Abstract
Background
Gallbladder and biliary diseases remain major global health concerns, with trends shaped by lifestyle, metabolic risk factors, and healthcare access. This study evaluated long-term changes in age-standardized incidence (ASIR), prevalence (ASPR), and mortality (ASMR) in high–Social Demographic Index (SDI) countries and the United States from 1990 to 2021.
Methods
Data were obtained from the Global Burden of Disease 2021 database. ASIR, ASPR, and ASMR were extracted for both regions. Joinpoint regression analysis generated annual percentage changes with 95% confidence intervals to identify significant temporal shifts.
Results
In high-SDI countries, males showed declines in ASMR (2.03 to 1.67), ASPR (3210.0 to 2962.4), and ASIR (987.4 to 932.0) per 100,000. Females showed similar reductions: ASMR 1.79 to 1.34, ASPR 5141.8 to 4352.3, and ASIR 1912.0 to 1706.7. In the US, ASMR, ASPR, and ASIR decreased from 1.57 to 1.29, 2495.8 to 2278.2, and 757.5 to 716.0 in males, and from 1.17 to 0.96, 4921.6 to 3796.5, and 1856.5 to 1519.4 in females.
Discussion
Mortality and prevalence declined in both regions, while incidence showed modest reductions. The persistently higher US burden likely reflects obesity, metabolic disease, and healthcare disparities, emphasizing the need for targeted prevention and equitable access to care.
Keywords: Gallbladder and biliary disease, Global Burden of Disease, incidence, mortality, prevalence
Gallbladder and biliary system diseases encompass a wide category, from relatively simple gallstones to more complex malignancies. They carry a significant impact on health economies, quality of life, and the longevity of human life across many nations worldwide.1 Gallbladder disease affects over 20 million adults in the United States, as estimated by the National Health and Nutrition Examination Survey III, with 14.2 million women and 6.3 million men affected.2
The global prevalence and mortality rates of gallbladder and biliary disorders have shown complex trends over recent decades, which might be influenced by changes in lifestyle, risk factor exposure, diagnostic practices, and advances in medical treatment.3 Knowledge of the long-term trends of these diseases is relevant for healthcare policies, prevention measures, and resource allocation strategies toward their management.4
For gallbladder and biliary disorders, the prevalence, mortality, disability-adjusted life years, years lived with disability, years of life lost, and incident number increased between 1990 and 2019, according to published research based on the Global Burden of Disease (GBD) 2019 data.5–7 This work updates and extends the previously published GBD 2019, with key metrics of the evaluation involving incidence, prevalence, and mortality due to gallbladder and biliary diseases in the US compared with high–Social Demographic Index (SDI) countries, with attention to gender differences.
METHODS
An update and extension of GBD 2019, GBD 20218 is a systematic evaluation that covers 204 nations and territories. It uses 100,983 data sources from 1990 to 2021 to offer information on the incidence, prevalence, mortality, and disability-adjusted life-years for 371 diseases and injuries, along with 88 risk variables.9 The Institute for Health Metrics and Evaluation gathers all the data. The Guidelines for Reporting Accurate and Transparent Health Estimates (GATHER) were followed by GBD 2021.9
The Global Health Data Exchange query tool (http://ghdx.healthdata.org/gbd-results-tool), a publicly available, deidentified source, was utilized to extract the data used in this investigation. As a result, both ethical review board approval and individual informed consent were not required.
Although the World Health Organization has not provided a precise definition, gallbladder and biliary disease is considered to include inflammation, infection, and obstruction of the gallbladder and associated structures involved in bile production and transport.10,11 Cholecystitis, gallstones, biliary colic, and biliary obstruction comprise the majority of these conditions. For gallbladder and biliary illnesses, the International Classification of Diseases 10th revision (ICD-10) codes range from K00 to K95 generally, but in particular K81.0–81.9, K80.0–80.4, K82.8–82.9, Z98.51, K83.0–83.2, K83.3–83.4, K74.3, Q44.4, K82.8, and Q44.7.
