Biliary events and an increased risk of new onset irritable bowel syndrome: A population-based cohort study

Abstract

Background

Prospective data are lacking to determine if IBS a risk factor for cholecystectomy, or if biliary disease and cholecystectomy predisposes to the development of IBS.

Methods

Validated symptom surveys sent to cohorts of Olmsted County, MN, (1988–1994) with follow-up in 2003. Medical histories were reviewed to determine any “biliary events” (defined by gallstones or cholecystectomy). Analyses examined: 1) time to a biliary event post initial survey and separately, 2) risk of IBS (Rome II) in those with vs. without a prior biliary event.

Results

1908 eligible subjects mailed a follow-up survey. For aim 1) of the 726 without IBS at initial survey, 44 (6.1%) had biliary events during follow up, in contrast to 5 of 93 (5.4%) with IBS at initial survey (HR 0.8, 95% CI 0.3-2.1). For aim 2) of the 59 subjects with a biliary event at initial survey, 10 (17%) reported new IBS on the follow-up survey, while in 682 without a biliary event up to 1.5 years prior to the second survey, 58 (8.5%) reported IBS on follow-up (OR=2.2, 95% CI 1.1-4.6, p=0.03).

Conclusion

There is an increased risk of new IBS in community subjects who have been diagnosed as having a biliary event.

Introduction

Irritable bowel syndrome (IBS) is a chronic, functional gastrointestinal disorder characterized by abdominal discomfort or pain, bloating, and altered defecation (1); a clinical diagnosis can be made when the presenting symptoms meet the multinational, symptom based Rome criteria. IBS is a major public health problem; it is a highly prevalent disorder which affects 15% to 20% of the population, has been shown to impair quality of life and is associated with high health care costs both prior to and after diagnosis (2, 3). Patients with IBS seek medical attention twice as often as age-matched patients without IBS, and these patients utilize more than double the health care dollars when compared to non-IBS patients (4–6).

Cholelithiasis occurs in up to 20% of men and 35% of women in Western nations but the majority are asymptomatic (7, 8). There is evidence from a referral study that patients with IBS were more likely to undergo abdominal and pelvic surgeries, most notably cholecystectomy, when compared to those individuals without IBS (9, 10) and others have speculated about this issue (9, 10). In the only published cross-sectional population based case-control study, Kennedy and Johnson demonstrated that individuals with IBS were more likely to have undergone cholecystectomy when compared to controls (11). The reasons for this are unknown. One could postulate that misdiagnosis of IBS leads to inappropriate surgical intervention. Alternatively, the surgical intervention itself may predispose to the development of IBS (11).

It is, therefore, unclear if IBS is a risk factor for cholecystectomy, or if biliary disease and cholecystectomy predisposes to the development of IBS. It also remains unclear whether patients with IBS have an increased prevalence of cholelithiasis or vice versa. We aimed to test the hypothesis that IBS and biliary tract disease are associated in a prospective cohort study.

Methods

Setting

This study was approved by the Institutional Review Board of the Mayo Clinic, Rochester, Minnesota. Rochester is located in Olmsted County, Minnesota, and the 2000 census indicated a population of approximately 124,000 persons, 89% of which are now white. The population of Olmsted County remains socio-demographically very similar to the white population of the U.S.; therefore, findings are likely to be generalizable to that population (12). Mayo Clinic and its affiliated hospitals (St. Marys Hospital and Rochester Methodist Hospital) are the major health care providers for the community and, since inception, have maintained a common and complete single medical record of all outpatient visits, consultations, and hospitalizations for each individual patient from birth through death (13). Since 1910, Mayo Clinic has maintained extensive indices based on clinical and histologic diagnoses and surgical procedures performed, the guiding principles of which have remained constant since inception (13). Due to the initiation of the Rochester Epidemiology Project, this system of medical record keeping was extended to the other health care providers in the Olmsted County community, namely Olmsted Medical Group (OMG) and Olmsted Medical Center (OMC). Therefore, this medical records linkage system forms what can be essentially regarded as an enumeration of the Olmsted County population from which samples can be drawn (12). During any given 3-year period, greater than 95% of local residents will have had at least one local health care contact (12). This resource has been utilized in many epidemiologic investigations, including a series of investigations into the epidemiology and impact of functional bowel disease (14–17).

