Prevalence of Gallstones in Ulcerative Colitis and Crohn’s Disease: A Systematic Review and Meta-Analysis

The meta-analysis aimed to investigate the prevalence of gallstones (GS) in Inflammatory bowel disease (IBD), especially ulcerative colitis (UC). A systematic and thorough search was conducted on online electronic databases (PubMed/Medline, Cochrane Library, and Google Scholar) from the databases' inception to April 30th, 2022. Review Manager 5.4.1 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen) was used for all statistical analyses and forest plots. Only studies that met inclusion criteria were selected. The selected studies were pooled using a random-effect model and the results were reported in the odds ratio (OR) with their corresponding 95% confidence interval (CI). Ten studies met the final inclusion criteria and were analyzed. Patients with UC had significantly higher prevalence of GS than those in the control group (OR=1.67 [1.32-2.11]; p < 0.0001; I2=58%). There was also significant prevalence of GS in Crohn’s disease (CD) than those in control group (OR=2.22 [1.82, 2.69]; p < 0.00001; I2=31%). Analysis also showed the prevalence of GS in studies conducted in Asia (OR=2.00 [1.48, 2.70]; p < 0.00001; I2=80%) and Europe (OR= 1.84 [1.32, 2.55]; p = 0.0003; I2=45%) compared to the control group. This study provided a conclusive answer to whether GS is significant in UC or not. Our meta-analysis provides a well-powered estimate that there is a prevalence of GS in UC. CD is also significantly associated with GS.


Introduction And Background
Inflammatory bowel disease (IBD) has been a global healthcare problem [1]. Studies estimate that 2.5-3 million people suffer from IBD in Europe [2]. The health economic burden and permanent work disability due to IBD is high in Europe, with a total yearly direct healthcare cost of 4.6-5.6 billion euros [3]. IBD is a hypernym of Crohn's Disease (CD) and ulcerative colitis (UC), which are distinct chronic bowel-relapsing inflammatory disorders [4]. UC affects the superficial mucosa, starting with the rectum, in a continuous pattern and is limited to the colon. CD is characterized by transmural inflammation that can affect any part of the GI tract from mouth to anus [2]. IBD has been associated with several extra-intestinal manifestations seen in 25% to 40% of patients with IBD patients, including peripheral arthritis, erythema nodosum, and episcleritis [5]. Those involving the extrahepatic biliary tract include gallstone disease [6].
The relationship between GS and CD has been well recognized since the 1960s, and this prevalence of CD has been estimated to be 13-14%, as reported in different series [7][8][9][10] but this same relation is subjected to variability when assessing UC. A meta-analysis by Zhang et al. clearly established a relationship between GS and CD but showed no significant association with UC [11]. Since this meta-analysis, a number of other observational studies have been published that presented varying associations of GS between UC and CD. Therefore, we aim to pool all the published data assessing the prevalence of gallstones in UC and CD separately to remove existing discrepancies amongst studies.
In the previous meta-analysis [11], studies included were from areas located in Europe. However, the epidemiology of this disease in Westernized nations is changing throughout the world at the turn of the 21st century [12]. Now, newer epidemiological studies suggest that incidence might be rising rapidly in South America, Eastern Europe, Asia, and Africa [13]. Any interruption in excretion and reabsorption of bile acids from the gut can result in the precipitation of gallstones [14][15][16]. Thus, an updated meta-analysis is conducted, which includes studies from other parts of the world, including Asia. The previous metaanalysis was limited by the fact that it included studies with smaller samples [11]. So we aimed to conduct an updated meta-analysis with recent studies having a much larger sample size for better, robust, and more reliable results.
The primary objective of this updated meta-analysis is to find out the prevalence of GS in patients with CD and UC. The secondary objective is to investigate if there is any geographical significance in the association of GS.

Search Strategy and Databases
Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) guidelines and protocols were followed for conducting this meta-analysis [17]. An online electronic search from databases namely, PubMed/Medline, Cochrane Library, and Google Scholar was conducted from the inception of databases to April 30th, 2022 with only English language-based literature. In addition, studies that were cited by previous meta-analyses, cohort studies, and review articles were screened as well to identify any relevant studies. A detailed literature search is provided in Table 1.

Search Engine Search Strategy
Pubmed/Medline

Quality Assessment and Data Extraction From Selected Studies
Two reviewers independently performed a literature search from electronic databases and a third author was consulted to resolve any discrepancies. References of the papers were exported to the EndNote Reference Library v.X7 (Clarivate Analytics, London) and duplicates were identified and removed.
Two separate reviewers independently extracted data and assessed the quality of included studies. Newcastle-Ottawa Scale (NOS) was used to assess the quality of the selected studies. A score >6 was considered a low bias and a score 6 or less was deemed as a significant bias.

