—  SHORT COURSE #44  —

Non-Neoplastic Disorders of the Intestines

Case 3 - Collagenous Colitis

Laura W. Lamps, M.D.
Audrey J. Lazenby, M.D.
Joel K. Greenson, M.D.


Clinical Presentation:
This 47 year old woman had an eight month history of diarrhea, nausea, vomiting, and peripheral eosinophilia of 11%.


Case 3 - Figure 1 - Low magnification shows thickened subepithelial collagen band as well as a mixed inflammatory infiltrate within the lamina propria and epithelium.
Case 3 - Figure 2 - Higher magnification highlights the inflammatory infiltrate typical of collagenous colitis, sometimes including increased eosinophils.


Endoscopic Findings:
Colonoscopy was essentially normal.

Diagnosis :
Collagenous colitis with increased eosinophils.

General Comments:
Collagenous colitis (CC) is a disease primarily of women, with a female to male ratio of 9:1. This disorder is seen primarily in middle aged females with a mean age of 59 years at diagnosis, but a wide age range at presentation. No well documented cases have been described in children.

Chronic watery diarrhea is the main symptom, and in most patients has been present for months to years. Nocturnal diarrhea is not uncommon. The patients often have crampy diffuse abdominal pain, which may cause confusion and misdiagnosis as irritable bowel syndrome. A nondestructive, seronegative, enteropathic arthritis is seen in about 7% of CC patients. A variety of other immunologic disorders have been noted in these patients, with 17-40% having other autoimmune illnesses.

Routine laboratory studies are usually normal. However, antineutrophilic cytoplasmic antibodies have been reported. Radiographic and endoscopic studies are also usually normal. Thus, it is essential for clinicians to biopsy grossly normal mucosa to establish this diagnosis.

CC is a clinicopathologic syndrome characterized by (1) chronic watery diarrhea and crampy abdominal pain and (2) distinctive colorectal histopathology that includes a thickened subepitihelial collagen band, prominent chronic inflammation in the lamina propria, and increased intraepithelial lymphocytes. In 1976, Lindstrom described the first case. Lindstrom coined the term "collagenous colitis" because of the histopathologic similarity to collagenous sprue, in which a collagen deposit is seen in a similar subepithelial location but in jejunal mucosa. Several studies have addressed the prevalence of CC. In persons with chronic diarrhea, the frequency of CC ranges from 0.3% to 5.0%. The incidence of this disorder has been estimated to range from 1.8 to 5.2 cases per 100,000 population. This disease is found mainly in "western" countries in Europe, Australia, and North America, but rare cases have been reported from Japan and Africa.

Pathologic features:
As the name implies, there are 2 main histologic components to CC: increased collagen deposition and colitis. A main histologic component is the presence of increased subepithelial collagen. The collagenous band is actually beneath the epithelial basement membrane; it is not a thickened basement membrane. The increased collagen can be recognized on conventional H&E stains as an eosinophilic band localized beneath the surface epithelium. On H&E and trichrome stains the basement membrane and the abnormal collagen band blend together visually. By immunoperoxidase stains, however, the subepithelial collagen band stains for a variety of collagens, primarily types I, III, and VI collagen, as well as tenascin. Stains for basement membrane components (type IV collagen and laminin) do not stain the abnormal collagen band. In normal patients, the subepithelial basement membrane is no greater than 3µm, but can be thicker in hyperplastic polyps and with tangential sectioning. In CC, the width of the band averaged 15µm in one series. In many patients, band thickness varies throughout the colon with the transverse colon usually having the thickest bands. The rectum can lack the subepithelial collagen band in up to 25% of cases, and in a small percentage, the rectum can be normal with no increase in inflammation. Consequently, multiple biopsy specimens should be taken in areas proximal to the rectosigmoid. In rare cases, subepithelial collagen has been noted to involve the duodenum and stomach in patients with CC.

The increased subepithelial collagen has qualitative and quantitative differences from normal colon. In normal colonic mucosa, the basement membrane has sharp, well defined borders. In CC, 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. To delineate mild increases in subepithelial collagen, a trichrome stain is helpful. Immunoperoxidase stains for tenascin have also been touted as a sensitive and specific marker for the subepithelial collagen band. Any increase in subepithelial collagen, in the proper inflammatory and clinical context, is diagnostic of CC. Hence, measurement of the thickness of subepithelial collagen layer is not necessary to diagnose CC.