Sampling, inclusion and exclusion criteria

From 1988 to 1994, this medical records system was used to draw a series of random samples of Olmsted County residents aged 20 to 85 years old which were stratified by age and gender. The results of these studies have been reported previously (18–21).

Initially, the complete (inpatient and outpatient) medical records of these randomly selected subjects were reviewed and subjects were excluded if they had significant illnesses which might lead to gastrointestinal symptoms or impair their ability to complete the questionnaire (e.g. metastatic cancer, major stroke), a major psychotic episode, mental retardation or dementia, or a history of major abdominal surgery. Because the Olmsted County population was almost exclusively white in the past, and only was representative of the U.S. white population (18, 19), non-whites were not included in the early survey studies, although this criteria was subsequently discarded. Inmates in the local Federal Medical Center and subjects for whom contact was prohibited for legal reasons were also excluded. Residency checks ascertained whether the individual still resided within the County. Each eligible randomly selected subject was mailed a validated gastrointestinal symptom questionnaire. Reminder letters were mailed at 2, 4 and 7 weeks. Subjects who indicated at any point that they did not wish to complete the survey were not contacted further. Otherwise, non-responders were contacted by telephone at 10 weeks to request their participation and verify their residence within the county. Subjects who completed the survey were offered $5 remuneration. Several of the initial surveys contained questions providing criteria for defining IBS, and subjects considered for inclusion in the current study had to have been mailed one of these types of questionnaires.

In 2003, a new study questionnaire and an explanatory letter were mailed to a sub-sample of subjects who had been mailed any of the prior surveys. Subjects who had died (n=1685), moved from Olmsted County (n = 1056), had subsequently denied research authorization (as required by Minnesota law) (n=331), and subjects greater than 80 years old (n=691) were excluded from this mailing, as were subjects who responded to (n=659), or explicitly refused (n=185) an earlier follow-up survey (22). Reminder letters were mailed at 2, 4 and 7 weeks. Subjects who indicated at any point that they did not wish to complete the survey were not contacted further. Otherwise, non-responders were contacted by telephone at 10 weeks to request their participation and verify their residence within the county. Subjects who completed the survey were offered $5 remuneration. There was a total of 4,194 subjects that were mailed the second follow-up survey, and of these subjects (51% females, overall median age 60 years), a total of 1908 had been mailed an initial survey containing the requisite items for defining IBS (52% females, overall median age 56 years). This subset provided the sample of eligible subjects potentially available for this study (figure 1).

Figure 1.

Flow chart documenting sample selection from the Olmsted County, MN population. FU = follow-up

Questionnaires

Subjects were initially mailed a validated symptom questionnaire, the Talley Bowel Disease Questionnaire (BDQ)(23, 24). The BDQ contains 46 gastrointestinal-symptom related questions, 25 questions that measure impact of symptoms on daily life activities, physician visits, and demographic information. The original BDQ was designed as a self-report instrument to measure symptoms experienced over the prior year and to collect past medical history data; each individual item has been assessed for reliability and concurrent validity. A modification of the original BDQ was used for the follow-up mailing deleting less relevant items.

Definition of IBS

The following definitions were used to identify individuals with each of the entities.

Irritable Bowel Syndrome (IBS)

Modified Rome II Criteria was used to identify individuals meeting criteria for IBS; the Rome II criteria (1) were not available at the time the initial surveys were mailed. IBS was defined as a combination of frequent abdominal pain (> 6 times within the past year) and 2 of the 3 following characteristics: (i) pain relief by defecation, (ii) increased or decreased number of bowel movements when pain began, or (iii) harder or looser bowel movements when pain began. We have applied these criteria in past studies (18, 19) and have previously validated the pain frequency criterion for identification of IBS (21).

