Exploring the Correlation Between Gallstone Disease and Sarcopenia Risk: Insights from a Cross-Sectional Analysis

doi:10.21203/rs.3.rs-5315952/v1

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Exploring the Correlation Between Gallstone Disease and Sarcopenia Risk: Insights from a Cross-Sectional Analysis

https://doi.org/10.21203/rs.3.rs-5315952/v1

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Background

Musculoskeletal disorders related to chronic liver and biliary diseases are increasingly recognized, with a growing body of observational studies linking these conditions. This study investigates the association between gallstone disease and sarcopenia, exploring the implications for patient health outcomes.

Methods

A cross-sectional analysis was conducted involving 1,683 participants to assess the relationship between gallstones and sarcopenia. Adjusted odds ratios (OR) for sarcopenia were calculated using logistic regression models, controlling for sociodemographic and health-related factors.

Results

Among the participants, those with gallstones had a higher likelihood of sarcopenia, with adjusted odds ratios of 2.15 in Model 1 and 2.71 in Model 2. The risk was particularly pronounced in females, with an odds ratio of 2.756. Additionally, individuals with diabetes faced an elevated odds ratio of 8.576 for developing sarcopenia. Although trends in increased risk were observed in other subgroups, such as those with hypertension and younger adults, these did not achieve statistical significance. An inverse relationship was also noted between appendicular skeletal muscle mass (ASM) and gallstone occurrence.

Conclusion

This study demonstrates that gallstone disease increases the risk of sarcopenia, highlighting the need for integrated management strategies that include nutritional evaluations and exercise interventions. Further longitudinal research is essential to clarify causal relationships and underlying mechanisms.

Sarcopenia

Gallstone Disease

Chronic Liver Disease

Musculoskeletal Disorders

Sarcopenia refers to the progressive loss of muscle mass and strength typically seen with age and the associated functional limitations(1). This condition increases the risk of falls and fractures and is strongly linked to functional impairment, disability, and higher all-cause mortality rates(2, 3). Furthermore, studies have shown that sarcopenia is linked to various diseases, including type 2 diabetes, osteoarthritis, cardiovascular diseases, cirrhosis, and certain inflammatory conditions, which may be driven by chronic inflammatory states and mitochondrial dysfunction(4–6). Sarcopenia is particularly prevalent among older individuals, with incidence rates ranging from 5–50%(7), and its occurrence is increasing globally due to the ageing population(8). This condition presents a significant challenge to public health systems, making it essential to identify and assess the risk factors associated with sarcopenia to improve health outcomes and quality of life(9).

Gallstone disease (GSD) is common in the general population and its incidence has increased in recent years(10). In the United States, gallstones are the leading cause of digestive diseases(11), affecting approximately 10–15% of the adult population(12). Gallstone formation is recognized as multifactorial, with risk factors including age, ethnicity, genetics, female gender, and lifestyle(13). Additionally, gallstone disease (GSD) is associated with insulin resistance, obesity, metabolic syndrome, and diabetes, all of which are significantly influenced by diet(14). Previous study found that gallstone disease is an independent risk factor for nonalcoholic fatty liver disease (NAFLD)(15). Furthermore, mortality related to gallbladder and biliary tract diseases, as well as gallstone disease, is associated with factors such as prediabetes or diabetes, liver stiffness, and the use of proton pump inhibitors(16).

Given the prevalence of gallstones and their close association with various metabolic and nutritional-related diseases, it is crucial to conduct in-depth research on the relationship between gallstones and sarcopenia. Such research will enhance our understanding of their mutual impact on metabolic health and provide new insights for clinical management. Currently, there is a notable lack of studies in this area. Therefore, this study aims to explore the association between the presence of gallstones and the incidence of sarcopenia. The findings could contribute valuable medical advice regarding nutritional management for patients with gallstones.

2.1. Study Population

The study utilized data from the National Health and Nutrition Examination Survey (NHANES) database, administered by the Centers for Disease Control and Prevention (CDC) in the United States. This comprehensive program gathers detailed information on individuals' health and nutritional status through interviews, physical assessments, and laboratory analyses. Participants were selected using a two-stage stratified cluster sampling method based on population and housing census information. Data collection involved household interviews and standardized physical assessments. Prior to the survey, written informed consent was obtained from each participant, and secondary anonymized data were used for analysis. The focus of this study was on data from the survey conducted between 2017 and 2018, during which participants underwent testing for gallstones and sarcopenia. The NHANES database is publicly available at: https://www.cdc.gov/nchs/nhanes/index.htm.

