Introduction
The annual incidence of newly diagnosed gallstones in Crohn’s disease (CD) patients is twice as high as compared to the general population.
1 Ileal disease localization and previous ileal resection (IR) have both been identified as risk factors for developing gallstones in CD patients.
1,2 The underlying pathophysiology for the increased risk of developing gallstones in CD patients with ileal disease or after IR is not fully understood. A disturbance of the enterohepatic cycle of bilirubin, due to bile salt malabsorption in the ileum, may increase bilirubin secretion into the bile and thereby increase formation of gallstones. Alternative hypotheses are supersaturation of cholesterol in the bile due to reduced bile salt absorption or reduced motility and emptying of the gallbladder.
3‐7
Data on the prevalence of gallstones diagnosed with abdominal ultrasound in CD patients are variable, probably due to the inclusion of pooled populations of both symptomatic and asymptomatic CD patients. The reported prevalence ranges from respectively 10.4 to 38.5% in females and 9.4 to 25% in males and is clearly higher as compared to the reported prevalence in the asymptomatic general population, respectively 10.5% in females and 6.5% in males.
1,2,6,8‐10 Available epidemiological data suggests an increased risk of symptomatic and/or complicated gallstone disease in CD patients.
1,2,6,10 A case-control study in 429 CD patients showed that the incidence rate of gallstones on abdominal ultrasound was 14.35/1000 persons/year compared to 7.48/1000 persons/year in matched hospital controls.
1 Additionally, this study suggested a significant proportion of patients with newly diagnosed gallstones would eventually require cholecystectomy for symptomatic gallstone disease ([9/41] 22%). A major limitation of this and other reports is the inclusion of small CD populations and lack of long-term follow-up data. In order to interpret the clinical relevance of the observed increased risk of gallstones in CD patients, studies assessing the risk of gallstone disease necessitating cholecystectomy are necessary. A high risk of cholecystectomy after IR justifies increased alertness in symptomatic CD patients and possibly even prophylactic measures at the time of IR, such as synchronous cholecystectomy. In this nationwide long-term follow-up study in the Netherlands, we aimed to assess the risk of—and identify risk factors for—cholecystectomy during long-term follow-up after IR in CD patients, including absolute annual and cumulative risk as well as the relative risk as compared to the general population.
Discussion
It has been well established that CD patients are at an increased risk of gallstone development, especially those with ileal involvement. The clinical relevance of this observed increase has however remained unclear. This large nationwide long-term follow-up study is the first to assess the risk of gallstone disease necessitating an intervention following IR, namely cholecystectomy. Our results show that, although over the past years the incidence of cholecystectomy in post-IR CD patients has increased and is currently higher than that in the general population, the annual incidence of cholecystectomy after IR is low. With thorough analyses, we were able to identify patients more likely to require cholecystectomy following IR. Female patients, those undergoing ileal re-resection, and patients with a later calendar year of first IR have an increased probability of cholecystectomy.
The observed incidence rate of cholecystectomy in our CD population after IR of 5.2/1000 persons/year is evidently lower than the reported incidence rate of gallstones found by ultrasound examination in CD patients in general. A large case-control study in 429 CD patients reported an incidence rate of gallstones on abdominal ultrasound of 14.35/1000 persons/year, which was significantly higher than that in matched controls (7.75/1000 persons/year,
p = 0.012).
1 Additionally, it was shown that in a subgroup of CD patients with newly developed gallstones, about 22% of the patients (9/41) eventually required cholecystectomy for symptomatic stones. Our nationwide study substantially adds to these data by describing the clinical consequences of gallstones in a large long-term follow-up cohort of CD patients. Our study shows that in a potentially high-risk population for gallstone disease, only a minority of patients of approximately 10.5% during 20 years will eventually require a cholecystectomy.
The observed cumulative incidence of cholecystectomy of 4.6% within 15 years of follow-up in our study is evidently higher than that observed in the general population. A recent large population-based cohort study of over 65,000 individuals found a cumulative incidence of cholecystectomy for gallstone disease of 1.8% within 15 years of follow-up.
22 To date, the only published study on gallstone disease necessitating cholecystectomy in CD patients was a case-control study including 134 CD patients with ileitis.
10 This study demonstrated that the incidence of cholecystectomy was not significantly different from an age- and sex-matched control group. The nationwide data in the current study significantly adds to previous reports by quantifying the rate of cholecystectomy in absolute and relative risk, annual cholecystectomy risk, and cumulative cholecystectomy risk during long-term follow-up.
Female sex is an important risk factor for cholecystectomy after IR in our study. This finding is in agreement with data from the general population, in which female sex has been identified as an important risk factor for gallstone development.