IBS subtype

i) Constipation predominant IBS: IBS and 2 or more of: less than 3 bowel movements per week; straining; hard stools; feeling of incomplete rectal evacuation, often; ii) Diarrhea predominant IBS: IBS and loose or watery stools often.

Biliary Events

(i) Documentation of gallstones on objective testing (abdominal ultrasound, oral cholecystography, hepatobiliary scintigraphy, abdominal computed tomography (CT) scan, abdominal magnetic resonance imaging (MRI), or cholangiography), or ii) Documented cholecystectomy; the presence or absence of gallstones at the time of surgery was recorded. This evaluation was performed by trained study coordinators in 2004–2005 who were unaware of the IBS status of the subjects.

Statistical analysis

The analyses examined three approaches to assess the association between reported IBS and occurrence of biliary “events”. In the first approach, the date of initial survey in each subject was used as the start point of observation. The time to a biliary event (or date of follow-up survey as a censoring time) was used in a proportional hazards regression model to estimate the hazard ratio (HR and 95% confidence interval) for the subsequent development of biliary events in those with IBS versus those without IBS at first survey, adjusting for age, gender, and body mass index (BMI). Subjects that had experienced a biliary event before the initial survey (n=33) were excluded from this analysis. A second approach examined the risk of IBS in those with vs. without a prior biliary event.

A logistic regression model was used to predict the reporting of IBS on the follow-up survey. This model provided an estimate the odds for reporting IBS in those who had experienced a biliary event relative to those who had not, adjusting for age, gender, and BMI. This second approach considered two separate logistic models, one in which the biliary event had to have occurred prior to the first survey (ignoring any biliary events between the first and second surveys), and a second in which the biliary event could have occurred up to 1.5 years prior to the second survey.

All P values calculated were two-tailed; the alpha level of significance was set at 0.05.

Study power

There was approximately 80% power to detect an increase in the cumulative proportion of subjects experiencing a “biliary event” by 10 years in the IBS group of 11.5% compared to the observed 4.3% cumulative proportion with a “biliary event” by 10 years in the non-IBS group. This assumes n=726 without IBS vs. n=93 with IBS, a maximum 15-year follow-up in subjects, an exponential pattern survival free of a biliary event and is based on the log rank test for the proportions at 10 years.

Results

From the initial qualifying surveys (1988 to 1994), 1908 eligible individuals had been mailed an initial survey containing items to define IBS, and of these, 852 individuals responded to both the appropriate type of initial survey and the follow-up survey (median [range] time between surveys was 11.7 [9.2, 15.3] years). A total of 722 had responded only to the initial survey, while 253 responded to neither, and 81 only to the follow-up survey. Overall, the mean (±SD) age of the 852 respondents was 46 (± 13) years and 55% were female. Body mass index (BMI) data was available for 535 respondents, with a mean BMI of 28.5±6.8 kg/m². The ethnic distribution was 98% Caucasian.

Those who responded to both surveys (N=852, number used in the current analyses) compared with subjects responding to the initial but not the follow-up survey (N=722) were similar demographically, although a logistic model indicated a modest, albeit significant, association with age (p=0.038, OR for response=1.008 per year [95% CI 1.000, 1.015]). There was no significant association of response with gender (p=0.073, OR (female: male) for response=1.20[0.98, 1.47]), or with IBS status at first survey (p=0.77, OR (IBS: no IBS) for response=1.05[0.76, 1.44]).

Predicting Development of Biliary Events

Out of 852 respondents, 33 were excluded due to the occurrence of biliary events prior to the initial survey. Of the 819 individuals remaining, the mean age was 46 (±13 years), 55% were female, and mean BMI was 28.3 ± 6.3 kg/m². A total of 726 respondents did not meet Rome II criteria for IBS, while 93 respondents (11.4%) met Rome II criteria for diagnosis of IBS.

In the non-IBS group, there were 44 biliary tract events, yielding a cumulative 10 yr. probability of 4.3% (Table 1). These 44 biliary tract events were represented by cholecystectomy for cholelithiasis in 36 individuals and cholecystectomy alone in eight individuals.

Table 1.

