Section 3 -

Collagenous and Lymphocytic Colitis Audrey J. Lazenby Professor, Department of Pathology University of Alabama School of Medicine Birmingham, AL

Collagenous Colitis Collagenous colitis is a clinicopathologic syndrome characterized by:(1) chronic watery diarrhea and crampy abdominal pain, and (2) distinctive colorectal histopathology that includes a subepithelial collagen band, prominent chronic inflammation in the lamina propria, and increased intraepithelial lymphocytes. Lindstrom described the first case in 1976, in a middle-aged Swedish woman, and coined the term collagenous colitis because of the histopathologic similarity to collagenous sprue, in which there is a subepithelial collagen deposit in jejunal mucosa [1]. Over the subsequent three decades, collagenous colitis has been increasingly recognized with a recent reported incidence of 6.1 per 100,000 persons, in Orebo, Sweden [2]. This disease is found mainly in "Western" countries in Europe, Australia, and North America, but cases have been reported from around the world including Africa [3]. Pathologic Features: As the name implies, there are two main histologic components to collagenous colitis: (1) increased collagen deposition and (2) colitis. In normal colon, a delicate basement membrane is visible just beneath the lumenal epithelium, measuring less than 3 microns in thickness [4]. In collagenous colitis, there is abnormal deposition of collagen immediately beneath the basement membrane. This collagen forms a subepithelial band in the superficial lamina propria, that is readily recognized on H&E stains. By immunohistochemical staining, this band contains collagens type I, III, and VI as well as tenascin [5]. Stains for basement membrane components, such as type IV collagen and laminin, do not mark the collagen band, emphasizing that the band is not a thick basement membrane but rather an abnormal deposit beneath the basement membrane. Electron microscopic studies also emphasize that the collagen band is separate from and beneath the basement membrane [6]. By H&E stains however, one cannot distinguish between the basement membrane and the collagen deposited beneath it. In collagenous colitis, the measured width of the band is variable between studies and within studies, between patients. In individual patients, band thickness can vary throughout the colon with the transverse colon usually having the thickest bands [7]. The rectum can lack a thick subepithelial collagen band in up to 33% of cases and in a small percentage, the rectum can be histologically normal with no increase in inflammation [7]. Consequently, multiple biopsy specimens should be taken in areas proximal to the rectosigmoid to establish or exclude the diagnosis of collagenous colitis. Rarely, collagenous gastritis is found [8], and functional as well as histologic abnormalities of the small bowel have been noted in patients with collagenous colitis [9, 10] . The increased subepithelial collagen has qualitative and quantitative changes from normal colon. In normal colonic epithelium, the basement membrane has sharp, well-defined edges. In early collagenous colitis, the increased collagen imparts a shaggy appearance to the lower border of the basement membrane with tendrils of collagen extending down into the upper lamina propria, where capillaries may be "entrapped" by the collagen. To delineate mild increases in subepithelial collagen, a trichrome stain may be employed. German investigators have touted immunoperoxidase stains for tenascin as a sensitive and specific marker for the subepithelial collagen band [11, 12]. Any increase in subepithelial collagen, in the proper inflammatory and clinical context, is diagnostic of collagenous colitis. Hence, measurement of the thickness of subepithelial collagen layer is not necessary to diagnose collagenous colitis. The second histologic component in collagenous colitis involves increases in inflammation both in the lamina propria and within the epithelium. The lamina propria is expanded by a mixture of inflammatory cells, including plasma cells, lymphocytes, eosinophils, and mast cells. Increased eosinophils can be striking in some cases. Eosinophil granule component as well as TGF beta made by the eosinophils, may be involved in the pathophysiology of the disease [13, 14, 15]. Early, small studies noted the occasional prominence of neutrophilic inflammation in some cases of collagenous colitis [16, 17] and proposed that acutely inflamed cases represent an earlier stage of the disease. These "IBD-like" features have been emphasized in larger, more recent studies. Ayata et al found small numbers of neutrophils in 30% of cases, Paneth cell metaplasia in 44% and rare crypt distortion in 7.6% of cases [18]. Extensive neutrophils and pseudomembranes are rare but have been described in a few cases, both with and without detectable C. difficile infection [19, 20, 21, 22]. When ulcers occur in collagenous colitis, there is usually a second etiology such as NSAID usage [23]. A distinctive component of collagenous colitis is increased intraepithelial lymphocytes. An increase in these cells is present in the majority, but not all, cases of collagenous colitis. Prominent diffuse increases in intraepithelial lymphocytes are not a feature of other forms of colitis or enteritis except for celiac disease and lymphocytic colitis. The intraepithelial lymphocytes of collagenous colitis are