Introduction

In the world, 10–15% of people suffer from gallstones, a prevalent gastrointestinal disease. The incidence varies among nations1. Approximately 10–20% of people in the US now have gallstones, and this number is increasing2. According to calculations, gallstone disease prevention and treatment in the US cost over $62 billion annually, which puts heavy financial strain on the healthcare system3. Complications include cholecystitis, cholangitis, and gallbladder cancer, which may occur in 3–8% of patients with gallstones4. These complications may have serious consequences and are sometimes even life-threatening. Both environmental and genetic variables can have an impact on gallstone development. In Western nations, cholesterol accounts for 75–80% of gallstones5. Cholesterol can be detected in 95% of gallstones in patients who have undergone gallbladder removal6. Various risk factors for the development of gallstones, including age, gender, race, pregnancy, obesity, diabetes, and high total cholesterol concentration, have been reported in previous studies7,8,9. However, there are currently no effective clinical indicators for predicting or preventing gallstone development.

Previous studies have revealed that an increased TyG index is strongly associated with coronary heart disease, kidney stones, diabetes, and other diseases. The TyG index combines two biomarkers, triglycerides and fasting blood glucose, to assess insulin sensitivity and measure insulin resistance (IR) in the human body10. It is considered an accurate biomarker to replace insulin resistance (IR). IR is a significant risk factor for several metabolic disease types, including diabetes11, obesity12, coronary heart disease13 and other diseases. There is increasing evidence that gallstones are related to insulin resistance, an important pathophysiological factor associated with biliary cholesterol saturation and gallstone formation14. IR increases the production of cholesterol gallstones by activating 3-hydroxy-3-methylglutaryl CoA reductase15. Biddinger et al. reported that hepatic insulin resistance promotes the formation of cholesterol gallstones by stimulating the bile's release of cholesterol16. Because the TyG index has been used as an alternative biomarker for IR17, it is worthwhile to explore if there is any relationship between the TyG index and gallstones. Nevertheless, no previous study has investigated the association between gallstones and the TyG index in the US population. Therefore, to investigate the association between gallstones and the TyG index, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020.

Materials and methods

Research population

The National Health and Nutrition Examination Survey (NHANES) is a national survey conducted by the National Center for Health Statistics (NCHS). The purpose of this survey is to assess the health status of American people. All participants in the NHANES program voluntarily participated in the study and provided informed consent. NHANES data are released every two years; however, the official NHANES program have posted that they were suspended in March 2020 because of the 2019 coronavirus disease (COVID-19). The sources are accessible through the NHANES website (https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx?Cycle=2017-2020). Consequently, NHANES 2017–2018 and 2019–March 2020 data were combined to create a nationally representative sample that included pre-pandemic NHANES 2017–March 2020 data. The gallstone questionnaire was only accessible from 2017 to 2020; therefore, data from that period was utilized in our study. A total of 15,560 participants participated, of whom 6328 lacked gallstone data, these participants were excluded. Participants who lacked the TyG index were excluded (n = 5286). In addition, data on missing covariates was not included. (Total, n = 54; including hypertension, n = 5; marital status, n = 4; coronary heart disease, n = 16; smoking status, n = 3; education level, n = 3; diabetes, n = 2; waist circumference, n = 21). A total of 3870 people participated in the study. (Fig. 1).

Figure 1
figure 1

Flowchart for choosing participants. NHANES, National Health and Nutrition Examination Survey.

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Study variables

Definition of gallstones

Gallstone occurrence was designed as an outcome variable. We used the questionnaire "Has DR ever said you have gallstones?" to determine the presence of gallstones. Individuals who gave a positive response were identified as having gallstones, whereas those who gave a negative answer were excluded.

Definition of the triglyceride-glucose index

We used the TyG index as the exposure variable in our analysis. The formula used to compute the TyG index is Ln [triglycerides (mg/dl) × fasting blood glucose (mg/dl)/2].

The concentrations of triglycerides and fasting blood glucose were measured using an automated biochemical analyzer through enzymatic measurement.

