Lymphocytic and Collagenous Colitis: Epidemiologic Differences and Similarities

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1 Dig Dis Sci (2013) 58: DOI /s ORIGINAL ARTICLE Lymphocytic and Collagenous Colitis: Epidemiologic Differences and Similarities Amnon Sonnenberg Robert M. Genta Received: 12 March 2013 / Accepted: 8 May 2013 / Published online: 26 May 2013 Ó Springer Science+Business Media New York (Outside the USA) 2013 Abstract Background It is unknown whether the subtypes of microscopic colitis (MC) represent distinct nosologic entities or related presentations of the same disease. Our aim was to search for epidemiologic differences among its various histopathologic subtypes. Methods In a computerized database of 789,568 colon pathology reports, we compared the characteristics of 8,745 MC patients with those of the remaining population. Results MC was diagnosed as three distinct histopathologic subtypes: lymphocytic colitis (LC) in 51 %, collagenous colitis (CC) in 43 %, and incomplete colitis (IC) in 6 % of patients. Only 0.65 % was simultaneously diagnosed with more than one subtype of MC. The prevalence of all three subtypes showed an age-dependent rise, with the average age (SD) being 63.3 (14.3) years in LC, 66.4 (12.1) years in CC, and 67.3 (12.7) years in IC (p \ ). There was a striking female predominance in all three subtypes, the female fraction being 72 % in LC, A. Sonnenberg (&) Department of Gastroenterology, Portland VA Medical Center P3-GI, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA sonnenbe@ohsu.edu A. Sonnenberg Oregon Health and Science University, Portland, OR, USA R. M. Genta Miraca Life Sciences, Irving, TX, USA R. M. Genta University of Texas Southwestern Medical Center, Dallas, TX, USA R. M. Genta Dallas VA Medical Center, Dallas, TX, USA 82 % in CC, and 79 % in IC (p \ ). All three subtypes showed similar geographic distributions among different US states. They were similarly associated with diarrhea and weight loss, the odds ratios for all MC being ( ) and 5.12 ( ), respectively, compared to control patients without MC. All three subtypes also harbored significantly less colonic adenomas, the overall odds ratio being 0.11 ( ). Conclusion MC comes in three distinct histopathologic entities, which show striking similarities of their general epidemiologic features. The slight differences in their demographic characteristics could point at varying sets of environmental influences that affect the occurrence of subtypes. Keywords Adenomatous polyps Collagenous colitis Geographic distribution Epidemiology Lymphocytic colitis Microscopic colitis Introduction Microscopic colitis (MC) is a chronic relapsing disease of the large bowel associated with watery diarrhea [1 4]. Although the lining of the large bowel may appear normal to macroscopic examination during colonoscopy, biopsies reveal increased lymphocytic infiltrates into the colonic epithelium and into the lamina propria, as well as an abnormal deposition of a broad band of collagen underneath the epithelium. In lymphocytic colitis (LC) the main histologic feature is a lymphocytic intraepithelial infiltrate (with more than 20 CD3? lymphocytes per 100 enterocytes) as well as a moderate infiltrate in the lamina propria, characterized by lymphocytes, plasma cells, and numerous eosinophils. Collagenous colitis (CC) is characterized by

2 Dig Dis Sci (2013) 58: similar infiltrates in both epithelium and lamina propria; in addition, there is the deposition of a collagen band (that, by definition, should be thicker than 10 l) immediately beneath the epithelial layer. Besides these two primary subtypes of MC, several authors have also described a third form termed intermediate or incomplete MC [5 8]. In this third type, the lymphocytic intraepithelial invasion and the subepithelial collagen layer may be restricted to few focal areas of the colonic mucosa, the collagen layer may not quite reach the critical thickness of 10 l, or the lymphocytic infiltration of the epithelium may not reach a critical threshold of 20 intraepithelial lymphocytes per 100 surface epithelial cells. Although the histopathologic features of the two main subtypes may co-exist simultaneously, most pathologists consider the presence of a thickened collagen band to be the major diagnostic determinant and, whenever it is present, they tend to make a diagnosis of CC. Therefore, two distinct patient populations are generally recognized. Long-term follow-up of patients with MC shows little conversion from one type into the other [6, 9, 10]. However, clinically the various subtypes present with similar symptoms and respond similarly to the same type of treatment. Because of this clinical, therapeutic, and at least to an extent histopathologic overlap, it has remained unresolved whether lymphocytic and CC represent distinct nosologic entities or related histopathologic presentations of the same disease [11]. The aim of the present study was to search for differences and similarities in the clinical epidemiology of the different subtypes associated with MC, using a large national database of histopathology reports. Methods Data Source The present case control study was conducted at Miraca Life Sciences, a specialized gastrointestinal laboratory, operating with private outpatient endoscopy centers distributed throughout the United States. The results of all surgical pathology were stored in a single electronic database. Besides demographic characteristics, each patient record also contained the clinical and endoscopic diagnoses, as well as a detailed list of all results of surgical pathology. If individual patients appeared in the database with multiple colonoscopy reports, only