The prevalence of inflammatory bowel diseases, microscopic colitis, and colorectal cancer in patients with irritable bowel syndrome

The diagnosis of irritable bowel syndrome (IBS) is symptom-based and experts have developed diagnostic criteria for IBS. Distinguishing inflammatory bowel diseases (IBD) from IBS, especially with mild disease activity, can be difficult. Another concern is microscopic colitis (MC). MC and IBS have similar symptoms and a normal endoscopic appearance. Our study investigated the prevalence of patients with IBD, MC, and colorectal cancer among 968 patients that fulfill the Rome III criteria for IBS. Among these patients, four were found with IBD (0.4%) and seven with MC (0.7%). Among the IBD patients, three suffered from Crohn’s disease, affecting the terminal ileum, and one with ulcerative rectosigmoiditis. Of the seven patients with MC, two had collagenous colitis and five had lymphocytic colitis. Two IBS diarrhea-predominant patients had adenocarcin oma in the sigmoid colon. These patients were a female aged 58 years and a male aged 56 years. We concluded from our study and earl ier studies that symptom-based diagnosis of IBS may lead to missing a number of other gastrointestinal disorders that require quite different management than that for IBS.


Introduction
Irritable bowel syndrome (IBS) is a chronic condition, which is characterized by abdominal discomfort or pain, abdominal bloating, and changes in bowel habits. 1,2About 15-25% of the world's population suffer from IBS. 1 Besides the increased morbidity caused by IBS, it represents an economic burden to society in different direct and indirect forms such as increased sick leave and over-consumption of healthcare resources. 2,3There are no biologic, anatomic, or physiologic markers for IBS. 3 Thus, the diagnosis is symptom-based and experts have developed criteria, such as the Rome III criteria, for the diagnosis of IBS. 4 In these criteria, warning symptoms such as weight loss, rectal bleeding, and the presence of inflammatory/infection markers should be excluded.IBS patients are subgrouped, on the basis of differences in predominant bowel patterns, as: diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), or a mixture of both diarrhea and constipation types (IBS-M).
Distinguishing inflammatory bowel diseases (IBD) from IBS can be difficult, especially with mild disease activity.Both conditions share a symptom complex with abdominal pain and altered bowel habits.Moreover, IBS-like symptoms are frequently reported before the diagnosis of IBD. 5,6Another concern is microscopic colitis (MC), which has similar symptoms to IBS and also a normal endoscopic appearance. 3Diagnostic overlap between IBS and IBD on one hand and IBS and MC on the other is important because of potentially different treatments for each disorder.Our study is an attempt to investigate the prevalence of patients with IBD, MC, and colorectal cancer among patients, who fulfill the Rome III criteria for IBS, referred to the gastroenterology section in our hospital in the last five years.

Patients
Patients referred to the gastroenterology section, Stord Helse-Fonna Hospital, from December 2005 to December 2010 who satisfied the Rome III criteria for the diagnosis of IBS were considered for inclusion in the study.Patients between 18 and 60 years of age who did not suffer from organic gastrointestinal disease or clinically significant system disease were included in the survey.Pregnant or lactating women were excluded.Furthermore, patients who had undergone any abdominal surgery, with the exception of appendectomy, Cesarean section, or hysterectomy, were excluded.In addition, patients with a history of psychosis or mental illness were not included.All patients underwent a complete physical examination and were investigated by blood tests including a full blood count; investigation of electrolytes, calcium, folic acid, vitamin B12, inflammatory markers; and kidney, liver, and thyroid function tests.

Ileocolonoscopy
Ileocolonoscopy was done in all patients as a routine in our hospital.Two biopsies were taken from the cecum, ascending colon, and right half of the transverse colon (the six biopsies pooled to represent the right colon), and two biopsies were taken from the left half of the transverse colon, descending colon, and sigmoid colon (pooled to represent the left colon).Three to four biopsies were also taken from the ileum, and from pathological findings that were observed.Biopsies were fixed in 4% buffered paraformaldehyde overnight, embedded in paraffin wax, and cut into 5 μm thick sections.Kristin Koppang for her enthusiasm and for assisting in and keeping up the patients' lists as well as organizing the medical records.Thanks are due to Åsa Helene Lundal at the Department of Pathology, Haugesund hospital, for co-ordinating the collaboration between Stord and Haugesund hospitals.We thank the nurses Eli Lillebø, Astrid Reinemo, and Lillian Salmelid for assisting during the colonoscopies.We would like to express our gratitude to Professor Hans Olav Fadnes, head of the Department of Medicine, Stord Helse-Fonna hospital, for his support and for reading the manuscript.This study was supported by a grant from Helse-Fonna.
Contributions: ME, planned the project, examined the patients, performed the colonoscopies on most patients, evaluated the results, and wrote the manuscript; JH contributed to the planning, examining of some of the patients with a colonoscopy, and writing the manuscript; BL-B, performed the histopathological examinations and participated in the planning and writing of the manuscript; DG participated in planning, evaluating of results, and writing of the manuscript.
Conflict of interest: the authors report no conflicts of interest.

