Prevalence and risk factors of gallstone disease in Korean patients with ulcerative colitis
Article information
Abstract
Background/Aims
The prevalence of gallstone disease in patients with ulcerative colitis (UC) is higher than in the general population. However, risk factors of gallstone disease in these patients remain unclear. Thus, we investigated the prevalence and risk factors of gallstone disease in Korean patients with UC.
Methods
Patients diagnosed with UC who underwent abdominal imaging studies between 1997 and 2020 were investigated using a well-established referral center-based large volume inflammatory bowel disease cohort. The prevalence and clinical characteristics of patients with gallstone disease were evaluated and compared with those without gallstone disease.
Results
Overall, 2,811 patients with UC were enrolled. During the follow-up period (mean, 5.7 years), 198 patients (7.0%) were diagnosed with gallstone disease and compared with those without gallstone disease (n = 2,613). The proportion of extensive colitis at maximum extent, primary sclerosing cholangitis (PSC), history of cytomegalovirus, corticosteroid use, immunomodulatory use, colectomy, and appendectomy were significantly higher in the gallstone group (all P<0.05). In multivariate analyses, age ≥ 60 years at gallstone evaluation (odds ratio [OR], 1.027; 95% confidence interval [CI], 1.002–1.052; P= 0.033), PSC (OR, 6.304; 95% CI, 3.162–12.565; P<0.001), and history of colectomy (OR, 2.494; 95% CI, 1.222–5.087; P= 0.012) were significant risk factors for gallstone disease in patients with UC.
Conclusions
The prevalence of gallstone disease in Korean patients with UC was 7.0%, and age ≥ 60 years at gallstone evaluation, PSC, and history of colectomy were significant risk factors for UC patients with gallstone disease.
INTRODUCTION
Inflammatory bowel disease (IBD), which consists of Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of unknown cause with a clinical course of relapse and remission that involves the gastrointestinal tract. The incidence and prevalence of IBD in Asia have been gradually increasing during recent decades [1,2]. IBD is a systemic disorder that can involve organs other than the gastrointestinal tract, which is called extraintestinal manifestation (EIM). The prevalence of EIM was reported to be 46.6% in patients with IBD in Western countries and was much lower in a recent multinational Asian study (11.3%) [3]. Musculoskeletal manifestations are the most common EIM, followed by skin, eye, hepatobiliary, and vascular manifestations. Primary sclerosing cholangitis (PSC) is a well-known hepatobiliary EIM and more common in patients with UC than CD. PSC in patients with UC is significantly associated with poor outcomes such as pancolitis, colorectal cancer, and cholangiocarcinoma [4-7].
Up to 50% of patients with IBD could be affected by hepatobiliary EIM [4], and gallstone disease is one of the common manifestations [8]. Previous studies reported a higher prevalence of gallstone disease in patients with IBD compared to the normal population [9-14]. The association between gallstone disease and CD has been studied more often compared with UC. A higher prevalence of gallstone disease has been reported in patients with CD compared to healthy controls (1.8%–34.2% vs. 0.7%–14.9%) [14]. In patients with CD, decreased bile acid reabsorption in the terminal ileum, the most commonly involved area in CD, causes a decreased bile acid pool leading to cholesterol super-saturation [15]. However, inconsistent results and considerable regional variation have been reported for the association between UC and gallstone disease [14,16]. In addition, different risks according to the disease extent of UC (extensive colitis vs. proctitis or left-sided colitis) had been reported, suggesting the need for more detailed evaluations [11].
Thus, in this study, we investigated the prevalence of gallstone disease and evaluated risk factors in Korean patients with UC using a well-established IBD registry.