Data sources and extraction
Disease registries, demographic censuses, and vital statistics were all systematically reviewed to provide the GBD data. Importantly, all country and region-specific estimates used in this study were derived from the GBD 2021 modeling framework. The GBD employs standardized case definitions, ICD mapping, data cleaning, and statistical modeling approaches to standardize heterogeneous data sources across countries. Bias correction and comparability adjustments are applied prior to the generation of final estimates. This ensures that trends across regions, including the United States and high-SDI countries, are directly comparable. The national hospital discharge survey, the national vital statistics system mortality data, the statewide inpatient databases, and the health insurance claims and encounter databases were the main sources of data for the United States. Data on the incidence, prevalence, and mortality of diseases related to gallbladder and biliary diseases, stratified by gender, were acquired for the USA and high-SDI countries.
The SDI is a composite indicator used in the GBD studies to reflect a region’s sociodemographic development. SDI ranges from 0 to 1, with higher values indicating greater socioeconomic development. Countries are classified into five categories based on their SDI values: high SDI, high-middle SDI, middle SDI, low-middle SDI, and low SDI. A high-SDI region represents populations with the highest income, highest education, and lowest fertility rates, reflecting advanced socioeconomic conditions. According to the GBD 2021 classification, the high-SDI region comprises Andorra, Australia, Austria, Belgium, Bermuda, Brunei, Canada, Cyprus, Denmark, Finland, France, Germany, Greece, Greenland, Iceland, Ireland, Israel, Italy, Japan, Luxembourg, Malta, Monaco, Netherlands, New Zealand, Norway, Portugal, San Marino, Singapore, Slovenia, South Korea, Spain, Sweden, Switzerland, and the United Kingdom. Although the United States is classified as a high-SDI country in the GBD framework, it was analyzed separately in this study to allow for direct comparison with the aggregated high-SDI group.
All outcome measures were age-standardized using the GBD standard population and stratified by sex, which minimizes confounding due to differences in age and sex distribution.
Statistical analysis
Age-adjusted mortality, prevalence, and crude incidence rates were calculated for gallbladder and biliary diseases. Every rate was stated per 100,000 people. The 2.5th and 97.5th percentiles from a batch of 1000 ordered draws were used to calculate the 95% confidence interval (95% CI). Using the Joinpoint Regression Program 5.0.2 from the Statistical Research and Applications Branch of the National Cancer Institute, the annual percentage changes (APCs) for age-standardized incidence (ASIR), prevalence (ASPR), and mortality (ASMR) were computed in the joinpoint regression analysis for 95% CI.12 Every joinpoint denotes a unique time interval during which there is a discernible change in the data trend. Starting with the fewest joinpoints, the software analyzes data patterns to determine the simplest joinpoint model. It then uses Monte Carlo permutation tests to check whether adding more joinpoints is statistically significant up to a stated maximum.13 The ideal quantity and locations of joinpoints in the dataset are allocated with the use of this test. The sensitivity of the analysis to identify notable trend changes over time is increased by using more joinpoints. A maximum of four joinpoints was permitted during the model-fitting procedure. The weighted average of APCs was then calculated to determine average APC. Every P value was assessed using two-sided hypothesis testing; a P value < 0.05 was considered statistically significant.
RESULTS
In high-SDI countries, ASMR and ASPR for gallbladder and biliary diseases declined significantly for both sexes from 1990 to 2021, while ASIR showed a slight decline or remained stable (Figure 1). Among males, ASMR declined from 2.03 to 1.67 per 100,000, ASPR from 3210.07 to 2962.47 per 100,000, and ASIR from 987.46 to 932.09 per 100,000. Among females, ASMR decreased from 1.80 to 1.35 per 100,000, ASPR from 5141.81 to 4352.35 per 100,000, and ASIR from 1912.07 to 1706.76 per 100,000.
