Association between gastric abnormalities and cholelithiasis: a cross-sectional study

Authors

Abstract

AimThe study aims to reveal the relationship between the most common abnormalities of the upper digestive tract and cholelithiasis.
MethodsThis cross-sectional study included 7651 patients, of whom 14318 tested positive for Helicobacter pylori (H. Pylori). Patients who underwent abdominal ultrasonography (USG) and esophagogastroduodenoscopy (between January 2014 and June 2022) were included. The following gastroesophageal conditions were examined to determine whether they affect the risk of cholelithiasis: atrophic gastritis (AG), gastric polyps, esophagitis, bile reflux, gastric ulcers, gastric mucosal erosion, superficial gastritis, and gastric H. Pylori infection. Logistic regression was used to calculate the unadjusted and adjusted odds ratios (OR) of H. Pylori infection for cholelithiasis occurrence. In addition, we examined whether AG influences the association between cholelithiasis and H. Pylori infection.
ResultsA total of 8753 patients (61.1%) were diagnosed with cholelithiasis. Multivariate logistic regression analysis showed that H. Pylori infection (OR 1.28; 95% CI 1.10-1.42) and atrophic gastritis (OR 1.38; 95% CI 1.21-1.41) were significantly associated with cholelithiasis, as were age, female gender (OR 1.82; 95% CI 1.56-2.01), gastric polyps (OR 1.45; 95% CI 1.06-1.82). No additional interaction was observed between H. Pylori infection and AG; however, the overall effect on the risk of cholelithiasis was only slightly greater than the sum of the individual effects.
ConclusionGastric disorders, such as gastric polyps, H. Pylori infection, and AG, increase the risk of cholelithiasis. However, there was no association between the development of cholelithiasis and esophagitis, bile reflux, erosive gastritis, gastric ulcers, or superficial gastritis.

Keywords

Introduction

Cholelithiasis is a common digestive disease with a high incidence and relatively low mortality.¹ Cholelithiasis is one of the most common diseases and its prevalence is increasing worldwide.²
Although cholelithiasis is the result of a complex interaction of genetic, environmental, metabolic, and related conditions, factors such as advanced age and sex cannot be modified. Diet and physical activity may be modifiable risk factors.³
Although there are numerous studies on the risk factors of cholelithiasis, there is a lack of data on its association with benign diseases of the stomach.
One-third of detected cholelithiasis cases are symptomatic. Similar symptoms were observed in gastric pathologies. Although several studies have examined the relationship between Helicobacter pylori infection and the risk of cholelithiasis, the results are still controversial.^4,5 On the other hand, the relationship between gastric pathologies such as atrophic gastritis, superficial gastritis, gastric polyps, bile reflux, esophagitis with gallstone formation is unknown.
Today, the easy accessibility of esophagogastroduodenoscopy and ultrasonography procedures facilitates the diagnosis and treatment of gastric and gallbladder diseases.
Large population-based cohort studies are rare in the research literature on factors associated with gallstones.^5,6 Therefore, we performed a retrospective analysis of a database of 65451 patients who underwent esophagogastroduodenoscopy to identify possible associations between cholelithiasis and various upper gastrointestinal diseases. We also examined the effect of the association between atrophic gastritis and Helicobacter pylori infection in cholelithiasis.

