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ARTICLE: FUNCTIONAL GI DISORDERS

Irritable Bowel Syndrome and Long-Term Risk of Cancer: A Prospective Cohort Study Among 0.5 Million Adults in UK Biobank

Wu, Shanshan PhD1; Yuan, Changzheng ScD2,3; Liu, Si PhD1; Zhang, Qian PhD1; Yang, Zhirong PhD4,5; Sun, Feng PhD6; Zhan, Siyan PhD6; Zhu, Shengtao PhD1; Zhang, Shutian PhD1

Author Information
The American Journal of Gastroenterology: May 2022 - Volume 117 - Issue 5 - p 785-793
doi: 10.14309/ajg.0000000000001674

Abstract

INTRODUCTION

Irritable bowel syndrome (IBS) is one of the most common disorders of gut-brain interaction, characterized by recurrent abdominal pain, altered bowel habits, and bloating without any organic abnormalities (1,2). Recent data estimated that the global overall prevalence of IBS was 10.1% and 4.1% according to Rome III and IV criteria, respectively (3). Although several treatments are available, IBS remains a major public health problem worldwide. IBS symptoms substantially affect work, social relationships, and quality of life, leading to considerable comorbidities and health resource use (4–7). It has been reported as the second leading cause of absence from work and/or school (8).

Because IBS shares common symptoms with other gastrointestinal diseases (i.e., inflammatory bowel disease [IBD] and colorectal cancer [CRC]) and is mainly based on exclusion diagnosis, the potential risk of developing organic diseases, particularly CRC, is a primary concern for patients with IBS. Hence, it is worthy of examining CRC risk/other digestive cancers in patients with IBS vs general population. However, relevant body of evidence was scanty. Although it has been well accepted as assuming no increased risk, association between IBS and CRC is yet inconsistent. Some studies (9–11) reported negative association, whereas others (8,12,13) demonstrated increased CRC risk. By contrast, a Denmark study (14) conversely observed decreased CRC risk in patients with IBS.

The discrepancies may be partly explained by different study designs and a short-term follow-up. Few studies adopted a prospective cohort design with concurrent matched comparators (11–13). Most studies were based on only a group of patients with IBS compared with local cancer incidence rates of general population using a standardized incidence ratio (defined as a ratio of observed to expected cancers) as the effect measure (8,14), neglecting potential confounders (i.e., lifestyle factors and comorbidity). Meanwhile, little is known regarding long-term risk of CRC. In addition, whether IBS may increase long-term risk of other types of malignancies and cancer-specific mortality remains unclear. To the best of our knowledge, the association between IBS and overall cancer, site-specific cancer, and cancer-specific mortality has not been thoroughly evaluated in a large, long-term, longitudinal cohort with a concurrent comparator.

Therefore, we used an outcome-wide approach to prospectively investigate whether IBS was associated with increased risk of overall cancer, site-specific cancers, and cancer-specific mortality in a large population-based long-term follow-up UK cohort.

METHODS

Study population

This study was based on a large-scale prospective cohort study, UK Biobank (UKB), with more than 500,000 participants ranging from age 37 to 73 years at enrollment. Briefly, participants from 22 assessment centers across England, Wales, and Scotland were enrolled between 2006 and 2010. All participants completed baseline questionnaires with anthropometric assessments and reported medical conditions. Detailed description of the UKB design was reported elsewhere (15). This study was approved by the North West Multicenter Research Ethical Committee, and all participants signed written informed consent.

We excluded 46,532 participants who had previous cancer diagnosis, 5,142 who had inflammatory bowel disease diagnosis, 1,190 who had celiac disease before baseline, and 1 participant whose baseline questionnaires and anthropometric information were missing. In addition, 1 participant withdrawal from UKB was excluded. Therefore, 449,595 participants were included in the final analysis.