Statistical Analysis
All statistical and analytical tests were performed using Review Manager v. 5.4.1 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen). All the extracted data from selected studies were pooled using random-effects model. Analyses of results were done by calculating the odds ratio (OR) with corresponding 95% confidence intervals (CI). Leave-one-out sensitivity analysis was done to see if any study had a significant effect on overall results. As per the Cochrane handbook, the value of heterogeneity I 2 = 25-60% was considered as moderate; 50-90% as substantial; and 75-100% as considerably high heterogeneity, and p <0.1 indicated significant heterogeneity [18]. A p-value of less than 0.05 was considered significant for all analyses. The chi-square test was used to assess any differences between the subgroups.

Literature Search Results
The initial literature search from the electronic online databases brought up 1,060 potential research studies. After removal of duplicates and exclusions based on titles and abstracts, the full text of 112 studies was read for possible inclusion. A total of 10 studies remained for quantitative analysis. The summary and results of literature search are given in Figure 1.

Publication Bias
No publication bias was noted in our meta-analysis on inspection of the funnel plot as shown in Figure 2.

Quality Assessment of Included Studies
Quality assessment for observational studies was done by Newcastle-Ottawa Scale. All the studies were of high quality and had a low risk of bias. Detailed assessment with individual components is shown in Table 3.    (iii) Geographical location: Out of 10 studies, four were from Asia (three were from the Republic of Korea and one from Taiwan), and five were from Europe (three were from Italy, one from the Slovak Republic, one from Sweden, and one from the United Kingdom). Analysis ( Figure 5)

Sensitivity Analysis
A sensitivity analysis was conducted to assess the influence of each study on the overall effect by excluding one study at a time, followed by the generation of pooled OR for the rest of the studies. It is vital to note that Yang et al. had around a million population in its study but still removing it in ulcerative colitis (OR= ) did not change the overall outcome which showed that the outcome was not influenced by this study [24]. On leave-one-out analysis, no significant change was seen in the p-value after removing studies one by one. This showed that the results were robust.

Discussion
This 53,542 IBD patients' analysis shows an instrumental result regarding the prevalence of GS in IBD patients. Although a previously published meta-analysis by Zhang et al. (2015) has explored this association, their results were limited by the small sample size (1,439 IBD patients). It also failed to establish any significant association between GS and UC [11].
A very prominent finding in our analysis is the association between GS and UC. Some articles have suggested and presented a statistically significant prevalence of GS in UC [8], but no previous meta-analysis has confirmed this outcome. This analysis provides a well-established result, highlighting the prevalence of GS in CD and UC. Based on our findings, it is suggestive that IBD patients have a risk of developing GS. Physicians should provide medication and proper lifestyle modification, which will improve the quality of life of IBD patients and act as prophylaxis for GS prevention.
It is pivotal to provide reasons for GS in CD and UC. Enterohepatic circulation is responsible for the excretion of bile acids by the liver into the small intestine, and then cholesterol is excreted through bile [14]. Any interruption in the mechanism of excretion and reabsorption of bile acids from the intestine results in the precipitation of gallstones. CD disrupts the enterohepatic circulation in the terminal ileum and can slow down the gallbladder contractility; therefore, it can lead to the formation of gallstones [15,16].
Several controversial studies show different results regarding the prevalence of GS in UC; however, a study conducted by Holmquist et al. showed that an affected ascending colon in UC could increase fecal bile excretion; therefore, loss of excess bile will result in precipitation of GS [26]. Several studies also showed gallstone development following the colectomy for UC [27], suggesting that the colon plays a minor role in bile reabsorption. However, the mechanism in the development of GS in UC is still disputed.
The studies showed the influence of the geographical variations of GS prevalence in IBD, highlighting the increasing incidence of GD in the Asia and Europe region [12][13]. Although no large-scale and diverse studies have been conducted that can profoundly state regional influence on GS. Our subgroup analysis shows that there is statistical significance in regions of Asia and Europe for the presence of GS.
Based on our findings, it is suggestive that IBD patients have a risk of developing GS, which ultimately leads to complications such as choledocholithiasis, acute cholangitis, and gallstone ileus, which in some cases can be life-threatening as it may proceed to acute biliary pancreatitis and gallbladder carcinoma [28]. This research will help physicians to better manage IBD patients for future occurrence of GS by an annual screening of the gallbladder via ultrasound. Also, physicians can prophylactically administer IBD patients with lipid-lowering agents such as statin drugs, along with a restricted cholesterol diet. A selected subgroup of patients with asymptomatic gallstones but who are at high risk of developing symptoms of gallbladder cancer or biliary pancreatitis can also be managed by prophylactic cholecystectomy [28].
Our study is limited by some factors such as (a) all studies were observational in nature, the results of which can have some bias (b) controls selected by some studies were based on hospital settings which might have overestimated gallstone formation. Further research is needed especially with more randomized studies.

Conclusions
This study provides a conclusive answer to whether GS is significant in UC or not. Our meta-analysis provides a well-powered estimate that there is a prevalence of GS in UC. CD is also significantly associated with GS. Although patients of CD and UC have overlapping clinical symptoms, patients with predominant UC symptoms also have a possibility of gallstones and should be kept in mind when presenting with right upper quadrant pain and other symptoms of cholelithiasis.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.