The NHANES database included a total of 5,569 participants aged 20 years and older during the 2017–2018 cycle. After excluding individuals without data on gallstones and sarcopenia, 2,025 participants remained. Further exclusion of individuals with missing covariate data (such as alcohol consumption, education, diabetes status, hypertension, and marital status) resulted in a final analysis cohort of 1,683 participants, comprising 840 men and 843 women.

2.2. Definition of gallstones

For our current study, we utilized a sub-sample of the National Health and Nutrition Examination Survey (NHANES) from the 2017 to 2018 cycle, which includes pertinent information related to gallstones. We determined whether participants had gallstones based on the results of the questionnaire “Has doctor ever said you have gallstones”. Individuals who replied in the affirmative were classified as having gallstones, whereas those who replied in the negative were classified as not having gallstones(17).

2.3. Definition of Sarcopenia

Dual-energy X-ray absorptiometry (DXA) was utilized to assess appendicular skeletal muscle mass (ASM), which reflects the total lean mass in the arms and legs. However, DXA measurements were not applicable for individuals who were pregnant, taller than 192.5 cm, or weighed more than 136.4 kg. The sarcopenia index is calculated by dividing ASM by body mass index (BMI), with values below 0.512 for females and 0.789 for males indicating the presence of sarcopenia(18).

2.4. Covariates

The survey questionnaire gathered extensive data on participants, encompassing factors such as age, sex, ethnicity, marital status, family income, body mass index (BMI), smoking habits, alcohol use, hypertension status, diabetes mellitus (DM), and hyperlipidemia. Hypertension was classified as a systolic blood pressure (SBP) of 140 mmHg or higher and/or a diastolic blood pressure (DBP) of 90 mmHg or higher, or the use of antihypertensive medications. Smoking status was divided into three categories: non-smokers (those who had never smoked or had smoked fewer than 100 cigarettes in their lifetime), former smokers (individuals who had smoked at least 100 cigarettes but had quit), and current smokers (those who had smoked at least 100 cigarettes and reported smoking within the last 30 days).

Alcohol consumption was categorized into four groups: never drinkers (individuals who had consumed fewer than 12 alcoholic beverages in their lifetime), former drinkers (those who had consumed more than 12 drinks but had abstained for at least one year), and current drinkers, who were further classified as mild, moderate, or heavy drinkers based on their daily intake and episodes of binge drinking. Education levels were divided into five categories: college graduates or higher, some college or an associate degree, high school graduates or GED equivalents, individuals with 9–11 years of education, and those with less than 9 years of education. Family income was classified into three tiers: high, moderate, and low income.

For this study, diabetes mellitus (DM) was defined by any of the following criteria: a fasting plasma glucose level of 126 mg/dL (7.0 mmol/L) or higher, a 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during an oral glucose tolerance test, an HbA1c level of 6.5% or greater, or a prior diagnosis of diabetes accompanied by ongoing treatment. Hyperlipidemia was defined as a total cholesterol level of 240 mg/dL (6.2 mmol/L) or higher, low-density lipoprotein cholesterol (LDL-C) levels of 160 mg/dL (4.1 mmol/L) or higher, or 130 mg/dL (3.4 mmol/L) or higher in high-risk individuals, triglycerides (TG) levels of 150 mg/dL (1.7 mmol/L) or greater, or high-density lipoprotein cholesterol (HDL-C) levels of less than 40 mg/dL (1.0 mmol/L) for men or less than 50 mg/dL (1.3 mmol/L) for women.

2.5. Statistical analysis

The analysis accounted for the complex multi-stage cluster survey design and sample weights, following the Centers for Disease Control and Prevention (CDC) guidelines for NHANES data. Participant characteristics were presented as means with standard deviations (SD) for continuous variables, and as unweighted counts and weighted percentages (%) for categorical variables. To compare continuous variables between groups, the Wilcoxon rank-sum test for complex survey samples was employed, while categorical variables were compared using a weighted Chi-square test. Sample-weighted logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to examine the relationship between gallstones and sarcopenia. The analysis was conducted using four models: the Crude Model, which was unadjusted; Model 1, adjusted for sociodemographic factors (age, sex, and gallstones); Model 2, which further adjusted for lifestyle and health-related factors, including ethnicity, poverty, education, marital status, smoking, and alcohol use; and Model 3, which additionally accounted for HbA1c, triglycerides, total cholesterol, BMI category, diabetes, hypertension, and cardiovascular disease. To gain deeper insights into specific populations, subgroup analyses were performed based on sex, age groups (20–60 years and 60–85 years), diabetes status, and hypertension status. This allowed for a more detailed examination of the relationship between gallstones and sarcopenia across various demographic and health-related factors. R version 3.4.0 was used to perform the data analysis (R Foundation for Statistical Computing, Vienna, Austria; available at http://www.R-project.org). All statistical tests were two-sided, and significance was considered at p < 0.05.

