Microscopic colitis is an idiopathic chronic inflammatory disorder of the colon histopathologically characterized by plasmacytic infiltration of the mucosal lamina propria and intraepithelial T lymphocytosis. 1–3 As a syndrome, these histopathologic changes are associated with chronic diarrhea and a normal (or near-normal) endoscopic appearance of the colonic mucosa. Microscopic colitis may be associated histopathologically with the presence or absence of a thickened subepithelial collagen band that, in turn, has given rise to the terms collagenous colitis and lymphocytic colitis, respectively.
Although the exact cause of microscopic colitis has yet to be determined, recent data in both animals and humans have furthered our understanding of this issue. Extensive data from animal models of colitis (mainly rodents) suggest that virtually all forms of colitis, including the spontaneous colitis-affecting HLA-B27 transgenic rats 4,5 or various chemical-induced colitides, 6 require a microbial flora for development. In humans, fecal diversion via an ileostomy has resulted in histologic improvement in microscopic colitis, 7 and an antiinflammatory drug-possessing antimicrobial activity (bismuth subsalicytate 8,9) has resulted in sustained remissions of microscopic colitis. Further support of the fact that there is an intraluminal antigen involved in the immunologic pathogenesis of microscopic colitis comes from the regular presence of colonic intraepithelial lymphocytosis in the histopathology. In fact, it is this feature that gave rise to the term lymphocytic colitis for the form of microscopic colitis that is without excess subepithelial collagen (even though intraepithelial lymphocytosis is seen in collagenous colitis as well, although not as prominently quantitatively). The presence of intraepithelial lymphocytosis, combined with the plasmacytosis of the lamia propria and the surface epithelial flattening and irregularity, makes the colonic lesion of microscopic colitis strikingly similar to the small bowel enteropathic lesion of celiac sprue.
In addition to their histopathologic similarities, microscopic colitis appears to be epidemiologically related to celiac sprue and refractory sprue, as a scattering of patients with these sprue syndromes have been reported to have this form of colitis. 10–12 From studies conducted in my department, the prevalence of microscopic colitis in celiac and refractory sprue patients is 5% and 67%, respectively. 13,14 Microscopic colitis also was shown to be the most common cause of chronic diarrhea in patients with previously identified celiac sprue that had been treated for at least 1 year with a gluten-free diet. 13 Furthermore, using both standard and morphometric histopathologic techniques, we showed that colonic histopathology in patients with these sprue syndromes is indistinguishable from that in the isolated microscopic colitis syndrome. 14
In the study by Matteoni et al. 15 that is in this issue of the Journal, the authors attempted to determine, by retrospective review of pathology reports, the prevalence of celiac sprue in 113 patients found to have microscopic colitis after presenting to their hospital with chronic diarrhea between 1987 and 1999. The authors argued (perhaps appropriately) that the risk of lymphoma associated with celiac sprue might warrant a search for this disease in all patients with this form of colitis if the coexistence of the syndromes was found to be high. Unfortunately, only 36 of 113 patients identified during the study period to have microscopic colitis had a small bowel biopsy, and only 8 of these had serologic testing for gluten sensitivity (antigliadin immunoglobulin G [IgG] and IgA, and antiendomysial IgA). Nevertheless, 4 of these 36 patients were found to have small bowel inflammation associated with either subtotal or total villous atrophy (2 each), characteristic of gluten-sensitive enteropathy. However, only two of these four patients underwent an antigliadin antibody serology, and both were negative; the other six patients (of the eight who had serologic testing) underwent both small bowel biopsy and serologic testing, which also resulted in negative serologic test results. By reviewing medical records, the authors were able to identify ten additional patients with microscopic colitis who underwent serologic assessment for gluten sensitivity (but not small bowel biopsy); these, too, were negative. Because no data were reported about treatment with a gluten-free diet and because all serologic test results for an immunologic response to gluten were negative, in a strict sense, the small bowel enteropathy seen in these patients with microscopic colitis can neither be considered to represent celiac sprue nor can it even be attributed to gluten sensitivity.