Materials and Methods

Study ParticipantsWe conducted a cross-sectional study of patients who underwent esophagogastroduodenoscopy and ultrasonography at our facility between January 2014 and June 2022. During this period, 65451 patients underwent gastroscopy and 107218 patients underwent ultrasonography. We included 15840 patients with a maximum interval of six months between esophagogastroduodenoscopy and ultrasonography. For repeated endoscopies, only the initial data were considered.
We excluded 1522 patients for the following reasons:
1) If the time between esophagogastroduodenoscopy and ultrasonography was more than 6 months
2) Technically inadequate or incomplete endoscopy
3) Gastrointestinal surgery
4) Diagnosis revealed gastrointestinal tumors
5) Continuous proton pump inhibitor and anti-ulcer drug use
6) Diagnosis of acute cholecystitis, choledocholithiasis, and cholangitis
Finally, 14318 participants were included in the analysis. A patient flowchart is shown in Figure 1. Gastrointestinal tract endoscopic examinations were performed by specialized gastroscopists. The endoscopy center database contains descriptive endoscopic findings. The presence or absence of gastric mucosal atrophy, gastric polyps, esophagitis, bile reflux, gastric ulcers, gastric mucosal erosion, and superficial gastritis were considered significant gastric disorders. The diagnostic criteria for the listed disorders were based on endoscopic and pathological findings.
Ethical ApprovalThis study was approved by the Ethics Committee of Istanbul Medeniyet University (Decision Date: 22.07.2022, No: 254).
Analytical StatisticsCategorical data are summarized as frequency (%) and continuous variables as mean standard deviation. The chi-square test and Mann-Whitney U-test were used for group comparisons. Collinearity between the gastric variables was examined using variance inflation factors, and no correlation was found.
Univariate logistic regression analysis was used to determine the association between gastric outcomes and cholelithiasis. Variables with p<0.1 were then added to a multivariate analysis. Odds ratio and 95% confidence interval were used to determine results. Statistical significance was set at p<0.05. Data analysis was performed using R 4.1.2 and SPSS statistics version 23.
We also examined whether the combined effect of Helicobacter pylori infection or atrophic gastritis on cholelithiasis was greater than the sum of the individual effects of each factor. Individuals were divided into four groups according to their Helicobacter pylori and atrophic gastritis status: Helicobacter pylori (-) and atrophic gastritis (-), Helicobacter pylori (-), atrophic gastritis (+), Helicobacter pylori (+), atrophic gastritis (-), Helicobacter pylori (+) and atrophic gastritis (+). Using the Helicobacter pylori (-) and atrophic gastritis (-) groups as the reference analysis, we calculated the odds ratios of the other three categories. We assessed the occurrence of additional interactions by calculating the synergy index, attributable proportion due to interaction, and relative excess risk due to interaction. The 95% confidence interval of relative excess risk and attributable proportion were >0 and the 95% confidence interval of synergy index was >1, indicating a positive interaction; the 95% confidence interval of relative excess risk and attributable proportion included 0.⁷

Results

Common Features of the TopicsOf the 14318 registered cases, 8753 (61,1%) had cholelithiasis. Of the study population, 60.5% were female, and the mean age was 52,3 years.
Table 1 lists the clinical characteristics of the participants with cholelithiasis and the controls without cholelithiasis. Age is expressed as mean (SD), and all other data are expressed as number (proportion).
Compared with the group without cholelithiasis, patients with cholelithiasis were older and had a female-to-male sex ratio of 1.52. They also had higher rates of atrophic gastritis, esophagitis, alkaline bile reflux, gastric polyps, gastric ulcers, erosive gastritis, superficial gastritis, and Helicobacter pylori infection.
The findings of logistic regressions of the two study populations are shown in Table 2.
One included all 14318 study participants, while the other included 7651 cases with H. Pylori (+) data. Univariate analyses of the two populations were performed. All studies showed that the risk of cholelithiasis was significantly influenced by age, sex, gastric polyps, esophagitis, gastric ulcer, erosive gastritis, superficial gastritis, AG, and H. Pylori.
Multivariate analysis included all indicators of the univariate analysis (Table 2) (P <0.1). The findings showed that age, sex, gastric polyps, H. Pylori infection, and AG were independent risk factors for cholelithiasis. We also performed a trend test and stratified age into four quartiles with 10-year intervals. An OR of 3.27 (95% CI, 2.82-3.96) (P for trend 0.001) was observed in those in the highest age quartile (> 60) (Table3).
The incidence of cholelithiasis was 27.5% in AG (-) and H. Pylori (-) patients, 34,9% in H. Pylori (+) and AG (-) patients, 44,9% in AG (+) and H. Pylori (-) patients, and 55.6% in AG (+) and H. Pylori (+) patients. People with AG (OR: 1.78, 95% CI: 1.56-2.05) had a higher incidence of cholelithiasis than people without atrophy and without H. Pylori infection, while people with H. Pylori infection (OR: 1.13, 95% CI: 0.99-1.30) had a lower incidence of cholelithiasis.
However, the relative excess risk attributed to the interaction was not statistically significant (RR: 0.14 (-0.31-0.55), AP: 0.07 (-0.14-0.26), SI: 1.14 (0.72-1.71). In addition, H. Pylori infection and AG were associated with a high risk of developing cholelithiasis.