Figure 1.
(a) Age-standardized mortality rates of gallbladder and biliary diseases in high–Social Demographic Index (SDI) countries and the United States, 1990 to 2021. (b) Age-standardized incidence (ASIR) and prevalence (ASPR) of gallbladder and biliary diseases in high-SDI countries and the United States, 1990 to 2021.
Similarly, in the United States, ASMR and ASPR declined significantly in both sexes, while ASIR remained stable or decreased slightly. In males, ASMR declined from 1.57 to 1.29 per 100,000, ASPR from 2495.76 to 2278.26 per 100,000, and ASIR from 757.57 to 706.48 per 100,000. In females, ASMR declined from 1.18 to 0.97 per 100,000, ASPR from 4921.67 to 3796.54 per 100,000, and ASIR from 1856.58 to 1534.00 per 100,000 (Supplemental Tables 1–3).
Mortality
High-SDI countries
For both sexes combined, mortality declined significantly from 1990 to 1997 (APC −3.17; 95% CI −3.27 to −3.27; P < 0.001), followed by a smaller but still significant decline from 1997 to 2006 (P < 0.001). A significant increase occurred from 2007 to 2017 (P < 0.001), followed by a significant decrease from 2017 to 2021 (P < 0.001). Among females, mortality declined significantly from 1990 to 2006, with the greatest reduction between 1990 and 1995 (APC −3.75; 95% CI −4.12 to −3.57; P < 0.001). Mortality then increased significantly from 2006 to 2017 (APC 0.57; 95% CI 0.48 to 0.70; P = 0.002), followed by a significant decrease from 2017 onward (P < 0.001). Among males, mortality declined significantly from 1990 to 1997 (APC −2.70; 95% CI −3.05 to −2.51; P < 0.001) and plateaued between 1997 and 2006. A significant increase occurred between 2006 and 2016 (P = 0.03). Another significant increase was reported from 2016 to 2021 (APC −0.64; 95% CI −1.05 to −0.32; P = 0.01).
United States
For both sexes combined, mortality decreased significantly from 1990 to 1998 (P < 0.001), followed by a significant increase from 1998 to 2001 (APC 2.24; 95% CI 1.47 to 2.66; P = 0.006). Mortality declined until 2013, increased significantly from 2013 to 2016 (P = 0.02), and then decreased significantly from 2016 to 2021 (P = 0.006). Among females, mortality declined significantly from 1990 to 1997 (P < 0.001), increased significantly from 1997 to 2002 (APC 1.32; 95% CI 0.99 to 2.08; P < 0.001), declined from 2002 to 2013, increased until 2016, and then decreased significantly from 2016 to 2021 (P = 0.002). Among males, mortality decreased significantly from 1990 to 1998 (APC −2.07; 95% CI −2.51 to −1.76; P < 0.001), increased significantly from 1998 to 2001 (P < 0.001), and then declined significantly from 2001 to 2021 (P < 0.001).
Incidence
High-SDI countries
Overall ASIR declined from 1448.80 (95% CI 1238.0–1699.0) to 1307.10 in 2021 (95% CI 1126.70–1496.80). Incidence decreased significantly from 1990 to 2000 (P < 0.001), showed a nonsignificant decline from 2000 to 2010 (P = 0.13), and continued decreasing until 2021, with the steepest decline occurring from 2015 to 2019 (P < 0.001). Among females, incidence declined significantly from 1990 to 2000 (P < 0.001), increased significantly from 2000 to 2004 (P = 0.02), and declined nonsignificantly from 2004 to 2010 (P = 0.37). Incidence declined significantly from 2010 to 2019 (P < 0.001), followed by a nonsignificant decline from 2019 to 2021 (P = 0.16). Among males, incidence declined significantly from 1990 to 1994 (P < 0.001), remained stable until 2005, increased significantly from 2005 to 2011 (P = 0.007), and then declined until 2019. Incidence plateaued from 2019 to 2021 (APC −0.00; 95% CI −0.15 to 0.11; P = 0.96).
