Highlights
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Patient Health Questionnaire-9 score is associated with gallstones incidence.
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People with depressive symptoms have an increased risk of gallstones.
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Clinically depressed individuals show 79% increased risk of gallstones.
Keywords: Depressive symptoms, PHQ-9, Gallstone, Prevalence, Cross-sectional study, NHANES
Abstract
Background
Gallstone disease is one of the most common gastrointestinal disorders. Despite extensive research exploring the risk factors associated with gallstones, the association between depressive symptoms and gallstones remains inadequately understood. This study aimed to assess the association between depressive symptoms and the prevalence of gallstones among adults in the United States.
Methods
In this study, a cross-sectional design utilized data from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2017 to 2020. The assessment of depressive symptoms was conducted through the utilization of the Patient Health Questionnaire-9 (PHQ-9), which assigns total scores ranging from 0 to 27. Participants with PHQ-9 scores equal to or exceeding 10 were categorized as having clinically relevant depressive symptoms. Multivariable adjusted logistic regression and subgroup analysis were used to assess the association between depressive symptoms and gallstone prevalence.
Results
A total of 7,797 participants aged 20 years or older were enrolled in this study, of whom 835 had a self-reported history of gallstones. After multiple adjustments, each one-point increase in PHQ-9 scores was associated with a 5 % increase in the risk of gallstones (odds ratio [OR], 1.05; 95 % confidence interval [CI], 1.03, 1.07, P < 0.001). Compared to individuals with PHQ-9 scores < 10, participants with PHQ-9 total scores ≥ 10 exhibited a 79 % higher risk of gallstones (OR = 1.79, 95 % CI: 1.43, 2.23, P < 0.001).
Conclusion
Depressive symptoms were associated with an elevated prevalence of gallstones. However, it is important to note that further validation through prospective cohort studies is warranted to confirm this finding.
1. Introduction
Gallstone disease is one of the most common gastrointestinal disorders, ranking as the second most frequently diagnosed condition necessitating hospitalization within the realm of gastrointestinal, hepatic, and pancreatic disorders in the United States (Peery et al., 2022). Although the majority of patients with gallstones are asymptomatic, approximately one-quarter of patients experience symptoms and a subset are at risk of developing severe complications like acute stone cholecystitis, acute cholangitis, and acute biliary pancreatitis (Gurusamy and Davidson, 2014). The economic burden of this disease is substantial, amounting to an annual expenditure of approximately $16.9 billion dollars in the United States (Peery et al., 2022).The formation of gallstones is a complex interplay of various factors, including both non-modifiable and modifiable risk factors. Non-modifiable risks include race, age, female, and genetics (Lammert et al., 2016), while modifiable risks include dietary habits, lifestyle, comorbidities, and the use of specific medications (Srikanth et al., 2021).
Depressive symptoms, characterized by a lack of positive feelings and low mood (Battle, 2013); continues to pose a significant global burden, affecting approximately 300 million individuals worldwide (Patel et al., 2016). Notably, the prevalence of depressive symptoms among adults in the United States has shown a substantial increase between 2017 and 2020 (Daly et al., 2021). Depressive symptoms frequently co-occurs with various chronic illnesses, including cancer, cardiovascular diseases, metabolic disorders, inflammatory conditions, and neurological disorders (Gold et al., 2020). The detrimental effects of depressive symptoms, encompassing both behavioral and psychobiological changes, can heighten the risk of chronic disease development and further exacerbate the course of existing medical conditions (Katon, 2011). Furthermore, patients with depressive symptoms exhibit a higher prevalence of digestive disorders compared to the general population (Avramidou et al., 2018, He et al., 2022, Kim et al., 2020). A cross-sectional study conducted in Spain indicates an elevated prevalence of gallstones and concomitant gastrointestinal disorders among individuals aged over 60 exhibiting depressive symptoms (Aguado and García Del Álamo, 2020). Similarly, a case-control study conducted in Taiwan identified a heightened susceptibility to depression in patients diagnosed with gallstones (Shen et al., 2015). However, the available evidence regarding the relationship between depressive symptoms and gallstones remains limited.