Hazards ratios for reporting irritable bowel syndrome on follow-up survey

Covariate	Cumulative Probability (%) of biliary event by 10 years (95% CI)	Hazard ratio† (95% CI)	Hazard ratio‡ (95% CI)
IBS – no (n=726)	4.3 (2.8,5.8)	1.0 (ref)	1.0 (ref)
IBS – yes (n=93)	2.2 (0,5.1)	0.84 (0.33,2.11)	0.67 (0.20,2.21)
Gender – Male (n=370)	5.8 (1.8,5.7)	1.0 (ref)	1.0 (ref)
Gender – Female (n=449)	4.2 (2.4,6.1)	1.55 (0.86,2.80)	1.44 (0.70,2.96)
Age - < 43 (median) (n=395)	2.0 (0.6,3.4)	1.0 (ref)	1.0 (ref)
Age - ≥ 43 (median) (n=424)	5.9 (3.6,8.2)	3.33 (1.67,6.54)	3.03 (1.30,7.06)
BMI 18–25 (n=183)	1.6 (0,3.5)	1.0 (ref)	1.0 (ref)
BMI 26–30 (n=192)	5.3 (2.0,8.4)	2.71(0.98,7.54)	2.70 (0.97,7.55)
BMI 31–35 (n=87)	6.9 (1.4,12.1)	4.31 (1.47,12.60)	3.88 (1.32,11.44)
BMI > 35 (n=51)	5.9 (0,12.1)	2.23 (0.53,9.33)	1.99 (0.47,8.36)

^†Univariate hazards ratios (95% CI)

^‡Multiple proportional hazards regression model hazard ratios (95% CI).

Multiple model based on n=513 subjects with BMI data.

IBS - irritable bowel syndrome

BMI - body mass index

The IBS group experienced a total of 5 biliary tract events (cumulative 10 probability of 2.2%, Table 1) These 5 events comprised 4 subjects with cholecystectomy for cholelithiasis, and cholecystectomy alone in 1 individual.

After adjusting for age, gender, and BMI, the hazard ratio for the development of a biliary tract event in patients with IBS was 0.84 (95% confidence interval [0.33, 2.11]). Age was the only covariate predictive of development of a biliary event, with a hazard ratio of 1.6 per 10 years [95% CI 1.2, 2.1].

Predicting Development of IBS

Among the 852 respondents, 99 subjects had reported IBS on the first survey and were not used in the initial logistic regression model to predict subsequent IBS (at the second survey). In the remaining subjects, 726 had not had a biliary event prior to the first survey (but some could have had one between the first and second surveys). Among these, 64 (8.8%) reported IBS at the second survey. In the 27 subjects that had a prior (to the first survey) biliary event (14 [52%] with gallstones and 13 with a cholecystectomy for gallstones), 5 (18.5%) reported IBS at the second survey (3 of 14 [21%] and 2 of 13 [15%]). The adjusted OR was 2.3 (95%CI [0.7, 7.9]) which was not statistically significant (Table 2).

Table 2.

Predicting irritable bowel syndrome (allowing gallstones only prior to 1^st survey)

Covariate	N (%) with IBS at follow-up	Odds ratio† (95% CI)	Odds ratio‡ (95% CI)
Biliary event – no (n=726)	64 (8.8%)	1.0 (ref)	1.0 (ref)
Biliary event – yes (n=27)	5 (18.5%)	2.44 (0.89,6.68)	2.34 (0.70,7.89)
Gender – Male (n=340)	19 (5.6%)	1.0 (ref)	1.0 (ref)
Gender – Female (n=413)	50 (12.1%)	2.35 (1.36,4.07)	2.97 (1.41,6.28)
Age - < 43 (median) (n=360)	31 (8.6%)	1.0 (ref)	1.0 (ref)
Age - >= 43 (median) (n=393)	38 (9.7%)	1.14 (0.69,1.87)	1.05 (0.56,1.99)
BMI 18–25 (n=163)	8 (4.9%)	1.0 (ref)	1.0 (ref)
BMI 26–30 (n=177)	22 (12.4%)	2.79 (1.20,6.45)	3.39 (1.44,7.98)
BMI 31–35 (n=80)	8 (10.0%)	2.23 (0.81,6.19)	2.52 (0.89,7.10)
BMI > 35 (n=52)	7 (13.5%)	2.99 (1.03,8.71)	2.80 (0.94,8.35)

^†Univariate odds ratios (95% CI).