Definition of IBS

All participants with IBS diagnosis using International Classification of Disease-10 (ICD-10) codes were identified (K58; see Supplementary Table S1, Supplementary Digital Content 1, https://links.lww.com/AJG/C440). IBS diagnosis was based on self-report or linkage to primary care and/or hospital admission data. Individuals with diagnosis date of IBS before baseline were considered in the exposure group (IBS group) while others without IBS diagnosis before baseline, regardless of IBS occurrence during the follow-up, were considered as the nonexposure group (non-IBS group).

Ascertainment of cancer outcomes and cancer-specific mortality

Cancer status was determined by “National cancer registries linkage to UKB” (UKB data category 100092) with a censoring date of June 2021, and details were described elsewhere (16). Cancer-specific mortality was ascertained through the primary cause of death (UKB data category 40001). The primary outcomes were overall cancer and cancer-specific mortality. Secondary outcomes included site-specific cancers (digestive, breast, female genital, male genital, central nervous system (CNS), thyroid and endocrine cancer, skin (melanoma and nonmelanoma), urinary tract, and hematological) and types of digestive cancers (colorectal, colon, rectal, liver and biliary tract, esophagus, stomach, and other digestive cancers). All types of cancers were classified according to the ICD-10 code (see Supplementary Table S2, Supplementary Digital Content 1, https://links.lww.com/AJG/C440).

Covariates

Based on epidemiological evidence, some sociodemographic characteristics, health behaviors, and comorbidities at baseline were adjusted as covariates (9–13). Potential confounders included age (continuous variable), sex (male or female), ethnicity (White or non-White), socioeconomic status, education level, body mass index (BMI), smoking status (never smoking, current smoking, or previous smoking), alcohol drinking (never drinking, current drinking, or previous drinking), diabetes (yes or no), long-standing illness (yes or no), overall health rating, family history of cancer, and physical activity. Socioeconomic status was based on quartiles of the Townsend deprivation index, which was calculated immediately before participants joining UKB using preceding national census output areas (17). Education was based on the self-report of the highest qualification achieved and classified as university or nonuniversity. Baseline BMI was classified into 4 categories (underweight, normal, overweight, and obese) according to the World Health Organization guideline (18). Self-reported overall health rating was categorized as excellent, good, fair, and poor. Family history of cancer was defined by an illness history of first-order relatives. Self-reported physical activity was divided into 3 levels (high, moderate, and low) based on the International Physical Activity Questionnaire.

Statistical analysis

Baseline characteristics were described by mean ± SD for continuous and absolute numbers with proportion for categorical variables. Comparison of baseline characteristics between 2 groups was conducted by using the Student t test for continuous variables and the χ2 test for categorical variables.

The Cox proportional hazard model was conducted to examine the association between IBS and overall cancer, site-specific cancers, and cancer-specific mortality. For overall cancer and site-specific cancer, the end point was the first diagnosis of cancers. The follow-up period started from baseline to the date of first diagnosis of any type of cancers or censored at the end of study (June 2021), date of death, or lost to follow-up for participants who did not develop any cancer. For cancer-specific mortality, end point was defined as death primarily caused by cancer, and the end of follow-up was the date of death or lost to follow-up or censored at the end of study (June 2021) for participants who were with incident cancer but still alive or did not develop cancer at all.

The incidence rate with 95% confidence interval (CI) of overall cancer, site-specific cancer, and cancer-specific mortality was calculated as the number of events per 1,000 person-years through Poisson regression and then stratified by age (<45, 45–59, ≥60 years) and sex. The 12-year cumulative incidence of overall cancer, site-specific cancer, and cancer-specific mortality was calculated by using the Kaplan-Meier method.

Considering a very small percentage of missing values (0.1%–2.6%), missing indicators were used. Proportional hazard assumption was ascertained and satisfied by testing linear regression of scaled Schoenfeld residuals on functions of time (the P value was 0.620 for overall cancer and 0.860 for cancer-specific mortality).