METHODS
1. Patients and Study Design
This was a retrospective study based on a well-characterized tertiary referral center-based large cohort of patients with IBD in Korea (Asan IBD registry). Medical records including demographic and clinical data associated with IBD and gallstones were reviewed. Patients diagnosed with UC and who underwent at least one more imaging studies that could detect gallstones (e.g., abdominal ultrasonography, abdominopelvic computed tomography, and magnetic resonance imaging) at the time of and after diagnosis of UC between January 1997 and March 2020 were reviewed. Abdominal imaging studies were performed at the discretion of the attending clinician considering the patients’ clinical symptoms or disease status. Patients who were already diagnosed with gallstone disease before the diagnosis of UC were excluded. The study protocol was reviewed and approved by the Asan Medical Center Institutional Review Board (IRB No. 2020-0854). The requirement for written informed consent was waived because of the retrospective nature of this study.
2. Variables and Outcomes
Demographic and clinical features of the included patients were investigated at the time of diagnosis of UC and evaluation of gallstones. A diagnosis of UC was based on the conventional clinical, radiologic, endoscopic and histopathologic criteria, consistent with previous studies [17-19]. The maximum disease extent of UC at gallstone evaluation was classified as proctitis (E1), left-sided colitis (E2), and extensive colitis (E3), according to the Montreal classification [19]. Standard treatment policies for UC in our center were basically the step-up approach, as described previously [20,21].
The primary study outcome was to investigate the prevalence of gallstone disease in patients with UC who underwent abdominal imaging studies, and evaluate the risk factors of gallstone disease in patients with UC. Immunosuppressive agents used after the diagnosis of UC were classified as follows: corticosteroids (orally or intravenously administered systemic prednisolone or methylprednisolone; a daily dose equivalent to ≥ 20 mg of prednisolone for ≥ 4 weeks), immunomodulators (azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, or tacrolimus), and biologics or small molecules (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, or tofacitinib). The use of topical budesonide was excluded from corticosteroid use considering its localized effect. Surgical history from UC diagnosis, such as colectomy and appendectomy, was also reviewed.
3. Statistical Analysis
Continuous variables were presented as the mean ± standard deviation and analyzed using the t-test. Categorical variables were presented as numbers with percentages and analyzed using the chi-square test or Fisher exact test. Logistic regression analyses were performed to evaluate the risk factors of gallstone development. Kaplan-Meier analysis with a log-rank test was performed to evaluate the trend of gallstone development during the follow-up period. All statistical analyses were performed using SPSS (version 27.0; SPSS Inc., Chicago, IL, USA). P-values < 0.05 were considered statistically significant.
RESULTS
1. Demographics and Baseline Characteristics
Overall, 2,811 patients diagnosed with UC who underwent abdominal imaging studies for gallstone evaluation were enrolled. During the follow-up period (mean, 5.7 ± 6.6 years), gallstone disease developed in 198 patients (7.0%) (Fig. 1). The mean age at UC diagnosis and gallstone evaluation was significantly higher in patients with gallstone development compared with those without gallstone development (age at UC diagnosis: 45.3 years vs. 38.8 years; age at gallstone development: 53.1 years vs. 44.0 years; all P<0.001). Proportions of extensive colitis in maximum extent, and PSC were significantly higher in the gallstone development group compared with the no gallstone development group (all P<0.05). In addition, proportions of patients with a history of cytomegalovirus infection, systemic corticosteroids use, colectomy, and appendectomy were significantly higher in the gallstone development group compared with the no gallstone development group (all P<0.05). In contrast, the proportion of patients with a history of immunomodulator use was significantly higher in the no gallstone development group compared with the gallstone development group (P=0.002) (Table 1).
Study flowchart. IBD, inflammatory bowel disease; UC, ulcerative colitis.