Hence, the primary objective of our study was to investigate the association between depressive symptoms and the prevalence of gallstones in a substantial cohort of American adult participants, utilizing data derived from a nationally representative survey.
2. Materials and Methods
2.1. Data sources and study population
The National Health and Nutrition Examination Survey (NHANES) has been evaluating the health and nutritional status of children and adults in the United States since 1960. For this study, data from the NHANES conducted between 2017 and 2020, administered by the National Center for Health Statistics (NCHS), were utilized. The NCHS Research Ethics Review Board approved the NHANES protocol. The entirety of the data used in this study is publicly accessible on the official website (http://www.cdc.gov/nchs/nhanes.htm). Participants who met the inclusion criteria for the analysis were individuals who were 20 years or older and had completed the survey. Pregnant women and individuals with incomplete gallstone or Patient Health Questionnaire-9 (PHQ-9) information were excluded from the study.
2.2. Assessment for depressive symptoms
The PHQ-9 was employed in this study as a screening tool to measure depressive symptoms experienced within the previous 2 weeks (Manea et al., 2015). The PHQ-9 yields total scores ranging from 0 to 27 and consists of nine items. To classify individuals with clinically significant depressive symptoms, a cut-off score of ≥ 10 was utilized. This threshold demonstrated a sensitivity of 88 % and a specificity of 88 % for identifying major depressive symptoms (Kroenke et al., 2001).
2.3. Assessment for gallstone
The presence of gallstones was determined using a self-report questionnaire, “Has a doctor or other health professional ever told you that you had gallstones” (Ke et al., 2023).
2.4. Covariates
The covariates considered in this study were age, gender, race, education level, marital status, family income, body mass index (BMI), smoking status, alcohol drinking status, hypertension, diabetes, recreational activity, sedentary activity hours, and workdays sleep hours. Race was classified into four categories: non-Hispanic White, no-Hispanic Black, Mexican American, and other races. Education level was categorized as less than 9 years, 9–12 years, or more than 12 years of education. Marital status was divided into two groups: living with a partner or living alone. Family income was stratified into three levels based on the family poverty income ratio: low income (≤1.3), medium income (>1.3 to 3.5), and high income (>3.5). BMI was calculated as the weight in kilograms divided by the square of height in meters, and it was classified into three categories using cut-off values of 25 and 30 kg/m2 (Khan et al., 2018). Smoking status was categorized as smokers and never smokers. Alcohol drinking status was divided into five groups: never, up to once a week, 2–4 times a week, 5–6 times a week, and daily or more. The medical conditions of diabetes and hypertension were ascertained through self-reporting, wherein binary variables were utilized to signify the existence or absence of these respective conditions. Recreational activities were divided into three groups: mild, moderate, and vigorous. A multivariate imputation method was employed for missing data.
2.5. Statistical analysis
The baseline data distribution of the study participants was presented according to different groups based on their PHQ-9 scores. Continuous variables were expressed as means ± standard deviation (SD), and categorical variables were expressed as percentages (%). To assess continuous variables with a normal distribution, the t-test was employed. Categorical variables, on the other hand, were analyzed using the chi-square test. Multivariate logistic regression models were utilized to calculate odds ratio (OR) and 95 % confidence interval (CI) to determine the association between PHQ-9 scores and gallstone occurrence. Confounders, assessed through directed acyclic graphs (Tennant et al., 2021), were selected based on their association with the outcome under investigation or if they resulted in a modification of more than 10 % in the effect estimate (Qu et al., 2020). The multivariable models were adjusted as follows: Model 1 was adjusted for age and gender; Model 2 was adjusted for age, gender, BMI, race, education level, marital status, and family income; and Model 3 was adjusted for age, gender, BMI, race, education level, marital status, family income, recreational activity, sedentary activity, workdays sleep hours, smoke, and alcohol consumption. Subgroup analyses were conducted using logistic regression models. Statistical analyses were performed using R 3.3.2 (https://www.R-project.org, The R Foundation) and Free Statistics software version 1.7. P < 0.05 was considered statistically significant.