The second histologic component in CC 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-ß produces by eosinophils may be involved in the pathophysiology of the disease. Crypt distortion is rare, but Paneth cell metaplasia is not uncommon, and a sprinkling of neutrophils can be seen in up to 25% of cases. Extensive neutrophils and pseudomembranes are rare, but have been described in a few cases, potentially in acute or early stages of the illness or in concomitant C. difficile infection.

A distinctive component of CC is increased intraepithelial lymphocytes. An increase in these cells is present in the majority, but not all, cases of CC. Prominent intraepithelial lymphocytes are not a feature of other forms of colitis or enteritis except for celiac disease and lymphyocytic colitis.The intraepithelial lymphocytes of CC are predominantly CD8+ T cells and expresss the alpha/beta form of T cell receptor. Surface epithelial damage (flattening, detachment) may also be present.

Misdiagnosis of CC can occur by focusing exclusively on the thickness of the subepithelial collagen band. CC is an inflammatory disorder of the colon, and thus increased mucosal inflammation is a prerequisite to the diagnosis. The basement membrane can appear artificially increased in size. For example, tangential sectioning of the basement membrane creates a thicker basement membrane than when correctly oriented.

Pathogenesis:
The cause of CC is unknown, and thus it can be considered a type of chronic idiopathic IBD, albeit of a "gentler and more subtle form." Hypotheses for the etiology of CC include immune dysregulation, abnormalities in pericryptal fibroblasts, intraluminal bacterial agents or toxins, plasmatic vasculosis, and drug induced damage.

Some of the most intriguing recent findings relate to the possible role of infectious agents in CC. Swedish investigators found that diverting the fecal stream caused clinical and histologic remission in 9 patients and that clinical symptoms and an abnormal collagen table returned after ostomy takedown. This, of course, suggests that some luminal agent or toxin is involved, Some investigators have found clinical improvement in patients treated with antibiotics or with bismuth subsalicylate, an agent thought to work via an antibacterial mechanism. Also, antibodies against Yersinia virulence factors are more common in CC than in controls. 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 self sustaining inflammatory condition.

CC has also been linked in rare cases to lansoprazole administration (although this association is actually more common with lymphocytic colitis). In these cases, the drug was clearly associated with the onset of symptoms, and resolved when it was stopped. NSAIDs have also been linked to CC by a few investigators.

The mechanisms of diarrhea are variable. Fasting improves, but does not totally abate, diarrhea in most patients, suggesting both an osmotic and a secretory component. Reduced sodium and chloride absorption are the main mechanisms of diarrhea in CC, but there is also an active component of chloride secretion. Down regulation of tight junction molecules, particularly occludin, is thought to contribute to diarrhea. While the diarrhea is felt to be mainly of colonic origin, some studies have also shown abnormal small bowel wall permeability.

Differential diagnosis:
Lymphocytic colitis. This disease is the most similar to CC. Histologic similarities include increased intraepithelial lymphocytes, increased chronic inflammation in the lamina propria, and minimal architectural distortion. The major difference is the absence of a thickened subepithelial collagen band in lymphocytic colitis.

Celiac disease. Celiac disease has histologic similarities to both CC and lymphocytic colitis, as all of these entities have a striking increase in subepithelial lymphocytes. Furthermore, collagenous sprue has a prominent subepithelial collagen band in the small bowel. Although some patients have been reported with both celiac disease and CC, the majority of CC patients have microscopically normal duodenal and jejunal biopsies (although ileal biopsies may show a slight excess of intraepithelial lymphocytes).

Crohn's disease and ulcerative colitis. In CC, the epithelium contains numerous lymphocytes but few neutrophils. The reverse is true for UC and CD, which feature few intraepithelial lymphocytes but prominent neutrophils in the epithelium accompanied by crypt abscesses, cryptitis, erosions, and ulcers. Moreover, crypt distortion is rare in CC but a prominent feature of CD and UC. Finally, CC has a distinctive thickened subepithelial collagen table, whereas CD has more diffuse transmural fibrosis.

Treatment and Natural History:
CC is usually a chronic process, but patients can have spontaneous remissions. This complicates 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 sulfasalazine or other 5-ASA derivatives. If that failed, patients were treated with steroids or immunosuppressive regimens. Currently, the two main therapeutic regimens are non-absorbable steroid preparations (such as budesonide) or high dose bismuth preparations. While patients usually respond to these, they frequently have flares of diarrhea once medication is stopped.

References:
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