the results of the index endoscopy were included, when the colitis was first diagnosed. Similarly for the comparison group, only the results of the first colonoscopy were considered. Surgical pathology diagnoses were coded in a pre-defined, standardized, and searchable fashion. The study was approved by the Miraca Life Sciences Institutional Review Board. All data of the study were collected exclusively by reviewing pre-existing records, and no direct contact with either patients or providers was made. No individual patient information was revealed and patient records were de-identified before being included in the present analysis. For these reasons, the study protocol was exempted from the need for informed consent from its participants. Biopsy Specimens Patients included in this study were referred to gastroenterologists by primary care providers or other specialists from almost every US state, comprising a broad sampling of primary gastroenterology practices in the United States. Approximately 1,500 individual gastroenterologists distributed throughout the US contributed to the database. The endoscopies were performed at private, community-based endoscopy centers or multispecialty surgery centers. All patients in the database who underwent colonoscopy with mucosal biopsies between January 2008 and December 2011 were included in the analysis. The presence of colon biopsy specimens was the sole criterion for inclusion. Biopsy specimens were processed centrally in three laboratories located in Irving, Texas; Phoenix, Arizona; and Boston, Massachusetts. Identical sectioning and staining procedures were followed in each laboratory. Slides were reviewed and interpreted by an experienced group of dedicated subspecialty-trained gastrointestinal pathologists, who have shared a common approach to biopsy evaluation. Uniformity among the pathologists was achieved through a standardized approach to specimen handling and a pre-determined set of diagnostic criteria and terminology for biopsy interpretation. Consensus has been maintained and updated through daily multi-headed microscope conferences, monthly didactic conferences, journal club, terminology and criteria review committee, and ongoing comprehensive quality assurance review. All three centers have participated simultaneously in these activities through teleconferencing. Over 350,000 tissue specimens have been examined per year. Miraca pathologists diagnosed lymphocytic and CC according to the criteria they have outlined in Carmack et al. [12]. Briefly, the criteria for LC included increased intraepithelial lymphocytes ([20 intraepithelial lymphocytes per 100 surface epithelial cells) in an architecturally normal colonic mucosa, accompanied by surface epithelial disarray and a mixed inflammatory infiltrate in the lamina propria [12, 13]. The infiltrate contained superficial lympho-plasmocytosis, typically with eosinophilia in the lamina propria. CC was distinguished by an increase in the thickness of the subepithelial collagen band more than 10 l

3 2972 Dig Dis Sci (2013) 58: (sometimes referred to as the collagen table ) in a setting otherwise typical of LC [13]. Miraca pathologists often saw in colon biopsies features of both lymphocytic and CC, but when results were reported, they made a diagnosis based on whatever feature predominated. When the lymphocytic intraepithelial invasion and the subepithelial collagen layer were restricted to few focal areas of the colonic mucosa or the collagen layer did not reach a critical width of 10 l, the pathologists used the diagnosis focal CC. This entity is identical to that referred to in the literature as incomplete MC and, for consistency, we use the latter term. Statistical Analysis The statistical analysis was carried out using AccessÒ and ExcelÒ (from Microsoft), as well as the statistical software of SAS in Cary, NC, USA. The primary outcome measure was the prevalence of each subtype of MC, expressed as rate per 1,000 colonoscopies with biopsies. The geographic distributions of each two subtypes were compared using least-square linear regression analyses. The regression analyses were restricted to the 35 largest US states with more than 2,000 colonoscopy patients per state in the database. Differences in age among the three subtypes were compared using analysis of variance. Differences in gender distribution among the three subtypes were compared using v 2 analysis. Varying frequencies of occurrence between cases (with MC) and controls (without MC) were compared, calculating odds ratios and their 95 % confidence intervals. Fig. 2 Age specific prevalence of lymphocytic colitis (LC), collagenous colitis (CC), and incomplete colitis (IC) Results In the database of 789,568 individual subjects, we found 8,745 unique patients with MC. Among the 8,745 cases, Fig. 3 Age distribution of patients with lymphocytic colitis (LC), collagenous colitis (CC), and incomplete colitis (IC) Fig. 1 Overlap among the three separate histopathologic diagnoses of microscopic colitis. LC lymphocytic colitis, CC collagenous colitis, IC incomplete colitis MC presented itself as three distinct histopathologic subtypes, that is, LC in 51 %, CC in 43 %, and incomplete colitis (IC) in 6 % of patients. Only 0.65 % of patients were simultaneously diagnosed with more than one subtype of MC (Fig. 1). The prevalence of all three subtypes showed an agedependent rise. This rise was observed similarly in females and males (Fig. 2). The age-specific prevalence of female LC and IC showed a slight drop in the oldest age group of years. Figure 3 depicts the proportional age distribution of the three diagnoses. The majority of patients presented with MC in the age groups and years.