3. Results
3.1. Baseline characteristics of the study participants
For this study, data from NHANES (2017–2020) were employed, consisting of a total of 15,560 participants who completed the survey. Among them, 6,328 individuals were below 20 years of age. Pregnant women (n = 87), as well as participants with missing information on gallstone (n = 21) and PHQ-9 scores (n = 1327), were excluded from the analysis. Consequently, a final cohort of 7,797 participants was included in this study (Fig. 1).
Fig. 1.
Flow chart of participant selection.
Table 1 presents the baseline characteristics of the study participants stratified by their PHQ-9 scores groups. The mean age of the participants was 50.9 ± 17.4 years, and 50.5 % of them were female. Approximately 10.7 % of the participants had gallstone. Among individuals with PHQ-9 scores ≥ 10, there was a higher proportion of females, higher BMI, a higher prevalence of hypertension and diabetes, and a higher likelihood of being a smoker.
Table 1.
Distribution of selected characteristics of American adults between 2017 and 2020, National Health and Nutrition Examination Survey (n = 7797).
| Variables | Total (n = 7797) |
PHQ-9 < 10 (n = 7076) |
PHQ-9 ≥ 10 (n = 721) |
P value |
|---|---|---|---|---|
| Age, Mean ± SD | 50.9 ± 17.4 | 51.0 ± 17.4 | 50.7 ± 17.0 | 0.68 |
| Gender, n (%) | < 0.01 | |||
| Male | 3862 (49.5) | 3582 (50.6) | 280 (38.8) | |
| Female | 3935 (50.5) | 3494 (49.4) | 441 (61.2) | |
| BMI, Mean ± SD | 30.1 ± 7.6 | 29.9 ± 7.4 | 32.0 ± 8.5 | < 0.01 |
| Race, n (%) | 0.81 | |||
| Non-Hispanic White | 2770 (35.5) | 2502 (35.4) | 268 (37.2) | |
| Non-Hispanic Black | 2069 (26.5) | 1881 (26.6) | 188 (26.1) | |
| Mexican American | 905 (11.6) | 825 (11.7) | 80 (11.1) | |
| Other | 2053 (26.3) | 1868 (26.4) | 185 (25.7) | |
| Education level, n (%) | < 0.01 | |||
| <9 | 542 (7.0) | 470 (6.6) | 72 (10) | |
| 9–12 | 2735 (35.1) | 2423 (34.2) | 312 (43.3) | |
| >12 | 4520 (58.0) | 4183 (59.1) | 337 (46.7) | |
| Marital status, n (%) | < 0.01 | |||
| Living with partners | 4514 (57.9) | 4205 (59.4) | 309 (42.9) | |
| Living alone | 3283 (42.1) | 2871 (40.6) | 412 (57.1) | |
| Family income, n (%) | < 0.01 | |||
| Low income | 2222 (28.5) | 1902 (26.9) | 320 (44.4) | |
| Medium income | 3045 (39.1) | 2753 (38.9) | 292 (40.5) | |
| High income | 2530 (32.4) | 2421 (34.2) | 109 (15.1) | |
| Smoke, n (%) | 3257 (41.8) | 2893 (40.9) | 364 (50.5) | < 0.01 |
| Alcohol, n (%) | 0.01 | |||
| Never | 1751 (22.5) | 1556 (22) | 195 (27) | |
| Up to once a week | 4351 (55.8) | 3954 (55.9) | 397 (55.1) | |
| 2–4 times a week | 1152 (14.8) | 1063 (15) | 89 (12.3) | |
| 5–6 times a week | 283 (3.6) | 260 (3.7) | 23 (3.2) | |
| Daily or more | 260 (3.3) | 243 (3.4) | 17 (2.4) | |
| Hypertension, n (%) | 3017 (38.7) | 2641 (37.3) | 376 (52.1) | < 0.01 |
| Diabetes, n (%) | 1196 (15.3) | 1033 (14.6) | 163 (22.6) | < 0.01 |
| Recreational activity, n (%) | < 0.01 | |||
| Mild | 4049 (51.9) | 3574 (50.5) | 475 (65.9) | |
| Moderate | 1845 (23.7) | 1690 (23.9) | 155 (21.5) | |
| Vigorous | 1903 (24.4) | 1812 (25.6) | 91 (12.6) | |
| Sedentary activity hours, Mean ± SD |
5.6 ± 3.4 | 5.5 ± 3.3 | 6.0 ± 3.8 | < 0.01 |
| Workdays sleep hours, Mean ± SD |
7.5 ± 1.6 | 7.5 ± 1.6 | 7.4 ± 2.1 | 0.06 |
| Gallstone, n (%) | 835 (10.7) | 700 (9.9) | 135 (18.7) | < 0.01 |
Abbreviation: PHQ-9, Patient Health Questionnaire-9; BMI, body mass index; SD, standard deviation.