N o n -c o m m e r c i a l u s e o n l y
Histopathology and immunohistochemistry The sections were stained with hematoxylin-eosin and immunostained with the avidin-biotin complex (ABC) method, using the Vectastain ABC-kit (Vector Laboratories) as described in detail earlier. 7The primary antibodies used were: monoclonal mouse antihuman leukocytes CD45 (DakoCytomation, code no.IS751) and monoclonal antibodies to collagen type III (Acris, code no P02461).The second layer of biotinylated mouse anti-IgG were obtained from DakoCytomation, Denmark.The stained and immunostained sections were examined for the possible occurrence of MC.
The diagnosis of lymphocytic colitis required an increase in intraepithelial lymphocytes (>15 lymphocytes/100 epithelial cells) and surface epithelial damage, with increased lamnia propria plasma cells and absent or min-imal crypt architectural distribution.For the diagnosis of collagenous colitis, an increase or irregularity in subepithelial collagen (>10 μm) that trapped superficial capillaries was required as well as the other inflammatory changes seen in lymphocytic colitis. 8

Patients
The study included a total of 968 patients with an average age of 32 years (range 18-59 years).Females made up 95% of all patients.Of the patients, 45% were IBS-D, 30% IBS-M, and 25% IBS-C (Tables 1 and 2).

Ileocolonoscopy
The ileum, colon, and rectum of all patients were macroscopically normal, except in four IBS-D patients who showed mucosal lesions.The first three had scattered aphthoid ulcers in otherwise normal mucosa of the terminal ileum.The fourth patient had diffusely erythematous, friable, and granular mucosa with the loss of the normal vascular pattern, extending for 10 cm of the sigmoid colon and including the whole rectum (Figure 1).These patients were three females and one male aged 32, 59, 35, and 57 years, respectively.This amounts to a prevalence of 0.4% of IBD in patients with IBS.Two IBS-D patients each showed a tumor in the sigmoid colon, from where biopsies were taken.These patients were a female aged 58 and a male aged 56 years.

Histopathology and immunohistochemistry
Histopathological examination showed that the four patients with mucosal lesions  Furthermore, seven IBD-D patients showed MC: two with collagenous and five with lymphocytic colitis (Figures 2 and 3).The two patients with collagenous colitis were females aged 36 and 42 years; those with lymphocytic colitis were four females and one male, aged 24, 27, 35, 36, and 42 years.Thus, the prevalence of MC in IBS patients was 0.7%.The histopathological examination in the two IBS-D patients with a sigmoid tumor confirmed the diagnosis of adenocarcinoma.