Covariates

The statistical model included the following covariates: age (years), gender (male/female), race (Mexican American/other Hispanic/non-Hispanic white/non-Hispanic black/other race), education level (below high school, high school, and above high school), marital status (cohabitation [married/cohabiting with partner] and living alone [widowed/divorced/separated/unmarried]), poverty-to-income ratio (PIR), alcohol consumption: participants were classified as drinkers if they consumed 12 or more alcoholic beverages per year, smoking status: participants were classified as smokers if they consumed at least 100 cigarettes per year. hypertension, diabetes, and coronary heart disease (individuals who answered "Yes" on the questionnaire were identified as having these illnesses), body mass index (BMI), fasting glucose level, low-density cholesterol level, triglyceride level, total cholesterol level and waist circumference(WC). Missing data in the covariates were excluded.

Statistical methods

The mean ± standard deviation (SD) was used to record continuous variables, whereas frequencies or percentages were used to express categorical variables. In three different models, the independent association between the TyG index and the risk of gallstones was investigated using multivariate logistic regression models. There was no covariate adjustment in Model 1. Gender, age, race, education level, and marital status were adjusted in Model 2. All variables in Model 3 were adjusted for gender, age, race, education level, marital status, poverty-to-income ratio (PIR), alcohol consumption, smoking status, hypertension, diabetes, coronary heart disease, BMI, fasting glucose level, low-density cholesterol level, triglyceride level, total cholesterol level and waist circumference(WC). To investigate potential variations in the relationship between the TyG index and gallstones, subgroup analyses were performed, considering factors such as age, gender, alcohol consumption, BMI, smoking status, diabetes, hypertension, and total cholesterol level. Additionally, we investigated the relationship between gallstones and the TyG index in more detail using the smooth curve fitting. All analyses were performed using Empower software and R version 4.0.2. P < 0.05 was considered statistically significant.

Ethics statement

The NHANES database is open to the public. The NCHS Research Ethics Review Board assessed and authorized the studies involving human participants. The participants provided their written informed consent to participate in this study.

Results

Basic characteristics of participants

Table 1 shows the basic demographic characteristics of the participants. The study analysis included 3870 participants, 403 of whom had gallstones and 3467 of whom had no gallstones, with a prevalence rate of 10.4%. The group with gallstones had a higher TyG index level (8.71 ± 0.67) than the group without gallstones (8.49 ± 0.69) (P < 0.001). Participants with gallstones were older, more likely to be female, and had a higher BMI. Gallstones were also significantly correlated with fasting glucose and triglyceride levels, race, hypertension, coronary heart disease, and diabetes (all p < 0.05) (Table 1).

Table 1 Basic characteristics of participants.
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An increased risk of gallstones was associated with a higher TyG index

The relationship between the TyG index and the risk of gallstones is shown in Table 2. In both unadjusted and fully adjusted models, the TyG index showed a stable and positive association with the risk of gallstones. The risk of gallstones increased by 53% for each unit increase in the TyG index in the unadjusted model (OR 1.53, 95% CI 1.33, 1.76). In the fully adjusted model, the association between gallstones and the TyG index remained stable; the risk of gallstones increased by 41% for each unit increase in the TyG index (OR 1.41, 95% CI 1.07, 1.86). For the sensitivity analysis, our study converted the TyG index into a quartiles variable and showed that higher-level TyG index groups were shown to have a higher risk of gallstones. (OR 1.93, 95% CI 1.27, 2.94) (Table 2).

Table 2 The TyG index and the risk of gallstones are analyzed using logistic regression.
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We investigated the relationship between gallstones and the TyG index in more detail using smooth curve fitting. As shown in Fig. 2, we found a positive linear correlation between TyG index and the risk of gallstones (Fig. 2).

Figure 2
figure 2

Smooth curve fitting exhibited the relationship between the TyG index and the risk of gallstones. Smooth curve fitting exhibited a positive linear correlation between the TyG index and the risk of gallstones in this figure, and a 95% confidence interval (Cl) was displayed for the region between the upper and lower dashed lines. Adjusting for all covariates. (gender, age, race, education level, marital status, poverty-to-income ratio (PIR), alcohol consumption, smoking status, hypertension, diabetes, coronary heart disease, BMI, fasting glucose level, low-density cholesterol level, triglyceride level, total cholesterol level and waist circumference(WC)).