^‡Multiple logistic regression model odds ratios (95% CI).

Multiple model based on n=465 subjects with BMI data. BMI - body mass index. IBS – irritable bowel syndrome.

Since some of the subjects without a biliary event prior to the first survey could have experienced one in between surveys, a second model was examined in which subjects with a biliary event up to 1.5 years prior to the second survey were considered in the biliary event subgroup (Table 3). An additional 12 subjects with a biliary event within 1.5 years of the second survey were not included in this model. Thus, of the 852 respondents, 111 were excluded for either meeting modified Rome II IBS criteria at the first survey (n=99), or a late biliary tract event (n=12) which may or may not have preceded the development of IBS criteria on the second survey (which asked about symptoms in the last year). Of the remaining 741 individuals, the mean age was 46 (±13 years), females comprised 55%, and the mean BMI of the group was 28.6 (±7.0) kg/m². A total of 682 respondents did not experience a biliary event, defined as either cholelithiasis alone or cholelithiasis with cholecystectomy and of these, 58 individuals (8.5%) went onto report symptoms consistent with IBS based upon modified Rome II criteria. In the 59 individuals who had a biliary event confirmed (40 with gallstones (68%) [18 of 40 without cholecystectomy, and 19 with cholecystectomy but no gallstones]), 10 respondents (16%) had IBS on the second survey (3 of 18 [17%] with gallstones alone and no cholecystectomy, 5 of 22 [23%] with cholecystectomy for gallstones, and 2 of 19 [11%] with cholecystectomy but no gallstones). In this model, the adjusted odds ratio for the development of IBS in those with a biliary event (relative to those without) was 2.2 (95% CI: [1.1, 4.6], p = 0.03). Among subjects with a biliary event up to 1.5 years prior to second survey, there was no significant association of cholecystectomy/gallstone status and type of IBS. For example, in those undergoing a cholecystectomy for cholelithiasis (n=22), 3 subjects reported IBS and diarrhea (13.6%) while 1 subject reported IBS and constipation (4.5%).

Table 3.

Predicting irritable bowel syndrome (allowing gallstones up to 1.5 years prior to 2^nd survey)

Covariate	N (%) with IBS at follow-up	Odds ratio† (95% CI)	Odds ratio‡ (95% CI)
Biliary event – no (n=682)	58 (8.5%)	1.0 (ref)	1.0 (ref)
Biliary event – yes (n=59)	10 (17.0%)	2.22 (1.07,4.61)	1.74 (0.70,4.37)
Gender – Male (n=404)	19 (5.6%)	1.0 (ref)	1.0 (ref)
Gender – Female (n=358)	49 (12.1%)	2.34 (1.35,4.05)	2.91 (1.37,6.19)
Age - < 43 (median) (n=358)	30 (8.4%)	1.0 (ref)	1.0 (ref)
Age - >= 43 (median) (n=381)	38 (9.9%)	1.20 (0.73,1.99)	1.13 (0.59,2.16)
BMI 18–25 (n=161)	8 (5.0%)	1.0 (ref)	1.0 (ref)
BMI 26–30 (n=174)	22 (12.6%)	2.81(1.21,6.50)	3.31 (1.40,7.82)
BMI 31–35 (n=79)	7 (8.9%)	1.93 (0.67,5.53)	2.01 (0.68,5.91)
BMI > 35 (n=51)	7 (13.7%)	3.02 (1.04,8.80)	2.85 (0.96,8.44)

^†Univariate odds ratios (95% CI).

^‡Multiple logistic regression model odds ratios (95% CI).

Multiple model based on n=458 subjects with BMI data. BMI - body mass index.