Baseline Demographic and Clinical Characteristics of Patients Enrolled in This Study
2. Factors Associated with Gallstone Development in Patients with UC
In the univariate analyses, age at UC diagnosis (odds ratio [OR], 1.028; 95% confidence interval [CI], 1.018–1.038; P<0.001), age ≥ 60 years at gallstone evaluation (OR, 1.037; 95% CI, 1.027–1.046; P<0.001), extensive colitis in maximum extent at gallstone evaluation (OR, 1.808; 95% CI, 1.292–2.528; P=0.001), PSC (OR, 4.212; 95% CI, 2.400–7.390; P<0.001), history of cytomegalovirus infection (OR, 1.768; 95% CI, 1.071–2.918; P=0.026), history of steroid use (OR, 1.380; 95% CI, 1.022–1.864; P=0.036), history of immunomodulator use (OR, 0.589; 95% CI, 0.419–0.828; P=0.002), history of colectomy (OR, 5.180; 95% CI, 3.743–7.170; P<0.001) and history of appendectomy (OR, 4.009; 95% CI, 2.881–5.578; P<0.001) were significantly associated factors. Finally, in multivariate analyses, age ≥ 60 years at gallstone evaluation (OR, 1.027; 95% CI, 1.002–1.052; P=0.033), PSC (OR, 6.304; 95% CI, 3.162–12.565; P<0.001) and history of colectomy (OR, 2.494; 95% CI, 1.222–5.087; P=0.012) were significantly associated with gallstone development in patients with UC (Table 2).
Associated Factors of Gallstone Disease in Patients with UC
3. Cumulative Risk of Gallstone Development during the Follow-up Period
The rate of gallstone development steadily increased during the follow-up period (mean, 5.73 ± 6.63 years) as shown by the Kaplan-Meier analyses (Fig. 2A). There was no significant difference in the cumulative risk of gallstone development between the age groups ( ≥ 60 years vs. < 60 years) (P=0.843) (Fig. 2B), whereas there were significant differences related the PSC and history of colectomy (all P<0.001) (Fig. 2C and D).
Cumulative risk of gallstone development in patients with ulcerative colitis and comparisons according to risk factors (long-rank test). (A) Overall patients, (B) patients aged ≥60 years (P=0.843), (C) patients with PSC (P<0.001), and (D) patients with a history of colectomy (P<0.001).
DISCUSSION
In this study, the prevalence of gallstone development in patients with UC was 7.0%. In multivariate analyses, age ≥ 60 years at gallstone evaluation, PSC, and history of colectomy were significant risk factors for gallstone disease in patients with UC during the follow-up period. In addition, there was a significant cumulative risk of gallstone development in patients with PSC and a history of colectomy compared to those without these factors during the follow-up period.
Gallstone disease is one of the most common gastrointestinal health problems. In the general population, risk factors of gallstones include aging (i.e., ≥ 50 years), female sex, ethnicity/race (i.e., white, American), medications (e.g., estrogen, lipid-lowering drugs, somatostatin analogs), rapid weight loss, obesity, and dyslipidemia. Abnormal bile acid composition is the main pathophysiology of gallstone formation. Cholesterol and pigment stones are the 2 main subtypes and they have somewhat different risk factors. In general, the prevalence of gallstone disease is higher in Western countries (10%–15%) compared to Asian countries (3%–10%), and is increasing due to increased aging populations, changes in dietary and lifestyle habits, and increased use of screening imaging studies. The prevalence of gallstones in the Korean general population was reported to be 2.4% in a recent nationwide population-based cohort study, which is much lower than that in our study of patients with UC (7.0%) [22]. In addition, older age ( ≥ 60 years) at gallstone evaluation was a significant risk factor for gallstone development in patients with UC (OR, 1.027), whereas female sex was not significant in this study.