Discussion

In this study, the ultrasonography and typical esophagogastroduodenoscopy findings of 14318 individuals were compared. These findings suggest that individuals with sex, age, gastric polyps, atrophic gastritis, and Helicobacter pylori infection have an increased risk of developing cholelithiasis. In addition, individuals with concurrent atrophic gastritis and Helicobacter pylori infections may have an even higher chance of developing cholelithiasis.
Recently, the link between Helicobacter pylori infection and cholelithiasis has attracted the attention of several researchers.^8,9,10 However, these results have not yet been conclusive. Although a number of studies have found a link between Helicobacter pylori and cholelithiasis, other studies have found no link between the two.^11,12 We hypothesized that these inconsistent findings may be partly related to the various Helicobacter pylori detection techniques, geographic regions, racial groups, and small sample sizes. Based on 477293 individuals in a nationwide database, a very large prospective analysis was performed to evaluate the association between cholelithiasis and the effect of gastric acid-suppressive drugs on gallbladder histology. The results showed an association with increased gallstone formation,¹³ whereas a retrospective cohort of 27881 individuals preliminarily evaluated the presence of Helicobacter pylori and concluded that it may not be associated with the development of gallstones.¹⁴
According to a previous study, the risk of developing cholelithiasis was higher in people with intestinal metaplasia, gastric polyps, and Helicobacter pylori infection, and findings showed that atrophic gastritis is an important parameter for cholelithiasis.¹⁵
Recently, it has been hypothesized that Helicobacter pylori infection is associated with a higher risk of developing cholelithiasis when coexisting with chronic atrophic gastritis.¹⁶ In our study, we found that the combined effects of Helicobacter pylori infection and atrophic gastritis on cholelithiasis were only slightly greater than those of each factor individually. Therefore, we hypothesized that Helicobacter pylori and atrophic gastritis may interact together and conducted additional research to support this hypothesis. Therefore, we performed additional tests for erosive and superficial gastritis. Although our data showed a positive additive interaction between these two factors and the likelihood of cholelithiasis, this was not statistically significant. However, we still recommend, especially in patients with atrophic gastritis, that Helicobacter pylori eradication may reduce the prevalence of cholelithiasis; however, this needs to be confirmed in the future.¹⁷ In addition, cholelithiasis was independently linked to atrophic gastritis without Helicobacter pylori infection but not solely to Helicobacter pylori infection alone.
As most atrophic gastritis cases are typically caused by Helicobacter pylori infection, prolonged Helicobacter pylori infection may be more important for the development of cholelithiasis.
Other theories have been proposed to explain the mechanisms underlying the association between Helicobacter pylori infection and cholelithiasis. First, Helicobacter pylori infection and atrophic gastritis cause hypergastrinemia, which may help in the development of cholelithiasis by promoting gallbladder mucosal damage.¹⁸ Some studies have found a link between gastrin and cholelithiasis, while others have found the opposite.^19,20 Second, persistent Helicobacter pylori infection causes chronic atrophic gastritis by reducing acid secretions. Low gastric acid levels can alter the gastrointestinal microbiota and cause bacterial overgrowth, which may contribute to the development of cholelithiasis.^20,21
Several studies have revealed that the detection rate of Helicobacter pylori in cholecystectomy is higher than in normal mucosa.^21,22 Consequently, Helicobacter pylori may locally trigger cholelithiasis by contacting the mucosa.
In a cohort study, the prevalence of cholelithiasis was higher in individuals with gastric polyps.²² However, the mechanisms involved remain unclear. The majority of gastric fundic gland polyps, which constitute the majority of gastric polyps, are symptoms associated with long-term proton pump inhibitor therapy.²³ Polyps may develop as a result of a decrease in the gastric acid barrier. Gastric polyps are closely associated with Helicobacter pylori infection and atrophic gastritis; however, the physiopathologic explanation for this association is still unclear.²⁴ Another hypothesis is that lifestyle, environmental and hereditary factors may significantly influence the mechanism underlying this association.²⁴ In our study, the presence of gastric polyps was more common in patients with Helicobacter pylori, and a significant association with cholelithiasis was found in parallel.
We understand that the risk of cholelithiasis is higher in females and older participants. Similarly, our study found that women were more likely to develop cholelithiasis than men were. In addition, the prevalence of cholelithiasis increases over time with age, with the highest odds ratio (3.27; 95% confidence interval: 2.82-3.96) seen in the older age group.
Therefore, it is necessary to discuss possible flaws in this study. First, because the present analysis is based on histological diagnoses and endoscopic findings, there may be subjectivity and diagnostic variability among observers. Although the lesions were described on endoscopy, the endoscopists did not biopsy every lesion. However, our endoscopists applied a standardized algorithm that enabled them to report similar interpretations on similar images.
Second, because the study was retrospective, we were unable to collect data on dietary patterns, lifestyle choices, medical history, substance use, and other confounding variables, but in other studies these confounding variables have had little or no effect on these associations.²⁵ Third, we used data from only one data center; therefore, different groups should establish the generalizability of our findings. Despite these drawbacks, our study is the first to examine the link between cholelithiasis and endoscopically detected gastric abnormalities using a large sample size.
Independent risk factors for cholelithiasis include gastrointestinal diseases such as gastric polyps, Helicobacter pylori infection, and atrophic gastritis. In addition, the combination of atrophic gastritis and Helicobacter pylori infections may cause a marginal increase in the risk of developing cholelithiasis. However, it is likely that the presence of cholelithiasis is not associated with conditions such as esophagitis, bile reflux, gastric mucosal erosion, gastric ulcers, and superficial gastritis. Therefore, screening ultrasonography should be considered when individuals are found to have gastric polyps, atrophic gastritis, or Helicobacter pylori infection after esophagogastroduodenoscopy.