4 Dig Dis Sci (2013) 58: Fig. 4 Gender distribution of patients with lymphocytic colitis (LC), collagenous colitis (CC), and incomplete colitis (IC) The patient population with LC comprised slightly younger patients and less pronounced peak at years. The average age (SD, range) was 63.3 (14.3, 12 96) years in LC, 66.4 (12.1, 18 97) years in CC, and 67.3 (12.7, 18 94) years in IC (F ratio = 46.22, p \ ). There was a striking female predominance in all three subtypes of MC, with the fractions of females being 72 % in LC, 82 % in CC, and 79 % in IC (v , p \ ) (Fig. 4). All three subtypes of MC showed similar geographic distributions among different US states. MC was most common in western states, such as Colorado, New Mexico, Idaho, Utah, Arizona, and Montana. Its prevalence was relatively low in eastern US states, such as Rhode Island, New York, Massachusetts, Connecticut, and New Jersey. The three correlations among the three subtypes were statistically significant, with r = 0.79, p \ for the correlation of lymphocytic versus CC; r = 0.50, p = for lymphocytic versus IC; and r = 0.65, p = for collagenous CC versus IC (Fig. 5). Table 1 summarizes the clinical presentations in patients with the three subtypes. Diarrhea, pain, and weight loss occurred in 84, 10, and 6 %, respectively, of all patients with MC. Compared to subjects without MC, all three subtypes were characterized by a significant rise in the occurrence of diarrhea and weight loss. Lymphocytic ileitis was a relatively infrequent comorbid condition in all three subtypes alike. There was a striking absence of adenomatous polyps in all three subtypes of MC. Overall, the three subtypes were characterized by relatively similar clinical presentations. Discussion Our epidemiologic study of the histologic subtypes associated with MC revealed that gastrointestinal pathologists tend to classify the features of MC in three distinct subtypes. LC and CC were the most commonly used diagnoses, with incomplete MC a distant third. Compared with the latter two, LC tended to affect slightly younger patients and more females. All three subtypes showed similar geographic variations within the US and tended to be associated with similar clinical presentations. There are several potential limitations of the present analysis. Because our study utilizes a database of patients undergoing colonoscopy, we had to calculate prevalence rates Fig. 5 Correlations between the geographic distributions of lymphocytic colitis (LC), collagenous colitis (CC), and incomplete colitis (IC) in the US. Each point represents a different US state, n = 35

5 2974 Dig Dis Sci (2013) 58: Table 1 Clinical characteristics in patients with microscopic colitis stratified by subtype Characteristic Colitis Control OR 95 % CI Lymphocytic colitis Age (years) Male 1, , Female 3, , ( ) Total 4, ,823 Ileitis 16 6, ( ) Adenoma , ( ) Anemia 47 18, ( ) Diarrhea 3,716 79, ( ) Constipation 52 38, ( ) Pain , ( ) Weight loss 276 9, ( ) Hematochezia 91 30, ( ) Screening , ( ) Collagenous colitis Age (years) Male , Female 3, , ( ) Total 3, ,823 Ileitis 17 6, ( ) Adenoma , ( ) Anemia 62 18, ( ) Diarrhea 3,206 79, ( ) Constipation 37 38, ( ) Pain , ( ) Weight loss 235 9, ( ) Hematochezia 35 30, ( ) Screening , ( ) Incomplete colitis Age (years) Male , Female , ( ) Total ,823 Ileitis 1 6, ( ) Adenoma , ( ) Anemia 7 18, ( ) Diarrhea , ( ) Constipation 8 38, ( ) Pain 58 75, ( ) Weight loss 31 9, ( ) Hematochezia 6 30, ( ) Screening , ( ) per colonoscopy patients with biopsies rather than prevalence rates per living population. Our reliance on pathology reports prevented us from considering in the control population any subjects without colonic biopsy or without colonoscopy at all. The numbers of case and control subjects available for individual US states were influenced not only by state size but also by geographic referral patterns to the Miraca pathology laboratory. These limitations may have affected overall magnitude of some of the associations reported here. For instance, the female predominance among patients with MC is tested against a background of a generally higher colonoscopy penetrance in women than men. Similarly, the association of abdominal pain with MC is being compared with the occurrence of pain among all subjects undergoing colonoscopy, whose baseline prevalence of pain may be higher than in the general population. These potential limitations need to be contrasted with some obvious advantages in using the Miraca database to carry out epidemiologic analyses. With its three main laboratories located in Dallas, Boston, and Phoenix, Miraca Life Sciences handles gastrointestinal biopsy specimens submitted from endoscopists distributed throughout the United States. All diagnoses in the database are based exclusively on histological evaluation by board certified pathologists specialized in gastrointestinal surgical pathology. These characteristics are of crucial importance in 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 were missed or erroneously assigned to the comparison group. Another obvious advantage of our reliance on a national database has been the ability to