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Subgroup analysis

We performed subgroup analyses to determine whether covariates including age, gender, BMI, drinking and smoking habits, total cholesterol, diabetes, and hypertension affected the relationship between the TyG index level and the risk of gallstones. We found that the association between the TyG index and the risk of gallstones showed significant differences in age (P for interaction < 0.05). Among individuals aged < 50 years, women, individuals with total cholesterol levels > 200 mg/dL, BMI > 25, and individuals without diabetes, the TyG index was significantly positively correlated with the risk of gallstones (all p < 0.05) (Table 3).

Table 3 Subgroup regression analysis between the TyG index and gallstone risk.
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Discussion

The relationship between gallstones and the TyG index has not been thoroughly examined, and our study is the first nationally representative sample of the US population. The study indicates that, in the fully adjusted model, the risk of gallstones increased by 41% for each unit increase in the TyG index (OR 1.41, 95% CI 1.07, 1.86). Notably, in the subgroup analyses, a positive association between gallstones and the TyG was observed in individuals aged < 50 years, women, individuals with total cholesterol levels > 200 mg/dL, those with BMI > 25, and individuals without diabetes. The smoothed curve fitting also showed a positive correlation between the TyG index and gallstones. According to this study, the TyG index may be used as a predictor of the risk of gallstones.

Recently, an increasing number of researchers have focused on the association between gallstones and insulin resistance (IR). Ahmed et al. found that gallstones are a result of the supersaturation and overproduction of bile salts, which are mostly caused by IR18. Additionally, previous studies have shown that IR increases the production of cholesterol gallstones by activating 3-hydroxy-3-methylglutaryl CoA reductase15. Therefore, IR is strongly associated with gallstones.

The TyG index is a new biomarker that can be calculated using triglyceride and fasting glucose levels. Guerrero-Romero et al. conducted a cross-sectional study of 99 participants in 2010. They found that the TyG index has high sensitivity (96.5%) and specificity (85.0%) compared to the gold standard (euglycemic-hyperinsulinemia clamp test), so the TyG index is the best tool for assessing IR19. Since then, clinical studies have proven the TyG index to be a reliable indicator for evaluating IR in individuals. Because of its high sensitivity and specificity, as well as its low cost, glucose and triglyceride measurements can be performed in virtually all clinical laboratories and do not require expensive tests for serum insulin level measurement. Therefore, the TyG index has gained popularity as a substitute for IR20.

It is unclear what mechanism underlies the correlation between the TyG index and gallstones. The explanation that supports our results is that the TyG index serves as an alternative biomarker for IR, with greater IR represented by a higher TyG index. IR is thought to play a central role in the pathogenesis of the metabolic syndrome. It leads to hyperglycemia, increased secretion of apolipoprotein B, atherosclerosis, increased secretion of bile cholesterol, and cholesterol stones21. According to experimental data, IR may promote gallstones by raising bile lithogenicity22. Nakeeb et al. concluded that increased bile cholesterol production and the development of cholesterol gallstones could be caused by hepatic IR23. IR may lead to increased hepatic cholesterol secretion and cholesterol supersaturation, as well as gallbladder motility disorders, which may enhance gallstone formation24. Related studies have shown that IR increases the production of cholesterol gallstones by activating 3-hydroxy-3-methylglutaryl CoA reductase15. The correlation between a higher TyG index and an increased risk of gallstones can be explained by the positive relationship between IR and gallstones.

In this study, the TyG index was positively associated with the risk of gallstones in individuals with BMI > 25. Insulin resistance, which correlates with the development of gallstones, is the primary cause of obesity and metabolic syndrome25. Leptin, which contributes to the formation of hyperleptinemia when obesity arises, is another element in the pathophysiology of gallstones26,27. Gallstone development is promoted by leptin. Consistent with our findings, obesity and the occurrence of gallstones are significantly correlated28. These results are consistent with those of previous studies on the effect of gender on gallstones. Women are more susceptible to gallstones than men. One significant risk factor for gallstones is estrogen29. By upregulating the expression of the HMG-CoA gene, estrogen enhances the excretion of cholesterol into the bile. This causes the cholesterol in the bile to become supersaturated, which encourages the production of gallstones30,31.