Declarations

References

1. Dan WY, Yang YS, Peng LH, Sun G, Wang ZK. Gastrointestinal microbiome and cholelithiasis: current status and perspectives. World J Gastroenterol. 2023;29(10):1589-1601. doi:10.3748/wjg.v29.i10.1589
   Article PubMed Google Scholar
2. Pak M, Lindseth G. Risk factors for cholelithiasis. Gastroenterol Nurs. 2016;39(4):297-309. doi:10.1097/sga.0000000000000235
   Article PubMed Google Scholar
3. Fatemi SM, Doosti A, Shokri D, et al. Is there a correlation between Helicobacter pylori and enterohepatic Helicobacter species and gallstone cholecystitis? Middle East J Dig Dis. 2018;10(1):24-30. doi:10.15171/mejdd.2017.86
   Article PubMed Google Scholar
4. Hjaltadottir K, Haraldsdottir KH, Moller PH. Gallstones: review. Laeknabladid. 2020;106(10):464-472. doi:10.17992/lbl.2020.10.602
   Article PubMed Google Scholar
5. Di Ciaula A, Garruti G, Frühbeck G. The role of diet in the pathogenesis of cholesterol gallstones. Curr Med Chem. 2019;26(19):3620-3638. doi:10.2174/0929867324666170530080636
   Article PubMed Google Scholar
6. Patel AM, Yeola M, Mahakalkar C. Demographic and risk factor profile in patients of gallstone disease in central India. Cureus. 2022;14(5). doi:10.7759/cureus.24993
   Article PubMed Google Scholar
7. Toneyan S, Tang Z, Koo PK. Evaluating deep learning for predicting epigenomic profiles. Nat Mach Intell. 2022;4(12):1088-1100. doi:10.1038/s42256-022-00570-9
   Article PubMed Google Scholar
8. Kunnuru SKR, Kanmaniyan B, Thiyagarajan M, Singh BK, Navrathan N. A study on efficacy of UGI scopy in cholelithiasis patients before laparoscopic cholecystectomy. Minim Invasive Surg. 2021;2021:8849032. doi:10.1155/2021/8849032
   Article PubMed Google Scholar
9. Zhang FM, Yu CH, Chen HT, et al. Helicobacter pylori infection is associated with gallstones: epidemiological survey in China. World J Gastroenterol. 2015;21(29):8912-8919. doi:10.3748/wjg.v21.i29.8912
   Article PubMed Google Scholar
10. Ari A, Tatar C, Yarikkaya E. Relationship between Helicobacter pylori positivity in the gallbladder and stomach and effect on gallbladder pathologies. J Int Med Res. 2019;47(10):4904-4910. doi:10.1177/0300060519847345
    Article PubMed Google Scholar
11. Wang L, Chen J, Jiang W, et al. The relationship between Helicobacter pylori infection of the gallbladder and chronic cholecystitis and cholelithiasis: a systematic review and meta-analysis. Can J Gastroenterol Hepatol. 2021;2021:8886085. doi:10.1155/2021/8886085
    Article PubMed Google Scholar
12. Dellon ES, Hirano I. Epidemiology and natural history of eosinophilic esophagitis. Gastroenterology. 2018;154(2):319-332. doi:10.1053/j.gastro.2017.06.067
    Article PubMed Google Scholar
13. Yang M, Xia B, Lu Y, et al. Association between regular use of gastric acid suppressants and subsequent risk of cholelithiasis: a prospective cohort study of 0.47 million participants. Front Pharmacol. 2022;12:813587. doi:10.3389/fphar.2021.813587
    Article PubMed Google Scholar
