Gallstone disease is a common digestive system disorder and has become an important issue in modern healthcare. With an annual incidence of 0.60–1.3% (1), the prevalence of gallstones in US adults hovers around 10–20%, and this number is increasing (2). Although gallstones are usually asymptomatic, they can still be harmful. More than 20% of gallstone patients eventually experience common symptoms including colic or infection (3). A few patients may even develop rare complications such as gallstone ileus, Mirizzi syndrome, and Bouveret syndrome (4, 5). These symptoms cause great discomfort to the patient and impose an enormous financial strain on society and families. Therefore, gallstones are considered a severe public health concern that deserves vigilant attention from the medical community.

It is generally recognized that inflammation contributes significantly to the many factors that lead to gallstone development (6–8). Several inflammatory markers have been identified as potential indicators of the promotion of gallstone formation. C reactive protein and high-sensitivity C reactive protein, indicators of systemic inflammation, have been linked to an elevated risk of gallstone disease (9, 10). Interleukin (IL)-6, a kind of cytokine, has been linked to gallstone formation due to its role in promoting inflammation (8). Additionally, there is clear evidence linking the systemic immune-inflammatory index to a significant increase in gallstone prevalence (11).

Integrating BMI, albumin, and neutrophil to lymphocyte ratio (NLR), the advanced lung cancer inflammation index (ALI) is a systemic inflammatory index. ALI was initially evaluated for lung cancer patients (12). Given the value of the inflammatory aspects of the ALI assessment, several studies have explored its role in hypertension, diabetes, heart failure, rheumatoid arthritis, coronary artery disease, and stroke (13–18). Although inflammation is known to be linked to gallstones, it is unclear how ALI and gallstones are related.

Therefore, we aimed to use National Health and Nutrition Examination Survey (NHANES) to explore the association between ALI and gallstones among US adults.

The relationship between ALI and gallstones among US adults is being examined for the first time with our cross-sectional investigation. The results suggested that elevated ALI was significantly associated with a higher gallstone prevalence after further adjustment for potential confounding variables. The smooth curve fits result further demonstrated the positive correlation. Additionally, the association between gallstones and ALI varied significantly according to gender. The prevalence of gallstones is more likely to be affected by high ALI levels in female individuals.

The impact of inflammation on gallstones is receiving more and more widespread attention. In a cross-sectional investigation involving 4,950 US adult participants based on the NHANES database, Meng et al. discovered that a higher systemic immune-inflammatory index was independently linked to the probability of gallstone prevalence under 50 (11). In a case–control research including 150 Iranian women, Ghorbani et al. discovered a considerable positive correlation between the incidence of gallstones and high-sensitivity C reactive protein (22). This is similar to our finding that the prevalence of gallstones in women is positively correlated with ALI levels. Pro-inflammatory diets can increase systemic levels of inflammation, and several studies have found that increased intake of pro-inflammatory foods is linked to an elevated risk of gallstones (19, 22). High levels of circulating inflammatory proteins, such as IL-6, IL-10, IL-12 (p70), and IL-13, were linked to an elevated incidence of gallstones, according to a cross-sectional study by Liu et al. with 299 participants from Shanghai, China (8). In a case–control study, Hsing et al. found that variants in several genes influencing inflammatory responses were associated with gallstones (23). Our research shows a correlation between high levels of ALI and higher gallstones prevalence, this agrees with the findings described above.

Gallstone development is influenced by environmental and genetic risk factors (3, 24). Among these risk factors, inflammation and nutritional status have a substantial effect on gallstone formation. Albumin, as one of the indicators of nutritional status, was found to be statistically significant in our study in the difference between gallstone formers (3.95 ± 0.35) and non-gallstone formers (4.07 ± 0.34). However, the difference is not clinically significant in clinical practice. The ALI is obtained from BMI, albumin, and NLR calculations and is an all-encompassing representation of the body’s nutritional and inflammatory conditions. Elevated BMI, one of the indicators used to assess obesity, is independently correlated with gallstone formation (25, 26). Our study found that the mean BMI of gallstone formers was 33 kg/m², meaning they have obesity class I, which also supports the above conclusions. Obese state is an inflammatory state, which is also associated with gallstone formation. Obese patients usually have higher cholesterol and triglycerides (27). In turn, higher cholesterol and triglyceride levels are associated with an increased risk of gallstone disease (3). High levels of insulin in obese individuals can lead to increased cholesterol production by stimulating 3-hydroxy-3-methylglutaryl-coenzyme a reductase activity, which consequently raises gallstones risk (28, 29). Immune cells and multiple kinds of inflammatory cytokines are involved in gallstone formation. One study carried out on immunodeficient mice demonstrated a noteworthy rise in gallstone occurrence after the transfer of T lymphocytes (30). Neutrophils are more likely to trespass into the bile in an inflammatory state, and neutrophil extracellular traps formed by neutrophils and their extracellular DNA can promote gallstone formation by agglomerating calcium and cholesterol crystals (31). Our study found a significant gender difference in ALI and gallstones, with a more significant association in women. This may be related to gender differences in immune function. Compared to men, women have higher levels of estrogen in their bodies. The number of neutrophils is higher in high estrogen populations (32) and estrogens also modify cellular communication to enhance neutrophil activity (33). In turn, increased neutrophils can further promote gallstone formation through pathways such as neutrophil extracellular traps (31).

This study reveals a positive correlation between ALI and the prevalence of gallstones. Specifically, the prevalence of gallstones increased significantly when the ln-transformed ALI exceeded 4.39. This finding not only provides a new perspective for understanding the mechanism of gallstone formation, but also provides guidance for clinical practice. In clinical practice, special attention should be paid to screening and prevention of gallstones in patients with high ALI. Regular ultrasonography and other imaging tests are performed to aid in the early detection of gallstones, leading to timely intervention. We also found this relationship to be more pronounced in women. Therefore, in clinical practice, more attention should be paid to monitoring and controlling ALI in female patients, especially those with higher ALI, to reduce the risk of gallstones.

There are various advantages to this study. The relationship between ALI and gallstones is being examined for the first time in this study. The study is based on the NHANES database, which offers a more objective picture of the American people and has a bigger and more representative sample size. The study was adjusted for confounding covariates to guarantee more reliable findings. Additionally, in order to examine the strength of the correlation between gallstones and ALI in various groups, we conducted subgroup analyses. This study contains several restrictions. It was not possible to investigate a causal link between ALI and gallstones because the study was cross-sectional. Gallstone, diabetes, and hypertension diagnosis were based on questionnaires without objective exams, which made the diagnosis less objective. Although several covariates were considered in the study, we were unable to exclude the influence of all potential confounders such as genetics, hematological disorders, rapid weight loss, previous bypass surgeries, cholesterol, and triglycerides.

In this study, we found that ALI was positively associated with gallstones and that ALI had a higher effect on women’s gallstone prevalence. The findings suggest that early and effective management of ALI may reduce the prevalence of gallstones and have greater benefits for the female population. To validate the authors’ findings, larger prospective studies are still required.