If we assume that the characteristic small bowel enteropathy does represent celiac sprue in the four patients with small bowel inflammation associated with villous atrophy, we must wrestle with the major limitation of this study that attempted to determine the prevalence of celiac sprue in microscopic colitis. 15 This limitation relates to the facts that this study was retrospective, it involved a review of only pathology reports (rather than a reassessment of the biopsy slides by a blinded pathologist), and, most importantly, less than one third of their patients with microscopic colitis actually underwent small bowel biopsy, an obvious source of potential selection bias for those having small bowel histopathology (e.g., if these patients had therapeutic refractoriness, nutrient malabsorption, or another clinical sign associated with celiac sprue more often than those not undergoing small bowel biopsy and if it led their gastroenterologist to perform an upper endoscope). Nevertheless, as the authors point out in the article, in the worst-case numeric scenario (it was assumed that all patients with microscopic colitis who did not have a small bowel biopsy did not have celiac sprue), we are left with a prevalence of celiac-like enteropathy in 4 out of 113 patients with microscopic colitis, or 3.5%, which is statistically significantly higher than the emerging 0.4% to 0.6% prevalence in the general American population. 16 This prevalence is similar to the frequency with which celiac sprue coexists with various other autoimmune syndromes (e.g., primary biliary cirrhosis, autoimmune hepatitis, type I diabetes, and Sjogren's syndrome, to name just a few).
Recent studies published by my research group 17,18 have shed some etiologic light on the association of the celiac-like enteropathy with microscopic colitis. We prospectively analyzed the HLA-DQ genotype of 53 patients with microscopic colitis syndrome, hypothesizing that the celiac-associated HLA-DQ2 allele (present in 90% of patients with celiac sprue) might have a strong presence in microscopic colitis patients, which might explain the coexistence of these syndromes. This turned out to be the case, as HLA-DQ2 was seen in 64% of the colitis patients, compared with only 31% in 429 normal controls (p < 0.02). A second HLA-DQ gene—this time an allelic combination, HLA-DQ1,3 (the latter as DQ1,7, DQ1,8, or DQ1,9)—also was statistically significantly more frequent in microscopic colitis as compared with controls (p < 0.02). When considered with HLA-DQ2, these two HLA types were expressed in over 90% of patients with microscopic colitis (whether or not excess subepithelial collagen deposition was present) and were associated with a calculated odds ratio of 6.7.
Serum also was analyzed prospectively for antigliadin and antiendomysial antibodies in all patients in our study, 17,18 and as part of a prospective protocol, distal duodenal biopsies were obtained and blindly analyzed by a research pathologist for signs of histopathology in 37 of the 53 patients (the 16 patients not undergoing small bowel biopsy were entered into a separate protocol that did not call for this procedure to be performed). Serologic tests for celiac sprue were weakly positive in 17% of our patients with microscopic colitis. Duodenal histopathology was present in 70%, with mild inflammation of the lamina propria and intraepithelial lymphocytosis, but without villous atrophy in 43% and inflammation plus partial or subtotal villous atrophy in 27%. Although antigliadin antibodies were detected in only 17% of all microscopic colitis patients (a prevalence that was not statistically different from a 12% positivity rate found in an ulcerative colitis disease control group), these antibodies were detected with an increased frequency in the patients with duodenal histopathology involving inflammation, and even more frequently when this was accompanied by villous architectural distortion, as compared with those with normal duodenal histology. Furthermore, two patients with microscopic colitis (but none with ulcerative colitis) and one each with partial or subtotal villous atrophy, lamina propria inflammation, intraepithelial lymphocytosis, and an HLA-DQ2 allele had both antigliadin and antiendomysial antibodies in serum. Therefore, it is likely that these two patients (3.8% of the total) have outright gluten-sensitive enteropathy because of the virtually 100% specificity of these latter antibodies for a diagnosis of celiac sprue. 19 This frequency exactly parallels the 3.5% (4 of 113) frequency identified by Matteoni et al. 15 and, as pointed out by these authors, warrants some type of screening for gluten sensitivity in patients with microscopic colitis.
Thus, I would agree with the conclusion of Matteoni et al. 15 that the presence of gluten sensitivity should be ascertained in every patient with microscopic colitis. Although performing an upper endoscopy for the purpose of obtaining small bowel biopsies in all patients with microscopic colitis will find those patients with the most severe enteropathic changes of classic celiac sprue (seemingly present in 3–4%) (based on the results of our studies 17,18), most patients have more limited inflammatory and/or partial villous atrophic changes that may be underappreciated by anatomic pathologists as being consistent with gluten-sensitive enteropathy. Furthermore, it has been shown that patients with gluten sensitivity that present with any one of a number of clinical syndromes (e.g., chronic diarrhea without steatorrhea, classic chronic malabsorptive diarrhea, only osteoporosis, only hypocalcemia, only iron deficiency anemia, etc.) also may have very subtle small intestinal enteropathy that requires sophisticated morphometric histologic techniques 20 or in vitro immunologic assessment to detect abnormalities or proof of immunologic gluten sensitivity. 21 Thus, the notion is evolving that small intestinal biopsy is an insensitive method for identifying all patients with clinically significant gluten sensitivity. Because serologic testing seems to be unable to detect celiac sprue or milder forms of gluten sensitivity in patients with microscopic colitis (and possibly, by analogy, other chronic T cell-mediated immunologic syndromes associated with celiac spree), more sensitive, noninvasive testing must be developed for those patients who possess an increased risk of developing immunologic gluten sensitivity, which is presumably related to an HLA genetic predisposition. 17,18