14. Zhang J, Zhang Y, Chen Y, Chen W, Xu H, Sun W, et al. Helicobacter pylori is not a contributing factor in gallbladder polyps or gallstones: a case-control matching study of Chinese individuals. J Int Med Res. 2020;48(10):300060520959220. doi:10.1177/0300060520959220
    Article PubMed Google Scholar
15. Santos MLC, de Brito BB, da Silva FAF, et al. Helicobacter pylori infection: beyond gastric manifestations. World J Gastroenterol. 2020;26(28):4076-4093. doi:10.3748/wjg.v26.i28.4076
    Article PubMed Google Scholar
16. Grigor’eva IN, Romanova TI. Gallstone disease and microbiome. Microorganisms. 2020;8(6):835. doi:10.3390/microorganisms8060835
    Article PubMed Google Scholar
17. Lee SH, Jang DK, Yoo MW, et al. Efficacy and safety of ursodeoxycholic acid for the prevention of gallstone formation after gastrectomy in patients with gastric cancer: the PEGASUS-D randomized clinical trial. JAMA Surg. 2020;155(8):703-711. doi:10.1001/jamasurg.2020.1501
    Article PubMed Google Scholar
18. Sharndama HC, Mba IE. Helicobacter pylori: an up-to-date overview on the virulence and pathogenesis mechanisms. Braz J Microbiol. 2022;53(1):33-50. doi:10.1007/s42770-021-00675-0
    Article PubMed Google Scholar
19. Faridi MS, Jaiswal MS, Goel SK. Expression of CCK receptors in carcinoma gallbladder and cholelithiasis: a pilot study. J Clin Diagn Res. 2015;9(7). doi:10.7860/jcdr/2015/12697.6152
    Article PubMed Google Scholar
20. Guraya SY, Ahmad AA, El-Ageery SM. The correlation of Helicobacter pylori with the development of cholelithiasis and cholecystitis: the results of a prospective clinical study in Saudi Arabia. Eur Rev Med Pharmacol Sci. 2015;19(20):3873-3880.
    PubMed Google Scholar
21. Carmack SW, Genta RM, Schuler CM, Saboorian MH. The current spectrum of gastric polyps: a 1-year national study of over 120,000 patients. Am J Gastroenterol. 2009;104(6):1524-1532. doi:10.1038/ajg.2009.139
    Article PubMed Google Scholar
22. Cen L, Wu J, Zhu S, et al. The potential bidirectional association between Helicobacter pylori infection and gallstone disease in adults: a two-cohort study. Eur J Clin Invest. 2023;53(2). doi:10.1111/eci.13879
    Article PubMed Google Scholar
23. Svistunov AA, Osadchuk MA, Mironova ED, Guliaev PV, Vasileva IN. Ter Arkh. 2022;94(2):194-199.
    PubMed Google Scholar
24. Abraham SC, Singh VK, Yardley JH, Wu TT. Hyperplastic polyps of the stomach: associations with histologic patterns of gastritis and gastric atrophy. Am J Surg Pathol. 2001;25(4):500-507. doi:10.1097/00000478-200104000-00010
    Article PubMed Google Scholar
25. Li L, Tan J, Liu L, Li J, Chen G, et al. Association between H pylori infection and health outcomes: an umbrella review of systematic reviews and meta-analyses. BMJ Open. 2020;10(1). doi:10.1136/bmjopen-2019-031951
    Article PubMed Google Scholar

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About This Article

Received:

October 18, 2023

Accepted:

November 20, 2023

Published Online:

January 3, 2024

Printed:

February 1, 2024