The medical charts of all subjects with IBS were reviewed and 10 subjects were identified as having co-existent organic disease (3 colon cancer, 5 inflammatory bowel disease, 1 cholangiocarcinoma, 1 pancreatic cancer). Re-running all of the models excluding these subjects did not appreciably alter any of the results.

Discussion

In this prospective population-based cohort study, we evaluated the association of biliary events and IBS. We found that of the 726 people without IBS at the initial survey, 6% had biliary events during the 10 years of follow-up, compared to a 5% rate of biliary events in people with IBS on the initial survey, a non-significant difference; most of these events were cholecystectomy for gallstones. On the other hand, in 59 subjects with a history of a biliary event at the initial survey, 16% reported the new onset of IBS over the follow-up, compared with a new onset rate of IBS of just 8.5% in the 682 without a biliary event up to 1.5 years prior to the second survey, a two fold increased risk that was significant. These results suggest that those experiencing biliary events are at higher risk of developing IBS.

The evidence that patients with IBS are more likely to undergo abdominal and pelvic surgeries, including cholecystectomy, hysterectomy, and appendectomy, is largely based on referral practice cross-sectional data (10, 25, 26). However, as many as 70% of people with IBS do not ever seek medical attention for their IBS symptoms, and thus these observations may be subject to referral bias. A possible association between IBS and surgery was first noted by Ryle in 1928 who reported that 36% of individuals with IBS underwent appendectomy (27). Longstreth and Yao noted that patients with IBS in an HMO setting underwent cholecystectomy three times as often as those without IBS, but showed that IBS patients were not more likely to undergo non-abdominopelvic surgery where indications for surgery were less likely to be confused with symptoms of IBS, such as coronary artery surgery and peptic ulcer surgery (9). In the only cross-sectional population-based study, Kennedy and Johnson reported that individuals with IBS were more likely to undergo cholecystectomy when compared to controls [4.6% versus 2.4% respectively, OR 1.9, 95% CI (1.2, 3.2); p<0.01] (11). They calculated that there was an excess of 16 cholecystectomies per 1000 women with IBS aged 20–69 years.

We failed to detect an increased risk of cholecystectomy in people with IBS in Olmsted County. We do not believe that diagnostic or selection biases are likely to account for the findings; for example, access to medical care is excellent in Olmsted County, and we generated population-based random samples (albeit there were some specific exclusions). The symptoms of IBS are somewhat nondescript and diverse, and diagnosis can be a challenge in practice. Often symptoms are easily confused with or attributed to other disorders, opening the door to misdiagnosis and unnecessary tests and procedures; however, we applied standard diagnostic criteria in this study. However, we cannot fully discount our results are due to bias; it is conceivable for example that less unnecessary operations are offered to this population than occur elsewhere, perhaps because the standard of medical care is high in this region dominated by the Mayo Clinic. Given the fact that no reliable serologic or radiographic findings are compatible with a diagnosis of IBS and the paucity of evidence that pharmacologic therapies are helpful in IBS, the foundation of diagnosis and therapy remains confidence in the diagnosis and a strong physician-patient relationship, and this likely varies widely (28).

Other data support the present results. Legorreta et al. reported that the rate of cholecystectomy procedures per 1000 HMO enrollees increased from 1.35 in 1988 to 2.15 in 1992 (29). While the incidence of gallbladder surgery does seem to be on the rise, this may not be attributable to misdiagnosis of IBS as some have claimed (30). Mallon et al. sent surveys to patients who had undergone cholecystectomy between 1988–1990 (open surgery group) and 1998–2000 (laparoscopic surgery group); 124 of 196 patients in the open group and 264 of 400 patients in the laparoscopic group replied, and there was no difference between the groups in the prevalence of IBS by Rome II criteria. They concluded that the increased cholecystectomy rate in the laparoscopic era is not explained by diagnostic confusion with IBS (31).