Discussion
Our study represents the largest evaluation of the diagnostic outcome of ileocolonoscopy and mucosal biopsies in patients with all subtypes of IBS, namely, IBS-D, IBS-M, and IBS-C.Furthermore, our study concentrated on the clinically relevant diagnoses, which call upon treatment measures other than those offered for IBS patients.Thus, IBD, MC, and colorectal cancer were considered.Other harmless structural lesions were not accounted for.
Several gastroenterologists believe that a symptom-based diagnosis, such as that based on the Rome III criteria, without warning symptoms is enough for the diagnosis of IBS and no further investigations are needed.The American College of Gastroenterology Task Force does not recommend routine colonic imaging in patients younger than 50 years of age without alarm features and colonoscopic imaging should be reserved for those over the age of 50 years for the purpose of cancer screening. 9In our study, two patients had had carcinoma of the colon.Both of them were over 50 years old.Thus, this recommendation seems to be suitable for detecting and diagnosing colorectal cancer in this group of patients.Actually, colorectal cancer is the diagnosis that patients fear the most and physicians are concerned to miss.In a previous study on 196 subjects with suspected IBS, one patient with colon carcinoma was found, amounting to a prevalence of 0.5%. 10ur study showed that 0.4% and 0.7% of patients that fulfilled the Rome III criteria without alarm symptoms suffered from IBD and MC, respectively.In the same material, 0.2% of colonic carcinoma was found.One of the patients with ulcerative rectosigmoiditis had had rectal bleeding in the last 25 years because of hemorrhoids.Rectal bleeding, therefore, was not a new sign to her.Thus, 1.3% of patients with organic gastroenterological disease who required different treatments would be undiagnosed, following the previously mentioned recommendations.Patients with IBD would be treated with cortisone first and then with drugs targeting TNF-a.Those patients with MC should be treated with budesnoid, which is the first-choice treatment. 11As for colorectal carcinoma, surgery and eventually chemotherapy are the available treatments.It is noteworthy that all the gastrointestinal organic diseases observed in our study occurred in IBS-D patients.
][15][16] Several studies have found that MC can mistakenly be diagnosed as IBS. 17-213][24][25][26][27][28][29][30] In patients with CD presenting in adulthood, minimal or atypical symptoms are encountered.The breadth of the spectrum of symptoms associated with IBS represents a potential for overlap between IBS and CD symptomatologies.Thus, individuals with CD presenting with relatively vague abdominal symptoms are at risk of being dismissed for having IBS.The situation becomes more complicated by the fact that in both CD and IBS patients, abdominal symptoms are triggered by ingesting wheat products.Whereas this can be explained in CD patients as a gluten allergy, one attributes this effect in IBS to the long sugar polymer, fructan, in wheat.In the same patient group investigated here, the prevalence of CD was 0.4%. 30None of the patients with MC had CD.
It is conceivable to conclude from our findings and from earlier studies that symptombased diagnosis of IBS may lead to missing a number of other gastrointestinal disorders that require quite different management to that for IBS.Sigmoidoscopy in IBS patients might be insufficient, as a considerable number of MC cases may not be identified without mucosal biopsies from the right colon. 20urthermore, performing a sigmoidoscopy would not exclude Crohn's disease lesions in the terminal ileum.Other blood tests seem to have a rather low sensitivity. 31Ileocolonoscopy is preferable, therefore, especially in IBS-D patients.
To perform an ileocolonoscopy with mucosal biopsies in IBS patients at first seems to add a greater economic burden to healthcare, which is already suffering from a lack of resources.In addition, it seems that resources for seriously ill patients would be provided to meet this task.IBS patients are already consuming a lot of the healthcare resources.3][34] Not only do IBS patients visit doctors more frequently but they also use more diagnostic tests, consume more medications, miss more workdays, have lower  work productivity, are hospitalized more frequently, and consume overall direct costs than those without IBS. 357][38] Actually, most IBS patients have undergone colonoscopy once or several times.Unfortunately, the doctors that refer them and those who perform colonoscopy directly or indirectly act as if they expect no pathologic findings and that the examination is unnecessary.This does not reassure IBS patients and they seek another examination again and again.To perform an ileocolonoscopy would reassure IBS patients and prevent them from seeking a new examination.In conclusion, performing an ileocolonoscopy with mucosal biopsies in IBS patients would not increase the economic burden of this patient group on society but instead would use the existing resources effectively.

Figure 1 .
Figure 1.Endoscopic appearance of the terminal ileum with aphthoid ulcers in a 32-year-old female (A), and in the sigmoid colon of a 57-year-old female (B).Both fulfill the Rome III criteria for irritable bowel syndrome.

Figure 2 .
Figure 2. Photomicrographs of the colon of a 36-year-old female who fulfills the Rome III criteria for irritable bowel syndrome.Sections are stained with hematoxylin and eosin (A), for collagen III (B), and for CD45 (C).

Figure 3 .
Figure 3. Lymphocytic colitis in a colonic section immunostained for CD45 in a 24year-old female.This patient fulfills the Rome III criteria.

Table 2 . Data of irritable bowel syndrome-diarrhea patients, who have been found to suffer from an organic dis- ease.
All had normal electrolytes, normal S-bilirubin, S-ASAT, SALAT, and S-glucose; *normal values.