In previous studies, a higher prevalence of gallstone disease in patients with CD was reported. Bile acid reabsorption mainly takes place in the terminal ileum; thus, ileal CD might cause abnormalities in the enterohepatic circulation of bile acids and fat digestion/absorption. In a previous study, terminal ileum involvement was reported to be a risk factor for gallstones in patients with CD (OR, 4.5; 95% CI, 1.5–14.1; P=0.009) [11]. In contrast, there are conflicting results on the prevalence of gallstone disease in patients with UC. Unlike CD, terminal ileum is rarely involved even in patients with extensive colitis except in case of backwash ileitis; however, unconjugated bile acid could be absorbed by diffusion in the colonic mucosa. Thus, severe colonic damage due to longstanding extensive colitis or history of colectomy itself might significantly impede bile acid absorption, and a higher prevalence and increased risk for gallstone disease in patients with UC was also reported [23]. In case-control studies in Korea, the prevalence of gallstones was higher in the UC group compared to the control group (8%–14% vs. 3%–4%), and old age ( ≥ 65 years) and hospitalization ( ≥ 3 times) were suggested to be significant risk factors for gallstone disease in the UC group [9,10]. In contrast, staged ileal pouch-anal anastomosis (IPAA) following colectomy in patients with UC was not regarded to be a risk factor of gallstone formation. In a case-control study using a national UC cohort from Denmark, colectomy was associated with an increased risk of gallstone disease and undergoing cholecystectomy, whereas IPAA was not associated with gallstone disease in patients who underwent colectomy for UC [23].
PSC is a chronic progressive inflammatory disease that causes bile duct sclerosis and obliteration. The prevalence of IBD-PSC ranges from 2% to 8% [24]. The exact pathogenesis of PSC combined with IBD has been poorly understood, but genetic susceptibility, immune-mediated pathway, altered bile acid homeostasis, and gut dysbiosis were suggested mechanism of pathophysiology [25]. It is a well-known risk factor for poor outcomes in patients with IBD [4,25]. Extensive colitis, backwash ileitis, rectal sparing, and increased risk of colorectal cancer and cholangiocarcinoma were more common in patients with UC and PSC compared with patients with UC only [8]. In contrast, a recent Korean nationwide population-based long-term study showed that the incidence of colorectal cancer in patients with UC and accompanied PSC was not significantly different compared with those without PSC, suggesting the need to consider different clinical features between Asian and Western countries [6,7,26,27]. In general, gallstone disease is more common in patients with PSC showing a higher prevalence (25%) compared with that of the normal population [28]. Thus, patients with UC and PSC are likely to be at high-risk for gallstone disease, which is consistent with our findings (OR, 6.304). Considering the high-risk of gallbladder or biliary tract cancer associated with gallstones in patients with PSC, early evaluation using regular abdominal imaging studies and subsequent cholecystectomy is a practical option for patients with UC and PSC and gallstone disease.
In this study, age ≥ 60 years at gallstone evaluation, PSC, and a history of colectomy were significant risk factors for gallstone development. Significantly higher cumulative risk of gallstone development in patients with PSC or history of colectomy was revealed in contrast to those without these histories (log-rank test P<0.001), and the differences became more prominent as the follow-up period extended (Fig. 2C and D). Therefore, in patients with longstanding UC with PSC and a history of colectomy, regular abdominal imaging studies such as ultrasonography as a routine follow-up are a reasonable option in clinical practice. Smoking habit and history of appendectomy have been reported as risk factors for gallstone disease in the general population [29,30], however they were not significant factors in this study. In addition, a history of medical treatment (history of corticosteroid, immunomodulator, biologics, and small molecule use) was not significantly associated with gallstone development in this study. These findings suggest that the final colonic condition as a result of relevant treatment, not temporal disease activity, is more important regarding gallstone formation in patients with UC. In this study, history of appendectomy was significantly more common in patients with gallstone disease (40.2% vs. 14.4%; P<0.001). The association between gallstone disease and appendectomy was suggested in previous study of general population in Taiwan [29], however it has been yet investigated in patients with UC. Further studies are needed to confirm these associations.
This study had some strengths. Although previous studies reported the prevalence of gallstone disease in patients with UC, most of them performed the comparison with a normal population with gallstone disease; thus, there are limitations in presenting risk factors in patients with UC (Table 3) [9,10,16]. One study reported age ≥ 65 years and multiple hospitalizations as risk factors for gallstones in UC patients; however, the number of patients diagnosed with gallstones was relatively small (n = 25) [10]. In this study, we analyzed a large number of UC patients who underwent abdominal imaging studies (n = 2,811) and were diagnosed with gallstone disease (n = 198) using a well-established IBD cohort and identified the disease-specific risk factors of gallstone disease in patients with UC. Thus, it would be helpful to consider regular abdominal imaging for early diagnosis and intervention of gallstone disease in patients with UC.