However, the function of age in the development of gallstones is still under discussion. Our study indicated that the TyG index is associated with the risk of gallstones in the population aged < 50 years. In fact, risk factors for illnesses in older adults include obesity and metabolic syndrome, which are more prevalent in older adults than in younger adults. However, some studies have found that obesity and metabolic syndrome have a greater effect on gallstones in younger individuals32. Further studies are necessary to evaluate the impact of age on gallstones. Gallstones may be found with > 95% accuracy using transabdominal ultrasonography33. Therefore, transabdominal ultrasound examination is important for gallstones in patients aged < 50 years with a high TyG index.

Furthermore, this study showed that among non-diabetic individuals, the TyG index was associated with a higher risk of gallstones. However, we know that diabetes is a risk factor for gallstones8,9. Diabetes was not specifically classified in the NHANES database. According to related studies, type 2 diabetes and gallstones are causally related34. However, among people between the ages of 20 and 40, there is a negative association between a higher incidence of type 1 diabetes and gallstones35. Chang et al. found that gallstones and insulin resistance are strongly associated with Korean men without diabetes36. Therefore, the association between diabetes and gallstones remains unclear, and further studies are required to confirm this. A possible explanation for this phenomenon is that the TyG index has been proposed as an alternative marker of insulin resistance. Patients with a higher TyG index often develop insulin resistance. In some patients, insulin resistance may precede diabetes11,37. Participants in our study with undiagnosed diabetes may already have insulin resistance. Insulin resistance is an important pathophysiological factor that is associated with biliary cholesterol saturation and gallstone formation. Previous studies have shown that insulin resistance leads to bile supersaturation by reducing bile salt secretion and increasing mucus production by inducing gallbladder inflammation, thereby making patients more susceptible to gallstones16. This is a possible reason why people without diabetes but with a high TyG index are prone to gallstones. This is an interesting finding that can help us evaluate and predict the risk of gallstones in the non-diabetic population using the TyG index.

Relevant studies have shown that the incidence of gallstones in patients with hypercholesterolemia is significantly higher than that in patients without hypercholesterolemia2. Gallstone development is primarily caused by the supersaturation of cholesterol in the bile and gallbladder38. Cholesterol gallstones are mostly formed by non-physiological supersaturation, which is often caused by excessive cholesterol release39. High total cholesterol concentration (TCH > 200 mg/dL) is a risk factor for symptomatic gallstones7. According to our stratified analysis of total cholesterol levels, a significant association was observed between the TyG index and the risk of gallstones in people with total cholesterol levels > 200 mg/dL, which is consistent with the above research results.

Limitations

The NHANES study participants were a representative sample of American citizens who closely adhered to a meticulously planned research strategy guarantee the validity of our findings. However, our study has several limitations. First, the limitations of cross-sectional studies prevent us from determining the causal inference between TyG index and gallstones. Second, there may be memory bias because the NHANES survey data were derived from questionnaires. Finally, in daily practice, abdominal imaging for metabolic dysfunction-associated steatohepatitis (MASH) is performed more often in people with metabolic syndrome than in lean people, and the possibility of incidental gallstones increases. Despite these Limitations, this is the first study to show the connection between the TyG index and gallstones, and the results strongly suggest that the TyG index may be used to predict the risk of gallstones. We will then conduct a multicenter prospective cohort study to investigate the effect of the TyG index on gallstones in more detail.

Conclusion

Our study showed a significant correlation between a higher TyG index and an increased risk of gallstones. In the following subgroups, this relationship is important and noteworthy: individuals aged < 50 years, women, individuals with total cholesterol levels > 200 mg/dL, BMI > 25, and individuals without diabetes. Therefore, the TyG index may be used as a predictor of the risk of gallstones.