United States
For both sexes, incidence decreased significantly from 1990 to 2000 (P < 0.001), showed minimal variation from 2000 to 2015, and then declined significantly in recent years (APC −0.87; 95% CI −1.13 to −0.68; P < 0.001). Among females, incidence decreased significantly from 1990 to 2000 (P = 0.008), stabilized until 2005, and declined until 2016 (P = 0.01). A significant decline occurred from 2016 to 2021 (APC −1.40; 95% CI −1.77 to −1.13; P < 0.001). Among males, incidence declined significantly from 1990 to 1993 (P = 0.002) and then remained stable with minor variations through 2021.
Prevalence
High-SDI countries
Overall prevalence declined significantly from 1990 to 2019 (P < 0.001), followed by a slight nonsignificant increase from 2019 to 2021 (APC 0.07; 95% CI −0.03 to 0.16; P = 0.15). Among females, prevalence declined significantly from 1990 to 2000 (P < 0.001), increased significantly from 2000 to 2004 (P = 0.02), declined nonsignificantly from 2004 to 2010 (P = 0.37), and declined significantly from 2010 to 2021 (P < 0.001). The largest reduction occurred from 2015 to 2019 (APC −1.15; 95% CI −1.22 to −1.08; P < 0.001). Among males, prevalence declined significantly from 1990 to 2019 (P < 0.001), with smaller reductions between 1994 to 2000 and 2005 to 2011. Prevalence increased significantly from 2019 to 2021 (APC 0.17; 95% CI 0.06 to 0.26; P = 0.008).
United States
Overall prevalence declined sharply from 1990 to 1993 (APC −1.95; 95% CI −2.54 to −1.49; P < 0.001), declined moderately from 1993 to 2000 (P = 0.01), and declined nonsignificantly from 2000 to 2005 (P = 0.77). Significant reductions occurred from 2005 to 2009 (P = 0.02) and 2016 to 2019 (P = 0.005). A minimal, nonsignificant increase was seen from 2019 to 2021 (APC 0.00; 95% CI −0.56 to 0.39; P = 0.98). Among females, prevalence declined significantly from 1990 to 2000 (APC −1.76; 95% CI −1.85 to −1.67; P < 0.001), increased nonsignificantly from 2000 to 2005 (P = 0.08), declined significantly from 2005 to 2009 (P = 0.04), and declined nonsignificantly from 2009 to 2016 (P = 0.11). A significant decline occurred from 2016 to 2021, with the steepest drop from 2016 to 2019 (APC −1.58; 95% CI −1.82 to −1.11; P = 0.006). Among males, prevalence declined significantly from 1990 to 2009 (P < 0.001), stabilized from 2009 to 2016 (APC 0.04; 95% CI −0.02 to 0.28; P = 0.13), declined significantly from 2016 to 2019 (P = 0.02), and then increased significantly from 2019 to 2021 (APC 0.64; 95% CI 0.10 to 0.99; P = 0.03). Age-standardized rates for mortality, incidence, and prevalence are summarized in Table 1.
Table 1.