3.1. Baseline characteristics

A total of 1,683 participants were included in the study. Among them, 1,446 had neither gallstones nor sarcopenia, 90 had gallstones without sarcopenia, 133 had sarcopenia without gallstones, and 14 participants had both gallstones and sarcopenia. The study also considered various relevant variables to adjust for potential confounders. These included age, BMI, HbA1c, triglycerides (TG), total cholesterol, and sex (categorized as female or male). Ethnicity was divided into several groups: Mexican American, Non-Hispanic Black, Non-Hispanic White, Other Hispanic, and Other Race (including Multi-Racial). Educational levels were classified as above high school, high school or equivalent, and under high school. Family income was grouped into high, medium, and low categories. Marital status was categorized as married or other. Additional variables included BMI categories (underweight, overweight, or obese), alcohol consumption (never, mild, moderate, or heavy drinkers), smoking status (never, former, or current smokers), and the presence of hypertension (yes or no). The specific relevant data are presented in Table 1.

3.2. Association between gallstone and sarcopenia

The association between gallstones and the risk of sarcopenia was evaluated using a sample-weighted multivariable logistic regression model, as shown in Table 2, and remained consistent across all adjusted models. In the crude model, patients with gallstones had 2.11 times higher odds of developing sarcopenia compared to those without gallstones (95% CI: 1.13–3.95, p=0.02), indicating that gallstones may be a significant risk factor for sarcopenia. In model 1, adjusted for age and sex, the odds of sarcopenia among patients with gallstones were 2.15 times higher compared to those without gallstones (95% CI: 1.22–3.78, p=0.01). In model 2, further adjustments were made for ethnicity, poverty status, education level, marital status, smoking status, and alcohol consumption. The association strengthened, with patients with gallstones showing 2.71 times higher odds of developing sarcopenia (95% CI: 1.59–4.61, p=0.001). In model 3, after additionally adjusting for HbA1c, triglycerides (TG), total cholesterol, BMI category, diabetes mellitus (DM), hypertension, and cardiovascular disease (CVD), the association remained significant, with gallstone patients being 1.89 times more likely to develop sarcopenia (95% CI: 1.13–3.18, p=0.02). This suggests that the relationship between gallstones and sarcopenia persists even after adjusting for a broad range of sociodemographic and health-related factors. The specific details are presented in Table 2.

3.3 Association between appendicular skeletal muscle mass and gallstone

DXA was employed to measure the appendicular skeletal muscle mass (ASM), which represents the aggregate lean mass in the arms and legs. RCS analysis showed that an increase in appendicular skeletal muscle mass (ASM) was negatively associated with the probability of developing gallstones, with an overall p-value of less than 0.05. This relationship exhibited a linear trend (P non-linear > 0.05). These findings highlight the connection between ASM and the likelihood of gallstone occurrence, suggesting an interrelationship between sarcopenia and gallstone disease. Detailed results are presented in Figure 1.

3.4 Subgroup analysis

The subgroup analysis concerning sex revealed that among males, patients with gallstones had a probability of developing sarcopenia that was 1.050 (95% CI: 0.226–4.882, p=0.947) times that of patients without gallstones. In females, the analysis indicated that patients with gallstones had a probability of developing sarcopenia that was 2.756 times higher (95% CI: 1.356–5.600) compared to those without gallstones, with a statistically significant P-value of 0.008. In the age subgroup analysis for individuals aged 40 to 60 years, patients with gallstones exhibited a probability of developing sarcopenia that was 1.108 times higher (95% CI: 0.313–3.918) compared to those without gallstones. For the age group of 20 to 39 years, individuals with gallstones had a 2.483 times higher probability of developing sarcopenia compared to their counterparts without gallstones (95% CI: 0.481–12.818). Although these findings did not reach statistical significance, they suggest that the presence of gallstones may still be associated with an increased risk of sarcopenia. In the diabetes-related subgroup analysis, individuals without diabetes exhibited a probability of developing sarcopenia that was 1.331 times higher (95% CI: 0.354–5.003), but this association was not statistically significant (p=0.652). Conversely, for individuals with diabetes, the probability of developing sarcopenia was markedly higher, with an odds ratio of 8.576 (95% CI: 1.800–40.858), which was statistically significant (p=0.01). These results indicate that the presence of diabetes significantly increases the risk of sarcopenia in affected individuals. In the hypertension-related subgroup analysis, individuals without hypertension showed a probability of developing sarcopenia with an odds ratio of 0.991 (95% CI: 0.238–4.125), indicating no significant association (p=0.990). In contrast, those with hypertension had a higher odds ratio of 2.952 (95% CI: 0.732–11.900); however, this association did not reach statistical significance (p=0.119). These findings suggest that while there may be a trend towards an increased risk of sarcopenia among individuals with hypertension, the results were not statistically significant. Detailed results regarding subgroup analysis are presented inTable3 and Figure 2.