3.2. Multivariable regression analyses
The results of the multivariate logistic regression analysis are presented in Table 2. After adjusting for potential confounders, a significant positive association between PHQ-9 scores and gallstone prevalence was observed. With each one-point increase in PHQ-9 scores, there was a 5 % increase in the risk of gallstones (OR = 1.05, 95 % CI: 1.03, 1.07, P < 0.001). Compared to individuals with PHQ-9 scores < 10, those with PHQ-9 scores ≥ 10 had a 79 % higher risk of gallstones (OR = 1.79, 95 % CI: 1.43, 2.23, P < 0.001) after multiple adjustments.
Table 2.
Relationship between PHQ-9 and gallstone in American adults from NHANES 2017–2020.
| Exposure | Non-adjusted model |
model1 |
model2 |
model3 |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| OR (95 % CI) | P value | OR (95 % CI) | P value | OR (95 % CI) | P value | OR (95 % CI) | P value | ||||
| PHQ-9 | 1.07(1.05 ∼ 1.08) | <0.01 | 1.06(1.05 ∼ 1.08) | <0.01 | 1.05(1.04 ∼ 1.07) | <0.01 | 1.05(1.03 ∼ 1.07) | <0.01 | |||
| PHQ-9 | |||||||||||
| <10 | Ref | Ref | Ref | Ref | |||||||
| ≥10 | 2.10(1.71 ∼ 2.57) | <0.01 | 1.99 (1.61 ∼ 2.46) | <0.01 | 1.85 (1.49 ∼ 2.30) | <0.01 | 1.79 (1.43 ∼ 2.23) | <0.01 | |||
Non-adjusted: no covariates were adjusted.
Model1: adjusted for age and gender.
Model2: adjusted for age, gender, BMI, race, education level, marital status, and family income.
Model3: adjusted for age, gender, BMI, race, education level, marital status, family income, recreational activity, sedentary activity, workdays sleep hours, smoke, and alcohol consumption.
Abbreviation: PHQ-9, Patient Health Questionnaire-9; OR, odds ratio; CI, confidence interval; Ref, reference.
3.3. Subgroup analyses
Subgroup analyses were performed to explore whether the association between PHQ-9 scores and the prevalence of gallstones was confounded by age, gender, BMI, race, alcohol, and recreational activity (Fig. 2). No significant interactions were observed among any of the subgroups (all P > 0.05).
Fig. 2.
The relationship between PHQ-9 and gallstone in the subgroup analysis of American adults from NHANES 2017–2020.
4. Discussion
In this study, a thorough analysis was conducted to investigate the potential association between depressive symptoms and gallstone prevalence among the adult population in the United States. The results revealed a significant positive correlation between depressive symptoms and an elevated prevalence of gallstones in this demographic. Subgroup analyses further confirmed a robust association between depressive symptoms and gallstones. Specifically, after adjusting for multiple confounding factors, our findings showed that each one-point increase in PHQ-9 scores corresponded to a 5 % increase in the risk of gallstones. These findings hold important implications for the management of gallstone prevalence, indicating the necessity for routine gallstone screening among individuals with depressive symptoms.
