AIM: To examine the demographic data on a large multi-ethnic population of patients with microscopic colitis (MC) in Southern California and to determine the association of MC with inflammatory bowel disease (IBD) and colorectal cancer.

METHODS: All patients diagnosed with MC by colonic biopsy from 1996-2005 were identified utilizing a pathology database. All biopsies were reviewed by experienced pathologists utilizing standard histologic criteria. Patients’ medical records were reviewed and data regarding patient age, co-morbidities, sex, ethnicity, and medications were analyzed. An age- and sex-matched standard control group was also generated. Chi-square test was used to evaluate the associations of co-morbidities between lymphocytic colitis (LC), collagenous colitis (CC) and the control group.

RESULTS: A total of 547 cases of MC were identified, 376 patients with LC and 171 patients with CC. The female/male ratio was 3:1 in CC and 2.7:1 in LC patients. Celiac disease (P < 0.001), irritable bowel syndrome (IBS) (P < 0.001), and thyroid diseases (P < 0.001) were found to have a higher occurrence in MC compared to the control group. No statistical differences in the occurrence of colorectal cancer, diabetes and IBD were found between the MC group and the control group.

CONCLUSION: This is the largest group of patients with MC known to the authors that has been studied to date. Conditions such as celiac disease, IBS, and thyroid diseases were found to be related to MC. Furthermore, neither an increased risk of colorectal cancer nor IBD was associated with MC in this study.

Microscopic colitis (MC) is a condition characterized by chronic, watery diarrhea with normal endoscopic appearance of colonic mucosa, yet abnormal histology. Further classification of this condition based on histology reveals two distinct entities: collagenous colitis (CC) and lymphocytic colitis (LC). Although both entities demonstrate colonic intraepithelial lymphocytosis, increased inflammatory cells within the lamina propria and preserved crypt architecture, the presence of a thickened sub-epithelial collagen band is characteristic of CC.

The incidence of CC is approximately 0.6-2.3/100 000 per year with a prevalence of 10-15.7/100 000, while LC has an incidence of 3.1/100 000 per year and a prevalence of 14.4/100 000[12]. However, more recently published data from Olesen et al[3] suggests that the incidence of microscopic colitides are on the rise. Observational studies have also suggested associations between MC and various autoimmune diseases including thyroid, rheumatoid, celiac, and inflammatory bowel disease (IBD)[4–7]. Various medications have also been linked with MC in published case reports. Currently, little is known regarding cancer risk associated with MC.

With the number of reported cases clearly increasing, surprisingly, its etiology is still mostly unknown. Furthermore, the relationship between collagenous and LC and their association with other diseases has yet to be clearly defined. Should a connection between MC and colorectal cancer or IBD exist, this would have huge ramifications on the management of MC. Most of the currently available data on MC are from European studies with relatively small and homogeneous populations. There are even fewer comparative studies on the subtypes of MC.

The purpose of this study was to observe and report the demographic data on a large multi-ethnic population in Southern California, USA, with MC. We also report on the pattern of concurrent diseases and cancers in this group of patients.

All patients diagnosed with MC (both collagenous and LC) from 1996 to 2005 by colonic biopsy were identified using the pathology database at Kaiser Permanente (a large health maintenance organization) in Southern California and the search words “MC, LC and CC”. This region includes eight major Kaiser Permanente medical centers that serve over three million members throughout Southern California.

The histological criteria for inclusion in this study were defined as follows: (1) An increase in intraepithelial lymphocytes (more than 10 lymphocytes/100 epithelial cells); (2) Surface epithelial damage; (3) Absent or minimal crypt architectural damage; (4) An increase in sub-epithelial collagen band > 10 micrometers was required for the diagnosis of CC (Figure 1).

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Figure 1 Collagenous colitis (A) and lymphocytic colitis (B).

Experienced gastrointestinal pathologists (JM, SW, NK, RZ, MK, JP, KG) at Kaiser Permanente reviewed all biopsies.

Patients with ulcerations, erythema or any other visible abnormalities seen on the colonic mucosa during the endoscopic exam were excluded from the study. We included patients with a history of colorectal cancer.

We reviewed medical records using the Kaiser Permanente Database System and recorded data regarding patient age at diagnosis, sex, ethnicity, and concurrent medical conditions. All medications taken by patients, within 1 year prior to the diagnosis of collagenous or LC, were also recorded for analysis.

Demographic data such as age at diagnosis, sex and ethnicity is presented as means and standard deviation. An age- and sex-matched standard control group was also randomly generated from the same Kaiser Permanente database. We used a chi-square test to evaluate the associations of co-morbidities between LC, CC and the control group.

Differences in the clinical characteristics between LC and CC were also evaluated using the chi-square test. Differences were assumed as significant at a P value of less than 0.05.

The study protocol was approved by the Internal Review Board of Kaiser Permanente in Southern California.

