The occurrence of inflammatory bowel disease (IBD) is characterized by a marked geographic variation.1, 2 In general, IBD is more common in the affluent societies of Westernized countries. In Europe and North America, IBD is more common among populations living in northern than southern latitudes.1–5 Within the U.S., several previous studies, using statistics of mortality, hospitalizations, physician visits, and colonoscopy, have confirmed a similar pattern of more frequent occurrence in northern than southern states.6–8 In these studies, ulcerative colitis (UC) and Crohn's disease (CD) were generally characterized by similar geographic distributions. Microscopic colitis (MC) is a condition that includes a spectrum of histological abnormalities of the colonic mucosa, ranging from an increase in the number of intraepithelial lymphocytes (“lymphocytic colitis”) to a diffuse lymphoplasmacytic infiltrate of the lamina propria, prominent intraepithelial lymphocytosis, and the formation of a thick subepithelial collagen band (“collagenous colitis”).9, 10 Clinically, MC is associated with watery diarrhea that responds to similar medications as CD and UC. Its epidemiologic and clinical relationships with other forms of IBD are still unknown. Overall, the epidemiology of MC is less well characterized than that of UC or CD. The clinical terms microscopic, lymphocytic, and collagenous colitis have been missing from the 9th and 10th revisions of the International Classification of Diseases (ICD). The diagnosis of MC relies primarily on the histological appraisal of its characteristic features in patients with chronic or intermittent diarrhea. Because the diagnosis cannot be made based on clinical criteria alone, it is less likely to enter disease registries, be recorded by health surveys, or become listed on death certificates. Caris Life Sciences, a specialized gastrointestinal laboratory, has maintained a large database of pathology reports from endoscopy patients distributed throughout the U.S. In the present study, we used this unique database to study the geographic distribution of MC and compare it with the geographic distributions of UC and CD.
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- MATERIALS AND METHODS
Over 670,000 individual patients were included in the present study, of whom 17,000 were diagnosed with UC or CD and 9,900 with MC. Besides UC and CD, the overall group of IBD also included 754 patients with indefinite colitis. Table 1 contains a stratification of the patient population by gender and histological diagnosis. MC was 3-fold more common among women than men: OR: 2.98, 95% CI: 2.84–3.12. By comparison, CD was only slightly more common in women (OR: 1.14, 95% CI: 1.07–1.21) and UC was slightly less common in women than men (OR: 0.93, 95% CI: 0.89–0.96). Patients with MC were significantly older (P < 0.0001) than CD or UC patients.
Table 1. Patient Population Stratified by Histological Diagnosis and Gender
| ||Microscopic Colitis||Crohn's Disease||Ulcerative Colitis||All IBD||All Colonoscopies|
|Age (SD)||62.6 (15.0)||46.6 (16.6)||49.4 (16.4)||48.7 (16.4)||59.2 (13.6)|
|Females||7,438 (2.19%)||2,050 (0.60%)||5,647 (1.66%)||7,697 (2.27%)||339,200 (100%)|
|Males||2,475 (0.75%)||1,758 (0.53%)||5,941 (1.79%)||7,699 (2.32%)||331,222 (100%)|
|Sex ns||6 (0.80%)||2 (0.27%)||11 (1.46%)||13 (1.72%)||754 (100%)|
|Total||9,919 (1.48%)||3,810 (0.57%)||11,599 (1.73%)||15,409 (2.30%)||671,176 (100%)|
Table 2 shows the patient population stratified by geographic region, gender, and histological diagnosis. Except for minor differences, the age and gender distributions were similar across patient populations from different census regions of the U.S. MC was significantly more common in the West than any other region, whereas CD was significantly less common in the West than any other region. UC was lowest in the South compared with other regions.