Three adjustment models in addition to univariable analysis were conducted: (i) model 1, adjusted for age and sex; (ii) model 2, additionally adjusted for Townsend deprivation index, education level, ethnicity, BMI, smoking status, and alcohol drinking; and (iii) model 3, additionally adjusted for International Physical Activity Questionnaire, diabetes, long-standing illness, overall health rating, and family history of cancer. Furthermore, subgroup analysis was performed to explore whether the association with IBS and overall cancer with cancer-specific mortality change varied by age (<45, 45–59, and ≥60 years) and sex. Effect modification was detected by adding interaction terms of age/sex and IBS group. Further stratified multivariable analysis was conducted to investigate the association of IBS with site-specific cancers and digestive cancers, along with subgroup analysis by age (<60 and ≥60 years) and sex.

To assess the robustness of the results, several sensitivity analyses were conducted. First, we excluded participants who had IBS diagnosis after recruitment in the non-IBS group. Second, incident cancer participants during 1 year or 2 years after baseline were excluded, respectively, to avoid detection bias. Third, a competing risk model, considering lost to follow-up and death as competing events, was conducted because those participants might develop cancer thereafter. Further propensity score matching (1:10 matching), adjustment, and inverse probability weighting methods were performed to assess the robustness of estimates. The propensity score was calculated by using binary logistic regression with covariates similar to adjusted model 3. Standardized mean difference between IBS and non-IBS groups in original population, matching population, and inverse probability weighting population was calculated to demonstrate the comparability of 2 groups.

In addition, the competing risk model was further performed to assess the robustness of association between IBS and site-specific cancer, with lost to follow-up, death, or diagnosed as other types of cancers considered as competing events.

A 2-tailed P value of <0.05 was considered to be statistically significant. All analyses were conducted using SAS software version 9.4 and R version 4.0.2 (forestplot, tableone, ggplot2, survival, Matching, and survey packages).

RESULTS

Baseline characteristics

Of all 449,595 participants, 46.7% were male. The mean (SD) age was 56.21 (8.11) years at baseline. Overall, 22,338 participants (5.0%) had IBS diagnosis before or at enrollment, and 427,257 participants (95.0%) were divided into the non-IBS group. Participants with IBS were more likely to be younger, be female, and be of White ethnicity, and were with a lower education level, lower level of socioeconomic deprivation, lower BMI, higher proportion of diabetes and long-standing illness, and lower rating of overall health (Table 1). The median follow-up period was 12.2 years (interquartile range: 11.3–13.0 years).

T1
Table 1.:
Baseline characteristics of all patients with IBS and reference individuals from general population

Incident of overall cancer and cancer-specific mortality

During the whole follow-up, 2,937 cases of incident cancer were diagnosed in IBS vs 60,556 cases in non-IBS. The incidence rate of overall cancer was 11.47 and 12.51 per 1,000 person-years in IBS and non-IBS, respectively (see Supplementary Table S3, Supplementary Digital Content 1, https://links.lww.com/AJG/C440). The 12-year cumulative incidence of overall cancer was 13.3% (95% CI: 12.8%–13.7%) in IBS vs 14.3% (95% CI: 14.2%–14.4%) in non-IBS (Figure 1a).

F1
Figure 1.:
Cumulative incidence of overall cancer and cancer-specific mortality in patients with IBS and reference individuals (estimated by using the Kaplan-Meier method): (a) overall cancer and (b) cancer-specific mortality. IBS, irritable bowel syndrome.

Regarding cancer-specific mortality, totally 512 and 12,282 deaths of cancer occurred in IBS and non-IBS. The cancer-specific mortality was separately 2.00 and 2.54 per 1,000 person-years in IBS and non-IBS (see Supplementary Table S4, Supplementary Digital Content 1, https://links.lww.com/AJG/C440). The 12-year cumulative cancer-specific mortality was 2.3% (95% CI: 2.1%–2.5%) in IBS vs 2.9% (95% CI: 2.8%–2.9%) in non-IBS (Figure 1b).