From January 1996 to July 2005 a total of 547 patients were identified with MC from our database. There were 27.1% male subjects, while 72.9% were female. The average age at diagnosis was 61.7 years for both men and women. We were able to identify the ethnicity in 465 cases. The percentage of each ethnic group was as follows: 72.4% Caucasian, 6.9% Hispanic, 2.6% Asian, 2.9% African American, and 0.2% Middle Easterners.

Increasingly, MC has become more and more recognized worldwide, yet little is know about its pathophysiology and the long term outcome of the disease. Currently, multiple hypotheses exist for the pathophysiology of MC and include immune dysregulation/autoimmunity. This hypothesis is further supported by findings that human leukocyte antigen haplotype is increased in A1 and DRW53 in LC[10]. While others have found increases in DQ2 and DQ1, three in LC and CC[11]. Autoantibodies such as ANA have also been found to be higher in patients with MC[12]. Indeed, multiple retrospective clinical studies have noted a higher incidence of autoimmune diseases in patients diagnosed with MC. This suspected relationship between immune dysregulation/autoimmunity and MC has led to the question of whether MC is a pre-IBD entity? If so, does the patient with MC require a higher level of surveillance and more aggressive treatment to prevent IBD from developing? These concerns were further illustrated by multiple case reports that seemed to convincingly suggest that MC may be the initial phase of a full blown IBD. However, the above theory has never been formally addressed in a large population study. In our investigation we were able to validate the previously known association between LC, CC and various autoimmune diseases, celiac disease and thyroid disorders in a large population study. Yet, interestingly, we found no significant correlation between IBD and CC/LC. Therefore, LC and CC may not be an indicator for intense surveillance to detect progression to IBD. To date, none of our LC or CC patients have been diagnosed with IBD.

Another theoretic risk for patients with MC is colorectal cancer. This concern is based on the IBD model where chronic inflammation can lead to increased dysplasia and malignancy. Thus far, to the authors’ knowledge, only one study has evaluated the risk of colorectal cancer in MC. Chan et al[13] studied 117 patients diagnosed with CC during a mean follow-up period of 7 years to examine the risk of colorectal cancer. A similar risk of colorectal cancer was found in MC patients and the general population in that study. Only one patient was diagnosed with colorectal cancer after being diagnosed with MC. This was confirmed in our study as no increase in colorectal cancer occurrence was found between our patients with MC and the control group.

Interestingly, we found that IBS was associated with MC in approximately 13% of our MC patients. Other studies have also shown a correlation between IBS and MC, with IBS diagnosed in up to 23% of patients with LC[1415]. The relationship is unclear, however it could be due to a similar clinical presentation between MC and IBS, as suggested by Barta et al[16]. There is also increasing evidence to support an inflammatory process in the pathogenesis of IBS. Furthermore, studies have shown that increasing amounts of intraepithelial lymphocytes can be seen in patients diagnosed with post infectious IBS[17]. Usually, the number of lymphocytes does not reach that needed for the diagnosis of MC in most post infectious IBS patients, however, there have been cases where patients with a clinical history of post infectious IBS have been diagnosed with MC. To accurately distinguish these entities is important, as their management and treatment may be very different. For example, currently, colonoscopy is rarely performed for the diagnosis of IBS. However, as a result of our findings, colonoscopy with random biopsy may be warranted as a part of the workup for suspected diarrhea predominant IBS in the future.

Endocrinopathies such as thyroid dysfunction and diabetes have been known to have correlations with MC as noted in previously published studies. Several studies showed that diabetes was found in up to 8.3% of CC patients and in up to 13.5% of LC patients[1819]. Despite reports of these associations, our study did not show a statistical significance when compared with our control group. One possible explanation for this is that LC, CC and diabetes tend to occur more frequently in elderly populations and thus could easily be thought of as related diseases. In a recent published study by Williams et al[20] after risk stratification of their data by age, the risk association between MC and the general population was no longer significant. Another possible explanation is that most of the previous studies were smaller in size which may have led to sampling error. However, the same argument can not be used to explain the high occurrence of thyroid dysfunction previously reported[21]. Indeed, we found a statistically higher occurrence of thyroid dysfunction in LC and CC patients when compared to the control group. The association between thyroid dysfunction, LC and CC is still unknown, although some suggest autoimmunity as a possible cause.

There are several limitations to our study. For example, because routine screening for other disorders that may be related to MC (such as celiac disease) were not performed in a prospective format, the prevalence of these associated disorders may be underestimated. Another limitation is the lack of long term follow up. Because of this lack of long term follow up, it is possible that colorectal cancers and IBD may not have had sufficient time to manifest. Due to this, we continue to actively follow these patients and long term data should be forthcoming in the future. Another limitation involves the retrospective nature of this study for which selection bias is commonly seen. However, we hope that the large patient population would minimize such bias.

Our analysis produced many interesting observations and provoked thoughtful questions regarding the etiology, disease mechanism, and associations with other diseases and medications in the largest study to date on MC. Several of these findings have been previously noted, however, some other relationships have yet to be reported. We believe that the large number of patients in our study makes this study less vulnerable to sampling error and provides a good representation of MC.