Summary of Studies on Gallstone Disease in Patients with Ulcerative Colitis
However, there were some limitations in this study. First, this study evaluated data from a single tertiary referral center in Korea, although we included a large number of patients. For example, the distribution of disease extent (E1: 17.4%, E2: 21.2%, and E3: 43.7%) significantly differed from the general situation (E1: 62.1%, E2: 17.0%, and E3: 21.0%) [19]. This discrepancy might be related to the specific situation of our center, the time interval between UC diagnosis and disease extent evaluation, and/or the higher disease burden necessitating abdominal imaging during UC surveillance. Thus, it is difficult to generalize our findings to all UC patients in Korea and other countries, especially in Western countries having different clinical phenotypes [31], national health insurance systems, and clinical impact of PSC [5,32]. Second, unlike the patients with CD who underwent abdominal imaging studies frequently, many patients with UC did not undergo abdominal imaging studies routinely. Thus there was a bias in the recruitment stage, and our results might not reflect the true prevalence of gallstone disease in Korean patients with UC. In addition, considering the disease burden and associated complications of UC, abdominal imaging studies are more frequently performed in patients with extensive colitis compared to those with mild proctitis. This might explain why extensive colitis was not identified as a significant risk factor for gallstone disease in this study. Third, clinically important factors regarding gallstone formation such as body weight, systemic disease other than UC, hyperlipidemia, and previous abdominal surgery other than colorectal resection were not included in the analyses. In addition, the subtype of gallstone could not be evaluated due to limited data. Treatment methods for gallstone disease (endoscopic retrograde cholangiopancreatography, laparoscopic cholecystectomy) and clinical impact due to gallstone-associated complications were not evaluated. The treatment method of PSC (medical treatment, endoscopic treatment, or liver transplantation) and colectomy (total or subtotal colectomy and IPAA) was also not included in the analyses. Finally, disease activity of UC at evaluation, history of response to steroids (steroid resistance or dependency), and the presence of hospitalization during the follow-up were not investigated due to limited data. In a previous study, extensive colitis was suggested to be a risk factor for gallstone disease in patients with UC [11], which was not consistent with our findings. We classified the maximum extent of colitis only as a disease-associated variable; however, the severity of previous colitis resulting in subsequent bowel damage was not included, which might bring abnormal colonic bile acid reabsorption. Further studies including these issues and variable populations are needed to prove our findings.
In conclusion, the prevalence of gallstone disease in Korean patients with UC who underwent abdominal imaging studies was 7.0%, which is higher than that in the general Korean population. Age ≥ 60 years at gallstone evaluation, PSC, and a history of colectomy were significant risk factors for gallstone development during the follow-up period. In addition, PSC and a history of colectomy were factors associated with an increased cumulative risk of gallstone development. These findings might be helpful for the management of patients with UC.
Notes
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
Myung SJ is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Data Availability Statement
Data sharing is not relevant because no datasets were created and/or analyzed for this study.
Author Contributions
Conceptualization: Nam K, Lee JY, Park SH, Hwang HW. Data curation: Nam K, Lee JY, Park SH, Hwang HW. Formal analysis: Nam K, Lee JY. Investigation: Nam K, Lee JY, Park SH, Hwang HW. Methodology: Nam K, Lee JY, Park SH, Hwang HW. Project administration: Park SH. Supervision: Park SH. Validation: Nam K. Visualization: Nam K, Lee JY. Writing - original draft: Nam K. Writing - review & editing: Lee JY, Park SH, Hwang HW, Lee HS, Oh K, Hong HS, Kim K, Park JH, Hong SW, Hwang SW, Yang DH, Ye BD, Byeon JS, Myung SJ, Yang SK. Approval of final manuscript: all authors.