Some patients with chronic idiopathic diarrhea have histologic evidence of colitis even though their colons appear normal by barium enema and by colonoscopy; such patients have the entity known as microscopic colitis (380). The term microscopic colitis has been used to include several distinct but probably related diseases, including collagenous colitis and lymphocytic colitis, although more accurately it is lymphocytic colitis that has been traditionally called microscopic colitis. The term microscopic colitis has also been used more broadly to include the finding of colitis in the absence of endoscopic abnormalities. As a result, the diagnosis could include IBD, especially Crohn disease and eosinophilic colitis and potentially other mild forms of colitis. This leads to confusion and we prefer to not make a diagnosis of microscopic colitis but to use more specific diagnoses of either lymphocytic colitis or collagenous colitis since these entities are well characterized.

Reports showing a progression of lymphocytic colitis to collagenous colitis have led to the suggestion that the formation of the subepithelial collagen band develops at a later stage in the disease process as a result of continued inflammation and subsequent fibrosis and that the two disorders are variations of the same disease (381).

Since patients with lymphocytic and collagenous colitis present with a history of watery, nonbloody, persistent or intermittent diarrhea, often lasting several years, it is reasonable to consider these two disorders as part of the watery diarrhea–colitis syndrome (WDCS), a distinct form of chronic colitis (382).

It is likely that similar immune abnormalities affect both groups of patients. They both have a significant increase in mean numbers of intraepithelial lymphocytes (IELs) with significantly more CD8+ than CD4+ IELs. Most IELs bear the TCRαβ; TCRγδ–bearing cells are not increased. CD4+ helper T cells predominate in the lamina propria. The colonic epithelium abnormally expresses human leukocyte antigen (HLA)-DR antigens. These findings suggest that a major histocompatibility complex (MHC)-restricted immune mechanism can be involved in the pathogenesis of both diseases (383). There is also an association with various gastrointestinal and autoimmune disorders. Two associations are particularly prominent: Degenerative osteoarticular disease and celiac disease (381,384,385). There are also reports of patients with these diseases who subsequently develop either autoimmune thyroid diseases, ulcerative colitis or Crohn disease (386), primary biliary cirrhosis, and the CREST syndrome (387). Lymphocytic colitis is more common than collagenous colitis in patients who develop Crohn disease (388). A family has been reported in which different family members had ulcerative colitis, Crohn disease, and collagenous colitis (389).

There is also a relationship between both diseases and the uses of some drugs, especially aspirin, NSAIDs, ticlopidine, lansoprazole, and flutamide. There may also be a relationship with smoking (390). Overall, the natural history of both collagenous colitis and lymphocytic colitis is benign and in some patients the disease resolves spontaneously.

The diagnosis collagenous colitis describes patients who suffer from chronic, watery diarrhea and who have subluminal deposits of a collagenous ground substance beneath the surface epithelium at the lamina propria interface (391). The female-to-male ratio is 10:1, with an age range of 23 to 86 and a mean of 54 to 66 years (385). The incidence of the disease in individuals who suffer from chronic diarrhea ranges from 0.3% to 5%. The incidence is reported to be about 16 cases per 100,000 population (384). The disorder sometimes affects children (392) and families (393).

Postulated etiologies include immune dysregulation leading to colonic inflammation, abnormalities in collagen synthesis, abnormalities in the pericryptal myofibroblasts, mast cell or eosinophil abnormalities, “plasmatic vasculosus,” drugs, and bacterial toxins (394,395,396,397,398,399). Plasmacytic vasculosus is a theory that proposed leakage of plasma proteins and fibrinogen through the subepithelial capillary walls and their subsequent replacement by collagen. Surface epithelial damage appears to cause the secretory diarrhea, whereas the thickened subepithelial collagen table appears to represent a variable response to the surface damage. The injury may result from bile acid malabsorption (400), mast cell infiltrates (395), prostaglandin effects (401), or drug exposures. A significant percentage of patients with collagenous colitis have a history of using NSAIDs or antibiotics (402). Yersinia infections may also trigger the development of collagenous colitis (403).

The symptoms vary in duration and intensity and long periods of remission have been described. Symptoms include watery, nonbloody diarrhea with up to 20 stools per day. The diarrhea can last for months or decades. Colicky abdominal pain occurs frequently. Nausea, vomiting, flatulence, incontinence, and weight loss vary in frequency. Patients may also present with protein-losing enteropathy (404). Rarely, collagenous colitis associates with chronic constipation (405) in the absence of watery diarrhea. The disorder typically involves the colon, although the small bowel and stomach may be involved, particularly in patients with celiac disease or other autoimmune disorders. Collagenous colitis exhibits spontaneous remissions and relapses; occasionally the disease resolves spontaneously (406,407). In some patients it resolves following treatment with drugs or by diverting the fecal stream.

The histologic hallmark of collagenous colitis is mucosal colonic inflammation associated with a broad, continuous, hypocellular, eosinophilic, linear, subepithelial, fibrous band immediately subjacent to the surface epithelium (Fig. 13.139). This collagen band measures 10 to 70 μm in thickness, with a mean of 12 to 30 μm (408), and it surrounds subluminal capillaries and myofibroblasts. A thickness of at least 30 mm provides the greatest consistency in establishing the diagnosis (409). There is little if any extension of the thickened collagen
table around the crypts, except in cases demonstrating marked intercryptal subepithelial thickening. In addition to its thickness, the relative inhomogeneity and irregularity of the collagen layer at its lower borders helps distinguish it from the normal subepithelial basement membrane (Figs. 13.139 and 13.140). The thickened subepithelial layer stains light pink with PAS and green with Masson trichrome stains. Congo red stains are negative. The thickened collagen table predominantly contains collagen IV and tenascin (410,411,412). Plasma cells, mast cells, and multinucleated giant cells may be underneath, or embedded within, the thickened collagen table. The changes are most marked in the proximal colon and the distal bowel may be spared. In one study biopsies from the transverse colon were more likely to be diagnostic of the disorder than biopsies from the rectosigmoid or right colon (409). The lesion is often continuous, but it may also exhibit a patchy
distribution, particularly early in the disease course or as it resolves (413,414). As the disease is treated, the basement membrane thickening disappears (407).