Table 2. Patient Population Stratified by Region, Gender, and Histological Diagnosis
| ||Northeast||Midwest||South||West||Region ns||Grand Total|
|Age (SD)||58.5 (13.6)||59.4 (13.7)||59.1 (13.7)||59.9 (13.3)||59.4 (13.3)||59.2 (13.6)|
|Females||61,121 (49%)||48,387 (50%)||144,882 (52%)||83,021 (50%)||1,789 (51%)||339,200 (51%)|
|Males||64,628 (51%)||47,271 (49%)||134,844 (48%)||82,795 (50%)||1,684 (48%)||331,222 (49%)|
|Sex ns||230 (0%)||213 (0%)||190 (0%)||118 (0%)||3 (0%)||754 (0%)|
|Microscopic colitis||1,476 (1.17%)||1,172 (1.22%)||3,946 (1.41%)||3,303 (1.99%)||22 (0.63%)||9,919 (1.48%)|
|Crohn's disease||764 (0.61%)||590 (0.62%)||1,716 (0.61%)||727 (0.44%)||13 (0.37%)||3,810 (0.57%)|
|Ulcerative colitis||2,621 (2.08%)||1,649 (1.72%)||4,358 (1.56%)||2,940 (1.77%)||31 (0.89%)||11,599 (1.73%)|
|All IBD||3,763 (2.99%)||2,444 (2.55%)||6,798 (2.43%)||4,033 (2.43%)||47 (1.35%)||17,085 (2.55%)|
|Total||125,979 (100%)||95,871 (100%)||279,916 (100%)||165,934 (100%)||3,476 (100%)||671,176 (100%)|
Besides analyzing the geographic distribution on a regional level, the data also provided the opportunity to study them by individual states. Based on state size and referral patterns, the total number of colonoscopies per state in the database varied between 1 and 62,476. Overall similar statistical results were obtained using the entire dataset or subsets restricted to larger states. To assure statistically reliable data for individual states, the final analysis was limited to the 30 largest states with populations greater than 3600 individual patients. Among these states, the number of patients with MC or IBD varied between 39 and 1090 or 68 and 1276, respectively. Table 3 shows the geographic distributions of the three diagnoses and all IBD combined among the 30 states with the largest numbers of colonic biopsy reports. Similar to previous studies, IBD tended to be common in states of the Northeast or North Central division of the Midwest and relatively rare among several Southern states. MC appeared to follow a somewhat inverse pattern, as it was most common among some states from the Southwest (Colorado, New Mexico, Arizona, Nevada) and other states of southern latitude, such as Florida, Georgia, California, but relatively uncommon among states in the Northeast.
Table 3. Geographic Distribution of Microscopic Colitis, and IBD Among 30 US States
| ||Microscopic Colitis||Crohn's Disease||Ulcerative Colitis||All IBD|
|Northeast|| || || || |
|Midwest|| || || || |
|South|| || || || |
|West|| || || || |
Within each diagnostic category, there was a strong correlation between disease frequency among women and men (P < 0.0001 for all diagnoses) (Fig. 1). UC and CD were also significantly correlated with each other, with R = 0.60 and P = 0.0004 (Fig. 2). Significant correlation coefficients were found if gender subgroups were compared with each other, that is, female UC with female or male CD, and male UC with female or male CD. However, no significant correlations were observed between MC and all IBD combined or between MC and UC or CD analyzed separately.
Figure 1. Correlations among the geographic distributions of male and female patients with UC, CD, IBD, and MC. Data expressed as proportional rates per 1000 colonoscopies with biopsies; each point represents a separate U.S. state. P < 0.0001 for all R-values.
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Figure 2. Correlations between the geographic distributions of UC and CD (left graph), and between IBD and MC (right graph). Data expressed as proportional rates per 1000 colonoscopies with biopsies; each point represents a separate U.S. state. P = 0.0004 for R = 0.60 and P = 0.5014 for R = −0.13.
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- Top of page
- MATERIALS AND METHODS
Little is known about the epidemiology of MC and possible environmental risk factors, which influence its occurrence. In using a large database of pathology reports, we analyzed the geographic distribution of MC within the U.S. and compared it with those of UC and CD. Whereas UC and CD showed similar geographic variations, no resemblance was found to that of MC.
