesity Facts 17, no. 1 (2024): 47-58.

[14] T. Unger, C. Borghi, F. Charchar, et al., “2020 International Society of Hypertension Global Hypertension Practice Guidelines,” Hypertension 75, no. 6 (2020): 1334-1357.

[15] American Diabetes Association, “2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2019,” Diabetes Care 42, no. Suppl 1 (2019): S13-S28.

[16] National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), “Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report,” Circulation 106, no. 25 (2002): 3143-3421.

[17] F. Scinicariello, M. C. Buser, L. Balluz, et al., “Perfluoroalkyl Acids, Hyperuricemia and Gout in Adults: Analyses of NHANES 2009-2014,” Chemosphere 259 (2020): 127446, https://doi.org/10.1016/j.chemosphere.2020.127446.

[18] R. M. Li, G. H. Dai, H. Guan, et al., “Association Between Handgrip Strength and Heart Failure in Adults Aged 45 Years and Older From NHANES 2011-2014,” Scientific Reports 13, no. 1 (2023): 4551, https://doi.org/10.1038/s41598-023-31578-9.

[19] M. Almohamad, E. Krall Kaye, D. Mofleh, and N. L. Spartano, “The Association of Sedentary Behaviour and Physical Activity With Periodontal Disease in NHANES 2011-2012,” Journal of Clinical Periodontology 49, no. 8 (2022): 758-767.

[20] J. H. Liang, S. Huang, N. Jiang, et al., “Association Between Joint Physical Activity and Dietary Quality and Lower Risk of Depression Symptoms in US Adults: Cross-sectional NHANES Study,” JMIR Public Health Surveillence 9 (2023): e45776, https://doi.org/10.2196/45776.

[21] A. Unalp-Arida and C. E. Ruhl, “Increasing Gallstone Disease Prevalence and Associations With Gallbladder and Biliary Tract Mortality in the US,” Hepatology 77, no. 6 (2023): 1882-1895.

[22] F. Lammert, K. Gurusamy, C. W. Ko, et al., “Gallstones,” Nature Reviews Disease Primers 2 (2016): 16024, https://doi.org/10.1038/nrdp.2016.24.

[23] M. Ghorbani, A. Hekmatdoost, Z. Darabi, A. Sadeghi, and Z. Yari, “Dietary Inflammatory Index and Risk of Gallstone Disease in Iranian Women: A Case-Control Study,” BMC Gastroenterology 23, no. 1 (2023): 311, https://doi.org/10.1186/s12876-023-02943-9.

[24] Z. W. Liu, T. J. Kemp, Y. T. Gao, et al., “Association of Circulating Inflammation Proteins and Gallstone Disease,” Journal of Gastroenterology and Hepatology 33, no. 11 (2018): 1920-1924.

[25] Y. K. Xiang, X. Y. Kong, C. Zhang, et al., “Free Fatty Acids and Triglyceride Change in the Gallbladder Bile of Gallstone Patients With Pancreaticobiliary Reflux,” Lipids in Health and Disease 20, no. 1 (2021): 97, https://doi.org/10.1186/s12944-021-01527-4.

[26] H. J. Kim, T. U. Kang, M. J. Kim, H. Swan, and S. M. Park, “Long-Term Weight Patterns and Physical Activity in Gallstones,” Scientific Reports 14, no. 1 (2024): 25817, https://doi.org/10.1038/s41598-024-77218-8.

[27] D. Aune, L. J. Vatten, and P. Boffetta, “Tobacco Smoking and the Risk of Gallbladder Disease,” European Journal of Epidemiology 31, no. 7 (2016): 643-653.

[28] S. Hayat, Z. Hassan, S. H. Changazi, et al., “Comparative Analysis of Serum Lipid Profiles in Patients With and Without Gallstones: A Prospective Cross-Sectional Study,” Annals of Medicine and Surgery 42 (2019): 11-13.

[29] Z. Q. Yu, D. S. Wu, G. C. Ruan, et al., “Association of Tooth Loss and Gallstones: National Health and Nutrition Examination Survey 2017-2018,” International Journal of Medical Sciences 21, no. 10 (2024): 1866-1875.

[30] A. Pooria, A. Pourya, and A. Gheini, “Comparison of Preoperative and One-Month Postoperative Serum Cholesterol After Cholecystectomy,” Annals of Medicine and Surgery 79 (2022): 104016, https://doi.org/10.1016/j.amsu.2022.104016.