accumulate a patient population that is orders of magnitude larger than in any of the previous analyses. Without such large case numbers it would have been difficult or impossible to reliably study the geographic distribution of MC or its inverse association with the presence of adenomatous polyps. In a previous study that followed 27 patients with LC for a mean of 38 months, none of the LC transformed over time into CC [9]. Similarly, most other studies have reported no or only very infrequent conversion between lymphocytic and CC [6, 10]. Occasionally, pathologists encounter difficulties in clearly differentiating between the two subtypes [8, 9]. Most of such difficulties stem from the inability to recognize a clear and broad collagenous band that extends underneath the epithelial layer. Compared with other studies, the group of GI pathologists at Miraca seemed more confident in assigning a definitive diagnosis of lymphocytic or CC with a relatively low rate of overlap. If Miraca pathologists saw features of both lymphocytic and CC, they generally chose between the two diagnoses based on the predominant feature. When it happened that one biopsy had all features of CC whereas another one showed characteristic LC, the pathologists were strongly discouraged from using a separate diagnosis for each site, because such practice would confuse the referring

6 Dig Dis Sci (2013) 58: clinician. Few patients were labeled as IC and even fewer patients were diagnosed simultaneously with a combination of the three subtypes. Our study revealed some statistically significant differences among the three subtypes of MC, especially with respect to their age and gender distribution. In spite of these differences, however, the overall age and gender distribution of the three histopathologic subtypes were quite similar in that all three affected predominantly elderly women. In addition, similar patterns were also found with respect to their other epidemiologic behavior, such as geographic variation and clinical associations. These similarities strongly suggest that lymphocytic, collagenous and incomplete MC represent related expressions of one single underlying disease process. Varying sets of environmental influences may affect the slight differences in the epidemiologic appearance of the three subtypes. The inverse relationship between the presence of colonic adenoma and MC is one of the most interesting findings of the present study. The strength of the association was partly unexpected. It was found similarly in all three subgroups of patients, adding credence to its overall relevance. One of the main reasons for performing colonoscopy is to take out polyps and prevent the future occurrence of colorectal cancer. There is no reason to assume that work-up for diarrhea and the sampling of random biopsies in any way would keep endoscopists from excising polyps during the same colonoscopy. In all patients with multiple colonoscopies, we included patients based on the results of the first colonoscopy. We cannot rule out, however, that some case and control subjects underwent a prior colonoscopy with polypectomy before their inclusion into the present database. But such possibility is unlikely to have accounted for a tenfold difference in the adenoma prevalence between patients without and with MC. A more likely explanation for the low adenoma rate in the case population could be that MC truly suppresses epithelial proliferation in the colon mucosa. The literature contains one additional investigation that demonstrates a decreased long-term risk of colorectal adenoma and colorectal cancer among patients with MC [14]. The mechanisms underlying any protective influence of MC against the formation of colorectal adenoma are currently unknown. In conclusion, MC comes in three distinct histopathologic entities, which show striking similarities of their general epidemiologic features. Subtle, but statistically significant differences with respect to their age and sex distributions, as well as their geographic variations, may point at varying sets of environmental influences that affect the occurrence of the three subtypes of MC. Acknowledgments Amnon Sonnenberg was supported by a grant from Takeda Pharmaceuticals. No funding was obtained for this study. Conflict of interest Robert M. Genta is employed by Miraca Life Sciences, Irving, TX. No funding was obtained for this study. References 1. Temmerman F, Baert F. Collagenous and lymphocytic colitis: systematic review and update of the literature. Dig Dis. 2009;27: Pardi SP, Kelly CP. Microscopic colitis. Gastroenterology. 2011;140: Yen EF, Pardi DS. Review article: microscopic colitis lymphocytic, collagenous and mast cell colitis. Aliment Pharmacol Ther. 2011;34: Münch A, Aust D, Bohr J, et al. Microscopic colitis: current status, present and future challenges: statements of the European Microscopic Colitis Group. J Crohn s Colitis. 2012;6: Fraser AG, Warren BF, Chandrapala R, et al. Microscopic colitis: a clinical and pathological review. Scand J Gastroenterol. 2002;37: Bjørnbak C, Engel PJH, Nielsen PL, et al. 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