Age-standardized mortality, incidence, and prevalence rates for mortality of gallbladder and biliary diseases in high-income countries compared to the USA from 1990 to 2021
| Rate | Year | Entire cohort of high-SDI countries |
Entire US cohort |
High-SDI females |
US females |
High-SDI males |
US males |
|---|---|---|---|---|---|---|---|
| ASMR | 1990 | 1.88 (1.68–2.02) |
1.32 (1.18–1.40) |
1.79 (1.55–1.93) |
1.17 (1.01–1.25) |
2.03 (1.86–2.15) |
1.57 (1.42–1.64) |
| 2021 | 1.49 (1.26–1.63) |
1.10 (0.96–1.18) |
1.34 (1.07–1.51) |
0.96 (0.81–1.04) |
1.67 (1.50–1.78) |
1.29 (1.15–1.36) |
|
| ASIR | 1990 | 1448.8 (1238.0–11699.0) |
1315.8 (1104.3–1570.1) |
1912.0 (1632.5–2251.7) |
1856.5 (1556.4–2235.6) |
987.4 (837.4 –1159.9) |
757.5 (635.8–891.8) |
| 2021 | 1307.1 (1126.7–1496.8) |
1117.0 (973.0–1279.3) |
1706.7 (1461.9–1978.7) |
1519.4 (1316.3–1757.5) |
932.0 (803.5–1073.6) |
716.0 (631.6–811.4) |
|
| ASPR | 1990 | 4188.4 (3551.4–4898.1) |
3746.5 (3146.6–4436.0) |
5141.8 (4401.3–6026.8) |
4921.6 (4128.5–5872.9) |
3210.0 (2713.9–3780.2) |
2495.8 (2088.4–22934.0) |
| 2021 | 3633.3 (3152.5–4179.4) |
3036.4 (2678.3–3441.0) |
4352.3 (3757.4–5049.9) |
3796.5 (3331.1–4336.6) |
2962.4 (2553.9–3426.4) |
2278.2 (2020.5 –2567.9) |
ASIR indicates age-standardized incidence rate; ASMR, age-standardized mortality rate; ASPR, age-standardized prevalence rate; SDI, Social Demographic Index.
DISCUSSION
The observed trends in gallbladder and biliary disease highlight important disparities and similarities between high-SDI countries and the United States over the past three decades. Both regions have experienced significant declines in ASMR and ASPR, with more pronounced improvements among females. However, ASIR in both settings remained relatively stable or only slightly declined, indicating that the burden of new cases remains a concern. Despite these shared trajectories, the US consistently showed a higher disease burden, particularly in incidence and prevalence, than high-SDI countries. These differences likely reflect variations in healthcare access and coverage, exposure to risk factors such as obesity and diet, and differences in national public health strategies. To the best of our knowledge, this is the first study to directly compare long-term trends in gallbladder and biliary disease between high-SDI countries and the US using GBD 1990–2021 data, providing a unique perspective on how sociodemographic development influences disease epidemiology.
The higher burden of gallbladder and biliary disease in the US can be partially attributed to the greater prevalence of obesity, metabolic syndrome, and type 2 diabetes mellitus, key risk factors for gallbladder disease.14 Dietary patterns characterized by high-fat, processed foods and sedentary lifestyles further contribute to gallstone formation and related conditions.15 Socioeconomic disparities also play a role, as limited access to healthy foods and educational inequalities disproportionately affect lower-income populations. These individual- and societal-level risk factors together contribute to the higher burden in the US compared with high-SDI countries.16
Differences in healthcare systems further compound these disparities. Many high-SDI countries offer universal healthcare, ensuring more equitable access to preventive services and early interventions. In contrast, the fragmented US healthcare system with inconsistent coverage and substantial financial barriers often leads to delayed diagnosis and treatment.17 Public health initiatives targeting modifiable risk factors, such as improving diet and increasing physical activity, have also been more comprehensive and consistently implemented in high-SDI countries. Evidence suggests that these coordinated national strategies have improved outcomes for obesity-related conditions, whereas the US has struggled to implement similarly effective nationwide measures.18
Disparities in gallbladder and biliary disease reflect broader patterns seen in other noncommunicable diseases, including obesity, diabetes, heart disease, and chronic lung disease. Despite significantly higher healthcare spending, the US consistently experiences worse outcomes compared to other high-SDI countries.19,20 For example, cardiovascular disease incidence and mortality remain higher in the US than in countries with more equitable healthcare access.21 Additionally, income-related inequalities in morbidity, life expectancy, and healthcare access are more pronounced in the US compared with its high-income peers.22 Research comparing 11 high-income countries also found that geographic health disparities are more widespread in the US, contributing to uneven health outcomes across states and communities.23 These findings align with broader evidence that systemic issues, including fragmented care systems, limited public health infrastructure, and a substantial uninsured population, create persistent barriers to high-quality and accessible healthcare in the US.