Epidemiological research has firmly established depressive symptoms as an independent risk factor for the prevalence of gallstones. For instance, a study conducted in Spain unveiled a heightened prevalence of gallstones and concurrent gastrointestinal disorders among individuals aged over 60 manifesting depressive symptoms (Aguado and García Del Álamo, 2020). Additionally, a recent Mendelian randomization study provided further confirmation of the association between depressive symptoms and gallstone prevalence (Li et al., 2023). Our own investigation of the adult population in the United States reaffirmed a notable correlation between depressive symptoms and gallstone prevalence.
Despite the uncertain mechanisms underlying the association between depressive symptoms and gallstone occurrence, our study findings align with existing evidence. Firstly, depressive symptoms is commonly accompanied by sleep disorders like insomnia or drowsiness (Murphy and Peterson, 2015). Genes encoding key hepatic enzymes for hepatic lipid metabolism are regulated by circadian rhythm-related transcription factors (Kudo et al., 2008). Sleep rhythm disruptions may therefore affect hepatic lipid acid metabolism and alter bile acid composition, as previously demonstrated in mice with abnormal bile acid and cholesterol metabolism that promotes gallstone formation (He et al., 2021). Secondly, the elevated cortisol/cortisone levels triggered by the activated HPA axis in individuals with depression (Belvederi Murri et al., 2014) may contribute to obesity, as well as disruptions in glycemic and lipid metabolism (Janssen, 2022). Hepatic lipid metabolism disorders can contribute to irregular cholesterol metabolism, leading to an imbalance in the cholesterol to bile acids and phospholipids ratio in bile. This imbalance contributes to the formation of gallstones (Kong et al., 2024). Thirdly, gender differences in depressive symptoms were first emphasized in the 1970s when Myrna Weissman reported that about twice as many women as men suffer from depression among adults (Weissman and Klerman, 1977). Our study similarly observed higher rates of depressive symptoms in women, who experience estrogen-induced overproduction of cholesterol and oversaturation of bile, leading to cholesterol deposition and gallstone formation (Sun et al., 2022). However, further prospective studies are essential to corroborate the impact of depressive symptoms on gallstones.
There are several limitations of this study. Firstly, the cross-sectional design precludes the establishment of a causal relationship between depressive symptoms and gallstones. Secondly, as with all observational studies, there are inherent uncontrolled confounding factors. Thirdly, caution should be exercised when generalizing our findings to other populations, given that our study exclusively focused on the American population. Lastly, survey data derived from NHANES were collected primarily through questionnaires, which may introduce the potential for recall bias.
5. Conclusion
Depressive symptoms were associated with an elevated prevalence of gallstones. However, it is important to note that further validation through prospective cohort studies is warranted to confirm this finding.
CRediT authorship contribution statement
Xinqi Chen: Writing – original draft, Software, Methodology, Data curation, Conceptualization. Hao Luo: Writing – original draft, Data curation, Conceptualization. Meizhen Ye: Writing – review & editing, Methodology, Data curation.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We thank Jie Liu, Ph.D. (Department of Vascular and Endovascular Surgery, Chinese PLA General Hospital) for his valuable comments on the study design and manuscript.
Author contributions
HL was responsible for the conception, design, collection and interpretation of data, analysis of the study and writing of the manuscript; MY was responsible for collection and interpretation of data; XC was involved with conception, design, writing, reviewing and editing of the manuscript. All authors have read and approved the manuscript.
Funding
This study did not receive any grants or funding from the public, commercial, or non-profit sectors.
Availability of data and materials
The entirety of the data used in this study is publicly accessible on the official website (http://www.cdc.gov/nchs/nhanes.htm).
Ethics approval and consent to participate.
The National Center for Health Statistics (NCHS) Research Ethics Review Board approved the National Health and Nutrition Examination Survey (NHANES) protocol. All participants completed written informed consent forms before participation.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.pmedr.2024.102771.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Data availability
Data will be made available on request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data will be made available on request.
The entirety of the data used in this study is publicly accessible on the official website (http://www.cdc.gov/nchs/nhanes.htm).