Association of IBS with incidence of overall cancer and cancer-specific mortality

Compared with non-IBS, no increased risk of overall cancer was detected in IBS with a crude hazard ratio (HRR) of 0.92 (95% CI: 0.89–0.95) and an adjusted HR (aHR) of 0.97 (95% CI: 0.93–1.00) according to fully adjusted model 3 (Table 2). Subgroup analysis demonstrated similar findings across age and sex subgroups (P for interaction was 0.007 for age and 0.903 for sex; Figure 2a).

T2
Table 2.:
Association between IBS and incidence of overall cancer and cancer-specific mortality
F2
Figure 2.:
Subgroup analysis for the association between IBS and incidence of overall cancer and cancer-specific mortality: (a) overall cancer and (b) cancer-specific mortality. Reference group = non-IBS group; all adjusted HRs were calculated by adjusting the following covariates: age, sex, Townsend deprivation index, education level, ethnicity, BMI, smoking status, alcohol drinking, International Physical Activity Questionnaire, diabetes, long-standing illness, overall health rating, and family history of cancer. BMI, body mass index; CI, confidence interval; HR, hazard ratio; IBS, irritable bowel syndrome.

By contrast, a significantly decreased risk of cancer-specific mortality was observed in IBS, with a crude HR of 0.79 (95% CI: 0.72–0.86) and an aHR of 0.83 (95% CI: 0.76–0.91) according to fully adjusted model 3 vs non-IBS (Table 2). Similarly, results of subgroup analysis were consistent without any significant modification across age and sex subgroups (P for interaction was 0.248 for age and 0.508 for sex; Figure 2b).

Association between IBS and site-specific cancers

The absolute incidence rate per 1,000 person-years and cumulative incidence of each site-specific cancer are listed in Supplementary Table S5 (see Supplementary Digital Content 1, https://links.lww.com/AJG/C440) and Supplementary Figure S1 (see Supplementary Digital Content 1, https://links.lww.com/AJG/C440). Skin and digestive cancers showed the highest incidence rate in both IBS (3.80 and 1.20 per 1,000 person-years) and non-IBS participants (4.15 and 1.67 per 1,000 person-years).

An evidently lower risk of digestive cancer (aHR = 0.79, 95% CI: 0.71–0.89) was observed in IBS vs non-IBS, whereas no significant association was detected for other cancer types (Figure 3). Further subgroup analysis according to age and sex indicated similar findings; lower risk of digestive cancer was observed in participants both ≥60 and <60 years (Figure 4).

F3
Figure 3.:
The association between IBS and site-specific cancers. Reference group = non-IBS group; all adjusted HRs were calculated by adjusting the following covariates: age, sex, Townsend deprivation index, education level, ethnicity, body mass index, smoking status, alcohol drinking, International Physical Activity Questionnaire, diabetes, long-standing illness, overall health rating, and family history of cancer. CI, confidence interval; CNS, central nervous system; HR, hazard ratio; IBS, irritable bowel syndrome.
F4
Figure 4.:
Subgroup analysis for the association between IBS and site-specific cancers: (a) by age and (b) by sex. Reference group = non-IBS group; all adjusted HRs were calculated by adjusting the following covariates: age, sex, Townsend deprivation index, education level, ethnicity, body mass index, smoking status, alcohol drinking, International Physical Activity Questionnaire, diabetes, long-standing illness, overall health rating, and family history of cancer. CI, confidence interval; CNS, central nervous system; HR, hazard ratio; IBS, irritable bowel syndrome.

Association between IBS and different types of digestive cancers

The absolute incidence rate per 1,000 person-years and cumulative incidence of each type of digestive cancer are shown in Supplementary Table S6 (see Supplementary Digital Content 1, https://links.lww.com/AJG/C440) and Supplementary Figure S2 (see Supplementary Digital Content 1, https://links.lww.com/AJG/C440). CRC had the highest incidence rate among all digestive cancers, with 0.60 (95% CI: 0.51–0.70) and 0.91 (95% CI: 0.88–0.94) per 1,000 person-years in IBS and non-IBS participants.