[31] S. Man, Y. X. Gao, J. Lv, et al., “Metabolically Healthy Obesity Was Significantly Associated With Increased Risk of Gallstones,” European Journal of Endocrinology 186, no. 2 (2022): 275-283.

[32] B. Angelin, L. Backman, K. Einarsson, L. Eriksson, and S. Ewerth, “Hepatic Cholesterol Metabolism in Obesity: Activity of Microsomal 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase,” Journal of Lipid Research 23, no. 5 (1982): 770-773.

[33] R. Ratheesh, M. T. Ulrich, S. Ghozy, M. Al-Jaboori, and S. S. Nayak, “The Association Between Diabetes and Gallstones: A Nationwide Population-Based Cohort Study,” Przeglądz Gastroenterology 18, no. 3 (2023): 292-299.

[34] C. H. Chen, C. L. Lin, C. Y. Hsu, and C. H. Kao, “Association Between Type I and II Diabetes With Gallbladder Stone Disease,” Frontiers in Endocrinology 9 (2018): 720, https://doi.org/10.3389/fendo.2018.00720.

[35] A. M. Bucceri, A. Brogna, and R. Ferrara, “Sonographic Study of Postprandial Gallbladder Emptying and Common Bile Duct Changes in Patients With Diabetes or Cholelithiasis,” Abdominal Imaging 19, no. 5 (1994): 427-429.

[36] P. Konyn, O. Alshuwaykh, B. B. Dennis, G. Cholankeril, A. Ahmed, and D. Kim, “Gallstone Disease and Its Association With Nonalcoholic Fatty Liver Disease, all-Cause and Cause-Specific Mortality,” Clinical Gastroenterology and Hepatology 21, no. 4 (2023): 940-948.e2.

[37] M. Arrese, V. Cortés, F. Barrera, and F. Nervi, “Nonalcoholic Fatty Liver Disease, Cholesterol Gallstones, and Cholecystectomy: New Insights on a Complex Relationship,” Current Opinion in Gastroenterology 34, no. 2 (2018): 90-96.

[38] Q. H. Qiao, W. H. Zhu, Y. X. Yu, F. F. Huang, and L. Y. Chen, “Nonalcoholic Fatty Liver Was Associated With Asymptomatic Gallstones in a Chinese Population,” Medicine 96, no. 38 (2017): e7853, https://doi.org/10.1097/MD.0000000000007853.

[39] Y. Chang, Y. H. Noh, B. S. Suh, et al., “Bidirectional Association Between Nonalcoholic Fatty Liver Disease and Gallstone Disease: A Cohort Study,” Journal of Clinical Medicine 7, no. 11 (2018): 458, https://doi.org/10.3390/jcm7110458.

[40] Y. L. Zhang, L. Sun, X. Wang, and Z. T. Chen, “The Association Between Hypertension and the Risk of Gallstone Disease: A Cross-Sectional Study,” BMC Gastroenterology 22, no. 1 (2022): 138, https://doi.org/10.1186/s12876-022-02149-5.

[41] P. Y. Su, Y. C. Hsu, Y. F. Cheng, C. T. Kor, and W. W. Su, “Strong Association Between Metabolically-Abnormal Obesity and Gallstone Disease in Adults Under 50 Years,” BMC Gastroenterology 19, no. 1 (2019): 117, https://doi.org/10.1186/s12876-019-1032-y.

[42] D. J. Cirillo, R. B. Wallace, R. J. Rodabough, et al., “Effect of Estrogen Therapy on Gallbladder Disease,” JAMA 293, no. 3 (2005): 330-339.

[43] M. M. Mamdani, K. Tu, C. van Walraven, P. C. Austin, and C. D. Naylor, “Postmenopausal Estrogen Replacement Therapy and Increased Rates of Cholecystectomy and Appendectomy,” Canadian Medical Association Journal 162, no. 10 (2000): 1421-1424.

[44] A. Di Ciaula, D. Q.-H. Wang, and P. Portincasa, “An Update on the Pathogenesis of Cholesterol Gallstone Disease,” Current Opinion in Gastroenterology 34, no. 2 (2018): 71-80.

RIGHTS & PERMISSIONS

2025 The Author(s). Journal of Digestive Diseases published by Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.