9,23 Especially women in fertile years are more likely to form gallstones as compared to men. This difference narrows after menopause.
24,25 However, previous data on the prevalence of gallstones in CD patients indicate there are no gender differences. A study in 251 CD patients showed no gender differences in the prevalence of gallstones (27% in females vs. 29% in males).
2 In accord, a more recent study in 330 CD patients reported similar results with a prevalence of 25% in females vs. 25% in males as found by ultrasound examination.
6 A possible explanation for the observed difference in our cohort may be the long-term follow-up and the larger number of included CD patients. Alternatively, the difference may be explained by our cohort’s relatively young median age of 37 years.
In line with expectations, ileal re-resection was associated with cholecystectomy. Previous studies have shown that the prevalence of gallstones is associated with the number of bowel resections and is significantly increased in patients in whom more than 10 cm of the ileum was resected.
2,26 In the current study, we assessed re-resection as a surrogate for the length of intestine removed by surgery and/or CD severity, and this was associated with an increased risk of cholecystectomy.
To our knowledge, this is the first study to report on an increase in gallstone disease necessitating cholecystectomy after IR in CD patients over calendar time. Our findings may well reflect the global trend of increasing gallstone prevalence observed in necroptic
27 and ultrasound studies.
24,28 In addition, cholecystectomy rates have increased, especially in the first decade after 1990.
29‐31 This increase may be attributed to the introduction of laparoscopic cholecystectomy in 1990, which may have lowered the threshold for a surgical procedure in cases of uncomplicated gallstones.
32,33 Still, the cholecystectomy rates may vary greatly between different countries. A recent nationwide study from Sweden, which assessed a total of 130,800 laparoscopic and 47,641 open cholecystectomies performed between 1998 and 2013, showed the annual rates of cholecystectomies remained stable.
34 In contrast, our data covering all cholecystectomies performed within the Netherlands between 1991 and 2015 indicates annual rates have increased between 1991 and 2007 and remained relatively stable with a minimal decline after 2012. This corresponds with the observed increase in probability of cholecystectomy after IR in our study population.
One of the strengths of our study is the selection of a large nationwide cohort with long-term follow-up data, with stringent inclusion criteria of a histology-proven CD and the use of the general Dutch population as a reference population. These data allowed a thorough assessment of gallstone disease necessitating cholecystectomy including risk factors, absolute, relative, and cumulative risk. In addition, due to the nationwide coverage of PALGA, there was a long-term follow-up for each individual patient after IR and full-scale cholecystectomy detection. However, some limitations need to be considered. Firstly, our inclusion criteria for a biopsy-proven CD (SNOMED D62160) might have been too stringent as some pathology reports only include SNOMED codes for ulcer, granuloma, or inflammation. Secondly, the PALGA database provides limited data on patient characteristics, making further subgroup analysis impossible. No data on initial diagnosis of CD and thus duration and/or severity of disease, length of the resected segment, ileal involvement earlier in the disease course, or other known risk factors (e.g., BMI, bariatric surgery) are provided. It would be highly interesting to assess these factors in such a large cohort. In addition, the PALGA database does not contain a date of CD diagnosis, thereby limiting the possibilities for time-to-event and risk factor analysis in a cohort of CD patients without IR. Further studies could focus on the comparison of the risk of cholecystectomy in CD patients without IR and those with IR. This would provide further evidence for the hypothesized role of IR in the development of gallstones in CD patients. Finally, data on the indication of cholecystectomy are lacking. Cholecystectomy rates in CD patients might be higher due to frequent contact with health care professionals and consequently a lower threshold for performing an abdominal ultrasound and a higher diagnosis rate of incidental gallstones. Furthermore, cholecystectomy may have been performed for indications other than complications of chole(cysto)lithiasis, e.g., polyp, tumor-like lesions, acalculous cholecystitis, and unexplained abdominal pain. However, in general, only a small proportion of patients undergo cholecystectomy for these indications.
34
In conclusion, this large nationwide study shows that annual incidence of cholecystectomy in CD patients after IR is 0.5% and increases almost linearly during follow-up to 10.5% after 20 years. Female sex, re-resection, and a later year of IR are associated with cholecystectomy. The incidence of cholecystectomy after IR in CD patients is currently three times higher than that in the general population. Nonetheless, overall, the risk of cholecystectomy is low. While this risk may justify increased alertness of gallstone disease and a lower threshold for abdominal ultrasound in symptomatic CD patients following ileal resection, it does not seem to warrant prophylactic synchronous cholecystectomy during IR in all CD patients.