Interestingly, a decreased risk of CRC (aHR: 0.73, 95% CI: 0.62–0.86) was detected in IBS vs non-IBS. The corresponding aHRs were 0.75 (95% CI: 0.62–0.90) for colon cancer and 0.68 (95% CI: 0.49–0.93) for rectal cancer (Table 3). No significant effect was detected in other types of digestive cancers (P values >0.05).

T3
Table 3.:
Association between IBS and incidence of different types of digestive cancers

Sensitivity analysis

The results of sensitivity analysis were similar to those of main analysis, indicating the robustness of the results (see Tables S7–S11, Supplementary Digital Content 1, https://links.lww.com/AJG/C440).

DISCUSSION

In this population-based prospective cohort study with a long-term follow-up of 0.5 million adults, we did not find any increased risk of overall cancer in IBS vs general population. Instead, a lower risk of incident CRC and cancer-specific mortality was observed in patients with IBS.

The finding that the presence of IBS does not adversely affect overall cancer in general population is important because few studies have examined this. Although one Taiwan study based on the National Health Insurance Research Database observed 18% excess risk of overall cancer in patients with IBS, increased risk became nonsignificant after excluding cancer within first year (8). Our well-designed study with concurrent comparators confirmed this as no increased risk, even after addressing detection bias. Moreover, cancer incidence of the non-IBS group might be underestimated even if detection bias existed, which would thereby support the conclusion of no increased risk. Thus, our results provide reassurance for both patients who suffer from IBS symptoms and physicians who treat them.

Owing to overlapping symptoms between IBS and other gastrointestinal diseases, patients with IBS always fear subsequent CRC risk in next few years. Our study suggests that long-term CRC risk in IBS is 27% lower than general population after adjusting multiple confounders. One possible explanation might be a greater extent of medical examinations, particularly a higher frequency of colonoscopy/sigmoidoscopy, in IBS than reference individuals. Thus, the increased surveillance may lead to increased likelihood of earlier detection of colorectal precancerous lesion, adenoma and polyps, and further earlier treatment, which could thereby obtain lesser risk of developing CRC in patients with IBS. In the latest large-scale global epidemiological study, individuals with functional gastrointestinal disorders were twice as likely to consult doctors for bowel problems (3). Another study indicated that 36.4% of patients with IBS underwent ≥3 distinct gastrointestinal medical procedures/diagnostic tests vs national average during a 24-month period surrounding the first diagnosis, with an average of 0.78, 1.33, and 0.72 colonoscopies, abdominal/colon/pelvic computed tomography scans, and ultrasounds per patient, respectively (19). Another Taiwan study demonstrated that patients with IBS were more likely to have colonoscopy/sigmoidoscopy than general population both within 2 years (13.0% vs 2.28%) and after 2 years (8.23% vs 3.52%) (11). Accordingly, a higher polyps' rate was detected in IBS both within 2 years (4.16% in IBS vs 0.88% in general population) and after 2 years (3.38% in IBS vs 1.49% in general population) (11).

The observed lower risk of rectal cancer in patients with IBS was consistent with the Danish cohort study (14). An overall 33% decreased risk was observed in 57,851 patients with IBS during the 8.8-year follow-up (14). By contrast, in a 5.7-year Asian cohort (11) with 91,746 IBS and another 6.5-year UK cohort (10), initial increased CRC risk was observed; however, no difference in CRC occurrence was detected after excluding cancers diagnosed within the first 1 year or 2 years. This negative association may be mainly attributable to detection bias.

In addition, our study indicated that the HR of IBS associated with CNS cancer was 1.14 (95% CI: 0.83–1.57) and even higher (HR = 1.21, 0.81–1.80) in female vs non-IBS. Because IBS is considered as a disorder of gut-brain interaction, it has been proved that patients with IBS experience altered CNS processing in sensory, emotional, arousal, and prefrontal cortical regions of the brain (1). Owing to long-lasting and recurrent gut-brain interaction, CNS cancer risk might be higher in patients with IBS. However, because of the limited number of incident CNS cancers, our results were with wide CI and statistical power was insufficient (power = 12.59%). Hence, the follow-up with a larger sample size of CNS cancer is necessary to rule out increased risk in patients with IBS.