predominantly CD8+ T cells and express the alpha beta form of the T cell receptor [24, 25]. Surface epithelial damage (flattening, detachment) may also be present. Pitfalls In The Diagnosis Of Collagenous Colitis Misdiagnosis of collagenous colitis can occur by focusing exclusively on the thickness of the subepithelial collagen band. Collagenous colitis is an inflammatory disorder of the colon, and thus increased mucosal inflammation is a prerequisite to the diagnosis. There can be a mildly thickened subepithelial collagen layer/thick basement membrane in some non-inflammatory conditions, such as hyperplastic polyps and diabetes mellitus [26, 27]. This basement membrane can appear artificially increased in size especially from tangential sectioning. To avoid misdiagnosis, remember that there are two words in the name of this condition – colitis as well as collagenous, and both components must be present for a correct diagnosis. Also remember that the rectum can lack the typical features of CC and thus more proximal biopsies are necessary to exclude CC. Pathogenesis: The cause of collagenous colitis is unknown, and thus it can be considered a type of chronic idiopathic IBD, albeit of a "gentler and more subtle form [28]." Hypotheses for the etiology of collagenous colitis include (1) immune dysregulation, (2) abnormalities in pericryptal fibroblasts, (3) intraluminal bacterial agents or toxins, (4) plasmatic vasculosis, and (5) drug induced damage. Some of the most intriguing recent findings relate to the possible role of infectious agents in collagenous colitis. Swedish investigators found that diverting the fecal stream caused clinical and histological remission in nine patients and that clinical symptoms and an abnormal collagen table returned after ostomy takedown, which suggests that some lumenal agent or toxin is involved [29]. Other lines of evidence point to an infectious trigger including greater frequency of antibodies against Yersinia virulence factors in collagenous colitis compared to control patients [30], and scattered case reports of collagenous colitis developing after C. difficile infection [19, 22]. The pattern of inflammation, with increased intraepithelial lymphocytes, suggests polarization of the immune system toward a luminal agent. One hypothesis is that a foreign luminal agent, possibly bacteria, initiates colorectal inflammation that leads to an immunologic cross-reactivity with an endogenous antigen in luminal epithelial cells leading to a self sustaining inflammatory condition. On the other hand, collagenous colitis has been linked in rare cases to lansoprazole administration, but the association is more common with lymphocytic colitis [31, 32]. In these cases, drug was clearly associated with onset of symptoms and resolved with lansoprazole was stopped. NSAIDs have also been linked to collagenous colitis by some but not all investigators [33]. The mechanisms of diarrhea are variable between patients. Fasting improves, but does not totally abate the diarrhea in most patients, suggesting both an osmotic and a secretory component to the diarrhea [34]. Reduced Na and Cl absorption are the main mechanisms of diarrhea in collagenous colitis, but there is also an active component of Cl secretion. Down regulation of tight junction molecules, particularly occluding, is thought to contribute to the diarrhea [35]. While the diarrhea is felt to be mainly of colonic origin, some studies have also shown abnormal permeability in the small bowel as well [36]. A plethora of inflammatory mediators have been found to be elevated in collagenous with the most recently investigated including basic fibroblast growth factor, nitric oxide, and vascular endothelial growth factor [37, 38, 39]. Clinical History: Collagenous colitis is a disease primarily of women with a female to male ratio of 9:1 in recent Swedish studies [2, 40]. This disorder is seen primarily in middle-aged patients in their 50's and 60's, but there is a wide age range of presentation. Chronic watery diarrhea is the main symptom and in most patients has been present months to years. Nocturnal diarrhea is not uncommon. The patients often also have crampy diffuse abdominal pain, symptoms which cause misdiagnosis with irritable bowel syndrome. Enteropathic arthritis is seen in approximately 7% of collagenous colitis patients, with the arthritis being seronegative for rheumatoid factor and nondestructive [41]. A variety of other immunologic disorders have been noted in this patient population, with 17%-40% of patients having coexistent autoimmune illnesses [42]. Routine laboratory studies are usually normal. However, antineutrophilic cytoplasmic antibodies have been described [43]. Importantly, gastrointestinal radiographic and endoscopic examinations usually show normal mucosa. Thus, it is essential for clinicians to biopsy grossly normal mucosa to establish this diagnosis. Treatment: While collagenous colitis is usually a chronic process, patients can have spontaneous remissions, thus complicating evaluation of drug effectiveness. While dietary modification (elimination of caffeine, lactose, or NSAIDs) may help some individuals, most require medication of some sort. In the past, first line therapy was with sulfasalazine or other 5-ASA derivatives [44]. If that therapy failed, patients were treated with steroids or even more potent immunosuppressives. Currently, two main therapeutic regimens are being