There are several potential limitations of the present analysis. Because our study used a nonpopulation-based dataset, we had to calculate proportional rates (per colonoscopies with biopsies) rather than prevalence rates per living population. The numbers of case and control subjects available for individual states were influenced not only by state size but also by geographic referral patterns to the Caris pathology laboratory. Our reliance on pathology reports prevented us from considering IBD cases with small bowel involvement only or diagnosed based on other criteria besides colonic biopsy. This limitation may have contributed to the relative dominance of UC over CD patients in our patient population, whereas most epidemiologic studies from North America have found ratios closer to 1 when comparing the two diagnoses.
These limitations need to be contrasted with some obvious advantages in using the Caris database to carry out epidemiologic analyses. With its three main laboratories located in Dallas, Boston, and Phoenix, Caris Life Sciences handles gastrointestinal biopsy specimens submitted from endoscopists distributed throughout the U.S. All diagnoses in the database are based exclusively on histological evaluation by board-certified pathologists specialized in gastrointestinal surgical pathology. These characteristics are especially important for MC, the diagnosis of which rests primarily on the microscopic appearance of colonic biopsy specimens. Since all patients of the present study underwent colonoscopy with endoscopic biopsies, it is unlikely that patients with a diagnosis of MC or IBD were missed or erroneously assigned to the comparison group. There is a possibility, however, that diligence and expertise in managing patients with chronic diarrhea varies among practices and that such variations contributed to the observed geographic patterns. Gastroenterologists specializing in IBD may be unevenly distributed throughout the U.S. and some of the observed patterns may be influenced by an underlying selection bias in the recruitment of endoscopy practices. One would expect such selection bias to affect MC and IBD alike rather than being restricted to one or the other disease entity alone. Moreover, expertise and specialization in colorectal diseases and IBD tends to parallel exposure to large patient populations harboring these diagnoses. The geographic distribution of IBD is validated by similar geographic patterns that have been reported by previous investigators relying on different types of epidemiologic data.1–8
Besides varying practice patterns among gastroenterologists, the observed geographic distributions could have been also influenced by underlying variations among pathologists in establishing the various diagnoses. The methods section lists multiple measures of quality assurance implemented among the three Caris laboratories. However, no amount of joint training, criteria touting, joint sessions, or conferences will ever be able to completely eliminate all interobserver variability in surgical pathology, or, for that matter, in any other specialty. Caris pathologists use all the above methods, including a criteria committee that prepares and attempts to enforce their use through a widespread quality control program. Besides Dallas, pathologists from the other two locations in Boston and Phoenix read 10% and 25% of all colon biopsies, respectively, and join conferences through video links that include telepathology, that is, high-quality live images delivered to each site. In addition, cases from various states are constantly shifted from one laboratory to another, depending on pathologists' availability, daily volume, and other factors. Therefore, the influence that any single site or individual pathologists can exert on the prevalence of a specific condition is likely to be negligible.
The distinct north–south gradient and the similarity among UC and CD are striking features in the geographic distribution of IBD.1–8 The reasons for this behavior are unknown. There is a significant correlation between amount of exposure to ultraviolet radiation and the occurrence of IBD. However, it is presently unclear whether such association reflects a causal relationship or represents a mere ecologic bias. The epidemiology of IBD is characterized by many striking features, such as large temporal, ethnic, occupational, and socioeconomic variations.1–3 Like its other epidemiologic features, the geographic distribution strongly suggests that environmental factors must play a role in the etiology of IBD. The similarity in the geography of UC and CD also suggests that the two diseases must share one or several identical risk factors. The dissimilar geographic distribution of MC alludes to a set of environmental risk factors that are different from those of UC or CD. The dissimilar age and gender distributions also point in the same direction.
In conclusion, the present analysis of a large pathology database confirms a similar geographic distribution of UC and CD across the U.S., as previously observed with respect to other morbidity parameters. UC and CD both appear to be generally more common in northern than southern U.S. states. MC does not share a similar geographic distribution with UC or CD. This difference in epidemiologic behavior points at a dissimilar set of risk factors that shape the occurrence of MC as opposed to UC or CD.