For the first time, we examine decreased cancer mortality risk in IBS vs general population, although IBS does negatively affect the quality of life and is associated with psychological illness. In addition to more frequent medical examinations and increased likelihood of treatment, patients with IBS may have a healthier lifestyle owing to chronic and relapsing symptoms. Currently, several guidelines (2,20) recommend reducing the intake of insoluble fibers, alcohol, and fat, as well as regular physical activity and adhering to a regular meal pattern, which has been proved to improve IBS symptoms and to contribute to lower cancer mortality (21–23). Ford et al. (24) also investigated the association between IBS and cancer deaths; however, because of the limited number of IBS (N = 81) and fewer cancer deaths, no definite conclusion could be drawn. Overall, we confirmed the benign condition of IBS that it would not shorten life span owing to cancer.

A major strength of our study is the use of a well-designed, large-scale, prospective cohort with concurrent control and the longest duration of the follow-up to date, which allows achieving a sufficient number of cases to investigate associated risk. Moreover, detection of cancers was based on linkage with national registries, which was accurate and reliable. In addition, we conducted various sensitivity analyses by accounting for protopathic bias, cancer latency, and further substantial subgroup analysis, verifying the robustness of the results.

Several limitations should be noted. First, some symptoms might lead to lifestyle changes during such a long-term follow-up (i.e., smoking and alcohol status). Hence, these time-varying covariates may bias the results. Second, residual confounders cannot be ruled out because some potential covariates, either unmeasured or unknown, may confound association between IBS and cancer/cancer-specific mortality, although we have carefully controlled for numerous potential confounders. Third, IBS identification was according to the ICD-10 codes, which might lead to misclassification because diagnostic criteria have shifted from Rome III to Rome IV. Finally, we could not further examine the association between IBS subtypes and cancer development/mortality because of data unavailability. Future long-term studies are needed to elucidate associated risk with IBS subtypes.

In conclusion, IBS does not lead to increased risk of overall cancer vs non-IBS individuals. Conversely, patients with IBS have a lower risk of incident CRC and cancer-specific mortality. In this circumstance, our findings provide reassurance for patients with IBS that IBS itself unlikely develops into CRC eventually and will not shorten life span owing to cancer. Both clinicians and patients with IBS should take this into consideration for better management of IBS conditions and save healthcare resources.

CONFLICTS OF INTEREST

Guarantor of the article: Shengtao Zhu, MD, PhD.

Specific author contributions: S.S.W. and S.T.Z.: designed the study. S.S.W.: drafted the article. S.S.W.: analyzed the data. Z.R.Y., F.S., and C.Z.Y.: revised the article. S.S.W., Z.R.Y., S.L., Q.Z., S.T.Z., C.Z.Y., and S.T.Z.: interpreted the results, incorporated comments for the coauthors, and finalized the article. All authors approved the final version of the article.

Financial support: This work was funded by the National Natural Science Foundation of China (No. 82070550).

Potential competing interests: None to report.

Data availability statement: All data relevant to the study were using the UK Biobank resource under application number 74444. No additional data were available.

Study Highlights

WHAT IS KNOWN

  • ✓ Cancer risk, along with cancer-specific mortality risk, is a primary concern for patients with irritable bowel syndrome (IBS).
  • ✓ Data on cancer and related mortality in IBS are limited to studies with insufficient events and no concurrent comparators.

WHAT IS NEW HERE

  • ✓ In this long-term prospective cohort with 0.5 million adults, IBS does not increase the overall risk of cancer.
  • ✓ Although affecting adversely quality of life, IBS is associated with lower risk of incident colorectal cancer and does not shorten life span owing to cancer.

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