Individual behaviors and social environments further contribute to the US health disadvantage. Obesity, a major risk factor for gallbladder disease and many noncommunicable diseases, is more prevalent in environments that discourage physical activity and where high-calorie, processed foods are widely available.19 Chronic lung diseases, such as chronic obstructive pulmonary disease and asthma, are influenced by poor housing conditions, air pollution, and historically higher smoking rates. The National Research Council and Institute of Medicine report highlights the significant impact of social determinants of health, including poverty, education, and income inequality, which are more pronounced in the US than in other high-income countries. Together, these systemic and environmental influences contribute to the higher burden of gallbladder and biliary disease observed in the US.
The GBD study provides valuable global insights into gallbladder and biliary disease, but several limitations should be acknowledged. First, GBD estimates rely on modeled data, and in regions with incomplete or low-quality records, this reliance introduces uncertainty. Variations in data quality, diagnostic criteria, and coding standards across regions can result in inconsistencies in parameter estimates.18 The GBD dataset also does not include social determinants of health such as socioeconomic status, education, or healthcare access, which are important contributors to disease burden and outcomes, especially when comparing the US with high-SDI countries. This study grouped high-SDI countries together without region-specific stratification, which may mask intraregional variability. Furthermore, gallbladder and biliary conditions were analyzed collectively without distinguishing between benign and malignant diseases, limiting disease-specific interpretation. As an observational dataset, GBD also restricts causal inference, and unmeasured confounders such as lifestyle patterns and healthcare access may influence the findings.
The stability of ASIR, despite declines in mortality and prevalence, underscores the need for further research into the underlying drivers of disease. Future efforts should focus on cost-effective strategies to reduce obesity and metabolic risk factors, improve healthcare access, and strengthen preventive health infrastructure. Comparative analyses between the US and high-SDI countries could help identify best practices in prevention and management, informing more effective public health policies aimed at reducing disease burden globally.
In conclusion, this study highlights significant differences in gallbladder and biliary disease burden between the US and high-SDI countries from 1990 to 2021. While both regions experienced declines in mortality and prevalence, incidence remained relatively stable, indicating persistent burden. The US consistently showed higher incidence and prevalence, driven by metabolic risk factors and healthcare disparities. Addressing modifiable risk factors, improving equitable healthcare access, and strengthening preventive public health strategies are essential for reducing this burden. Comparative studies and targeted policies may help guide future efforts to reduce disparities and improve global health outcomes.
Supplementary Material
AUTHORS CONTRIBUTION
MAN conceptualized the study and contributed to study design, data analysis, interpretation, and manuscript drafting. AJW conducted statistical analysis, critically reviewed data interpretation, and contributed to manuscript revision. FA assisted in data acquisition, literature review, and drafting the manuscript. ARA contributed to study methodology, data extraction, and critical review of manuscript drafts. MN assisted in statistical analysis, data visualization, and formatting the manuscript. HA contributed to manuscript editing, literature review, and final proofreading. RJ participated in data collection, reference management, and manuscript structuring. MAQ assisted in methodological refinement and preparation of tables and figures. JI provided insights into data interpretation and contributed to manuscript writing. AU assisted with statistical modeling, quality control of data, and manuscript refinement. ABS provided expert review of the study methodology, ensured consistency in reporting, and critically revised the manuscript. AHS supervised the research process, guided statistical approaches, and reviewed manuscript drafts for intellectual content.
Disclosure statement/Funding
The authors report no funding or conflicts of interest.
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