The most striking result in the present study was observed among those subjects with a history of a biliary event up to 1.5 years prior to the follow-up survey; 16% reported the onset of IBS on the follow-up survey, compared with an onset rate of IBS of just 8.5% in those without a biliary event up prior to the follow-up survey. We applied two similar models to assess these interrelationships, and reassuringly found similar results, albeit this was not significant in one of the models presumably because this analysis was under-powered. Although common diseases can occur together just by chance, such as IBS and gallstones (32), this does not seem to account for our observations. It is conceivable that the underlying etiopathogenesis of IBS might involve the gallbladder first before affecting the luminal gastrointestinal tract, and this explains the association. Kellow et al. at the Mayo Clinic (33) observed that the responses of the gallbladder to graded intravenous infusions of cholecystokinin octapeptide (CCK-OP) was different in IBS; those with constipation contracted their gallbladders more and those with diarrhea contracted the gallbladder less in response to the peptide. Kamath et al. (34) in a follow-up study confirmed these observations and suggested that this abnormality in IBS might be explained by an atypical response at the level of the target tissues. Others have demonstrated higher fasting and postprandial gallbladder volumes by ultrasound in IBS (35) although this has been disputed (36). Gallbladders resected for uncomplicated gallstones had a greater proliferation of nerves visible histologically compared with gallbladders involved by acute cholecystitis (37); it is therefore possible that increased gallbladder nerve proliferation predisposes some people to develop abdominal pain post-cholecystectomy that mimics IBS, via a wind up of the central nervous system pain pathways.

In healthy subjects, the bile acids continuously secreted by the liver are stored in the gallbladder and are maximally expelled postprandially, to be later reabsorbed by the distal small intestinal mucosa. After cholecystectomy, the bile acids flow continuously in the intestine and are propelled from the intestine by the activity front of the migrating motor complex (MMC) into the colon, where they may reach a higher than normal concentration (38). The excess of bile acids in the colonic lumen may cause diarrhea as happens not only in bile acid malabsorption (39), but also in the “postcholecystectomy diarrhea” syndrome, where an increase in fecal bile acids has been demonstrated (40)), (41). As postcholecystectomy diarrhea may develop in 10% to 20% of patients (42) is it possible that some of the patients with IBS type diarrhea found in our study have diarrhea because of bile salt overflow. A higher prevalence of IBS with diarrhea (13.6%) versus IBS with constipation (4.5%) was found in the present study in patients who underwent a cholecystectomy for cholelithiasis. In comparison, the prevalence of IBS with diarrhea and IBS with constipation in the general population may generally be similar (43, 44) although some population-based studies do suggest that IBS with diarrhea is the most common subtype (45). However, the cholecystectomy rates among IBS subtypes were based on very small numbers and no statistically significant association was detected; thus any potential association needs to be further evaluated.

Alternatively, preoperative medical therapy might predispose to the development of IBS. Mendall and Kumar, in a case-control study, have reported that exposure to antibiotics was associated with nearly a four fold increased risk of IBS (46). Whether treatment with antibiotics at the time of surgery or post-surgery is important in predisposing to future IBS, perhaps via the alteration of intestinal flora, remains unknown.

The strengths of this study include its prospective design and evaluation of a representative community sample. The responders to the survey were similar to non-responders, and we consider selection bias to be unlikely. We used chart review to confirm biliary events and their type rather than relying on patient recall, and the resources in Olmsted County allow complete ascertainment of all consulting events and diagnostic testing undertaken in the cohort. On the other hand, the study power was limited in terms of assessing specific types of biliary events, and we only had symptom data available at limited time points. Furthermore, we could not perform an abdominal ultrasound or hepatobiliary scintigraphy to detect undiagnosed gallstones or gallbladder dyskinesia in this population, and hence our results largely apply to symptomatic gallbladder and biliary tract disease presenting in the community. Finally, our analysis was based on an essentially white population and therefore our results cannot be extrapolated to any other ethnic groups.

In conclusion, we have shown that in those subjects with IBS, there appears to be no increased risk of the development of a biliary event (gallstones or cholecystectomy) over a median 10 year time frame in this community. However, community subjects who have experienced a biliary event appear to have a two-fold increased risk for development of new onset IBS, suggesting that this is possibly a disease maker.