1. Read NW, Krejs GJ, Read MG, et al. Chronic diarrhea of unknown origin. Gastroenterology 1980; 78:264–71.
2. Lazenby AJ, Yardley JH, Giardiello FM, et al. Lymphocytic (microscopic) colitis: a comparative histopathologic study with particular reference to collagenous colitis. Hum Pathol 1989; 20:18–28.
3. Lee E, Schiller LR, Vendrell D, et al. Subepithelial collagen table thickness in colon biopsies from patients with microscopic colitis and collagenous colitis. Gastroenterology 1992; 103:1790–6.
4. Hammer RE, Maika SD, Richardson JA, et al. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27–associated human disorders. Cell 1990; 63:1099–112.
5. Rath HC, Herfarth HH, Ikeda JS, et al. Normal luminal bacteria, especially Bacteroides
species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. J Clin Invest 1996; 98:945–53.
6. Garcia-Lafuente A, Antolin M, Guarner F, et al. Incrimination of anaerobic bacteria in the induction of experimental colitis. Am J Physiol 1997; 272:G10–5.
7. Jarnerot G, Tysk C, Bohr J, et al. Collagenous colitis and fecal stream diversion. Gastroenterology 1995; 109:449–55.
8. Fine KD, Lee EL. Efficacy of open-label bismuth subsalicylate for the treatment of microscopic colitis. Gastroenterology 1998; 114:29–36.
9. Fine K, Ogunji F, Lee E, et al. Randomized, double-blind, placebo-controlled trial of bismuth subsalicylate for microscopic colitis [abstract]. Gastroenterology 1999; 116:A880.
10. Breen EG, Farren C, Connolly CE, et al. Collagenous colitis and coeliac disease. Gut 1987; 28:364.
11. Sylwestrowicz T, Kelly JK, Hwang WS, et al. Collagenous colitis and microscopic colitis: the watery diarrhea-colitis syndrome. Am J Gastroenterol 1989; 84:763–8.
12. DuBois RN, Lazenby AJ, Yardley JH, et al. Lymphocytic enterocolitis in patients with refractory sprue. JAMA 1989; 262:935–7.
13. Fine KD, Meyer RL, Lee EL. The prevalence and causes of chronic diarrhea in treated celiac sprue. Gastroenterology 1997; 112:1830–7.
14. Fine KD, Meyer R, Lee EL. Colonic histopathology in untreated celiac sprue and refractory sprue: is it lymphocytic colitis or colonic lymphocytosis? Hum Pathol 1998; 29:1433–40.
15. Matteoni CA, Goldblum JR, Wang N, et al. Celiac disease is highly prevalent in lymphocytic colitis. J Clin Gastroenterol 2001; 32:225–7.
16. Berti I, Horvath K, Green P, et al. Prevalence of celiac disease among risk groups and the general population in USA [abstract]. Gastroenterology 2000; 118:A696.
17. Fine K, Lafon G, Ogunji F, et al. The genetic and histopathologic relationship of microscopic colitis and celiac sprue or refractory sprue [abstract]. Gastroenterology 1999; 116:A879.
18. Fine K, Lafon G, Ogunji F, et al. High prevalence of celiac sprue-like HLA-DQ genes and enteropathy in patients with the microscopic colitis syndrome. Am J Gastroenterol 2000; 95:1974–82.
19. Valdimarsson T, Franzen L, Grodzinsky E, et al. Is small bowel biopsy necessary in adults with suspected celiac disease and IgA anti-endomysium antibodies? 100% positive predictive value for celiac disease in adults. Dig Dis Sci 1996; 41:83–7.
20. Cooper BT, Holmes GK, Ferguson R, et al. Gluten-sensitive diarrhea without evidence of celiac disease. Gastroenterology 1980; 79:801–6.
21. Picarelli A, Maiuri L, Mazzilli MC, et al. Gluten-sensitive disease with mild enteropathy. Gastroenterology 1996; 111:608–16.