Musculoskeletal disorders related to chronic liver and biliary diseases are garnering increasing attention, and numerous observational studies have explored the risk of these disorders in patients with chronic liver and biliary disease(19). In this study involving 1,683 participants, a significant association between gallstones and sarcopenia was identified. Participants with gallstones had a notably higher likelihood of developing sarcopenia, with adjusted odds ratios of 2.15 in Model 1 and 2.71 in Model 2, indicating a robust relationship even after controlling for various sociodemographic and health-related factors. Furthermore, the analysis revealed that appendicular skeletal muscle mass (ASM) was inversely related to the likelihood of gallstone occurrence, suggesting a potential interplay between these two conditions. Subgroup analyses highlighted that the increased risk of sarcopenia associated with gallstones was particularly pronounced in females, where the odds were 2.756 times higher compared to their counterparts without gallstones. Notably, individuals with diabetes exhibited a markedly elevated risk of sarcopenia, with an odds ratio of 8.576, underscoring the compounded effects of metabolic conditions on muscle health. While trends indicating increased risk were observed in other subgroups, such as those with hypertension and younger adults, these associations did not achieve statistical significance. Overall, the findings emphasize the complex interrelationship between gallstone disease and sarcopenia, warranting further investigation to clarify the underlying mechanisms and potential clinical implications.

The underlying mechanisms linking sarcopenia and gallstone disease warrant further exploration. Chronic inflammation and metabolic dysfunction, which are common in both conditions, may play a pivotal role in their interrelationship(20). Chronic inflammation is a significant contributor to both malnutrition and sarcopenia, impacting metabolism through mechanisms such as elevated resting energy expenditure and increased muscle catabolism(21, 22). Inflammatory bowel disease (IBD) patients, for instance, often experience malnutrition, with prevalence rates as high as 65–75% for Crohn's disease and 18–62% for ulcerative colitis, primarily due to malabsorption, dietary restrictions, and increased energy demands associated with their inflammatory state(23). Notably, malnutrition is closely linked to alterations in body composition, including weight loss and reduced skeletal muscle mass, which could exacerbate the risk of developing sarcopenia(24). Furthermore, micronutrient deficiencies common in IBD, such as those in iron, zinc, and vitamins, along with insufficient protein intake, can further drive the onset of sarcopenia. This relationship highlights how disruptions in nutrient intake and gut health may contribute to the etiology of both sarcopenia and gallstones, as poor nutrition can lead to metabolic dysfunction and inflammatory responses that promote gallstone formation. Additionally, vitamin D deficiency plays a crucial role in IBD-related sarcopenia, with lower serum levels linked to decreased vitamin D receptor expression, which is essential for muscle health(25). Therefore, addressing malnutrition and monitoring micronutrient levels, particularly vitamin D, may provide therapeutic opportunities to mitigate both sarcopenia and gallstone disease through improved metabolic health. Additionally, emerging evidence highlights the intricate relationship between skeletal muscle mass, glucose homeostasis, and gut microbiota(26), suggesting potential mechanisms that may link sarcopenia with gallstone disease. Decreased skeletal muscle mass, characteristic of sarcopenia, can impair glucose regulation, which in turn may contribute to metabolic dysfunction and the formation of gallstones. The gut microbiota plays a crucial role in this interplay by modulating lipopolysaccharide (LPS) production and short-chain fatty acids (SCFA), which influence host metabolism, including that of skeletal muscle(27, 28).