touted, either therapy with (budesonide) or high dose bismuth preparations. Budesonide is a topically acting steroid with high first pass metabolism in the liver, and so little systemic side effect. While patients usually respond to the above medications, it is not infrequent for there to be flares of diarrhea after the medication is stopped [45, 46, 47]. Lymphocytic Colitis Lymphocytic colitis has similar clinical features to collagenous colitis. Watery diarrhea is the main symptom with most individual also noting a mild, intermittent, crampy abdominal pain [48]. Most patients are middle-aged, but in contrast to collagenous colitis, there is less of a gender gap, with a female:male ratio of 2.4:1. [49]. The incidence of lymphocytic colitis is reported as 5.7/100,00 individuals, in Sweden from 1996-1998 [2]. Routine hematologic tests are usually normal, but occasionally the Westergren sedimentation is increased. Some patients have increased titers of anti-nuclear antibodies, anti-parietal cell antibodies, and anti-microsomal antibodies [42, 50]. Lymphocytic colitis patients have an increased frequency of HLA A1 and of a diminished frequency of HLA A3 compared to controls [42]. Pathologic Features: The main histologic feature of lymphocytic colitis is increased intraepithelial lymphocytes. In a normal colon, the number of intraepithelial lymphocytes (IELs) is approximately 5 per 100 epithelial cells, while in lymphocytic colitis, the median number of IELs is 30 lymphocytes per 100 epithelial cells (range 10 to 50) [52]. As in collagenous colitis, the intraepithelial lymphocytes are CD8+ T lymphocytes, employing primarily alpha-beta forms of the T cell receptor [24]. Surface epithelial damage may be present and a mild increase in chronic inflammation in the lamina propria is also seen. There is minimal to no increase in intraepithelial neutrophils, and crypt distortion is generally absent, which sets these cases apart from ulcerative colitis and Crohn's disease. In contrast to collagenous colitis, there is not a subepithelial collagen band – the basement membrane has a sharp, discrete lower border [52, 53]. Also, in comparison to collagenous colitis, there are usually fewer eosinophils, and the amount of chronic inflammation in the lamina propria is usually less. Pathogenesis: While collagenous colitis is a tightly coherent clinicopathology entitiy, lymphocytic colitis is a more a more amorphous condition occurring in varied clinical settings [49, 54, 55]. While most of the cases are idiopathic and chronic, some are associated with celiac disease and will resolve when the patients go on a gluten-free diet [56]. A small group of cases is also associated with particular drugs, including ticlopidine, carbamazepine, cimetidine, ranitidine, simvastatin, and some drugs used primarily in France including veinotonics and vinburnine [50]. Finally, cases have been reported following certain infections, and thus may represent a slowly resolving infection or perhaps and abnormal persistent immune response following an infectious trigger [57]. While most early studies describe chronic diarrhea, a more recent Swedish study found a single attack in 63% of cases, with a chronic persistent or chronic intermittent course in the remaining [49]. In this same study, there was a family history of some type of intestinal inflammatory disease in 12% of patients, suggesting a genetic underpinning in some [49]. The histology is slightly different between the cases of classical, idiopathic lymphocytic colitis and those with known etiologies. Lymphocytic colitis that is associated with celiac disease, related to certain medications, and post-infections seem to have less inflammation in the lamina propria and may have mainly increased intraepithelial lymphocytes. Some prefer to diagnose these cases with known etiologies as "colonic epithelial lymphocytosis". My practice is to lump all the cases together as lymphocytic colitis and to always add a note as follows: "Lymphocytic colitis can be seen in varied clinical settings including celiac disease, post-infectious, in association with certain medications and as an idiopathic condition". Pitfalls In The Diagnosis Of Lymphocytic Colitis Compared to biopsies from classical, idiopathic inflammatory bowel disease, such as ulcerative colitis, the histologic changes in lymphocytic colitis are relatively mild and subtle. But, all mild and subtle changes from "normal" are not synonymous with lymphocytic colitis. Regional variations in normal histology and focal changes may lead to an over-diagnosis of lymphocytic colitis. In different regions of the large intestine, there is a variation in histologic "normalcy". Compared to the rest of the colon, the cecum normally displays more crypt mitotic figures, decreased epithelial mucin, slightly more plasma cells and eosinophils and lamina propria, and slightly more intraepithelial lymphocytes. Thus, be aware that biopsies from the cecum are normally "busy". Also, some cases of Crohn's disease, in addition to the normal histologic features, have focal increases in intraepithelial lymphocytes [58, 59]. Lymphocytic colitis is characterized by a diffuse increase in intraepithelial lymphocytes, usually with more chronic inflammation of the lamina propria. Thus, pay attention to the location of the biopsy and look for diffuse changes to insure a correct diagnosis. 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