The findings highlight significant clinical implications regarding the association between sarcopenia and gallstones. This connection underscores the importance of incorporating metabolic and nutritional considerations into the management of gallstone disease, particularly in the aging population, where both conditions are prevalent. Early identification of individuals at risk for sarcopenia could enhance preventive strategies and therapeutic outcomes. For example, integrating nutritional evaluations and personalized exercise programs into the care of gallstone patients may help prevent muscle loss and improve overall health. Physical activity and nutrition interventions are crucial treatments for sarcopenia, with compelling evidence supporting the benefits of adequate protein and nutrient intake, as well as exercise, in maintaining muscle mass and strength(29). Additionally, vitamin D has been shown to promote the proliferation and differentiation of myogenic cells, directly increasing muscle mass. Recent studies indicate that vitamin D supplementation can enhance strength and physical performance in patients with lower baseline levels(30). The elevated risk of gallstones in females further emphasizes the need for gender-specific screening and intervention strategies, highlighting the value of tailored approaches in clinical practice.

To our knowledge, this study is among the first to explore the relationship between sarcopenia and gallstone disease. The potential implications of sarcopenia could include increased risk of functional impairment, disability, and higher rates of comorbidities, which may negatively impact patients' quality of life. Our findings suggest the need to consider not only pharmacological treatments for gallstones but also the roles of exercise and nutrition in managing patients who may be at risk for sarcopenia. Given the rising incidence of gallstones and the prevalence of sarcopenia among older adults, these insights may help inform more comprehensive management strategies. By emphasizing nutritional interventions and encouraging physical activity, healthcare providers could potentially enhance outcomes for patients with gallstones and address the risks associated with sarcopenia.

Despite the study’s strengths, this study has several limitations that should be acknowledged. Firstly, the cross-sectional design restricts the ability to establish causal relationships between sarcopenia and gallstone disease, highlighting the need for longitudinal studies to explore the temporal dynamics between these conditions. Additionally, the assessment of gallstones relied on self-reported data, which may introduce reporting bias, as participants might not accurately recall or disclose their medical history. Lastly, while utilizing data from the NHANES database, the findings may not be generalizable to all populations, as the sample may not fully represent individuals with gallstone disease or sarcopenia outside the demographic characteristics captured in the dataset. Therefore, a large-scale, prospective, multi-center study is necessary to thoroughly explore the relationship between gallstone disease and sarcopenia, as well as to identify potential underlying mechanisms and effective management strategies.

Consent for publication

All authors unanimously agreed to submit this manuscript for publication.

Availability of data and materials

All data generated or analyzed during this study are included in this published article. All figures in our study are original and have not been previously published.

Consent for publication

Not applicable.

Human Ethics and Consent to Participate declarations:

Not applicable.

Clinical trial number:

Not applicable

Ethics Declaration

This study utilized data from the National Health and Nutrition Examination Survey (NHANES), a publicly available dataset provided by the Centers for Disease Control and Prevention (CDC). All data were anonymized prior to analysis, and NHANES participants provided informed consent at the time of data collection. The NHANES protocol is reviewed and approved by the National Center for Health Statistics (NCHS) Research Ethics Review Board, and all procedures are conducted in accordance with the Declaration of Helsinki.

Competing interests

The authors declare that they have no competing interests. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflict-of-interest statement:

All authors have no conflicts of interest regarding the current paper.

Author contributions:

Di Zeng: Conceptualization (equal), Data curation (lead), Formal analysis (lead), Investigation (lead), Methodology (lead), Writing – original draft (lead), Writing – review & editing (lead). Jiong Lu: Supervision (lead), Conceptualization (equal), Methodology (lead), Writing – review & editing (equal), Investigation (equal). Jinhong Chen: Conceptualization (lead), Formal analysis (equal), Investigation (equal), Writing – review & editing (lead).

Funding

Research Funding Project for Outstanding Young Talents in the Health Industry of Gansu Province(GS WSQN2022-12）

Acknowledgements

Not applicable.

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Tables 1 to 3 are available in the Supplementary Files section

No competing interests reported.

Table1.docx
Table1: Basic information of included patients.
Table2.docx
Table2:Association between gallstones and the risk of sarcopenia evaluated using a sample-weighted multivariable logistic regression model.
Table3.docx
Table3:Subgroup analysis of the association between gallstones and the risk of sarcopenia.

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You are reading this latest preprint version

Exploring the Correlation Between Gallstone Disease and Sarcopenia Risk: Insights from a Cross-Sectional Analysis

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Abstract

Figures

1. Introduction

2. Methods

2.1. Study Population

2.2. Definition of gallstones

2.3. Definition of Sarcopenia

2.4. Covariates

2.5. Statistical analysis

3. Results

4. Discussion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1