PRACTICAL GASTROENTEROLOGY • SEPTEMBER 2002 41

INTRODUCTION

Collagenous colitis (CC) (Figure 1) and lympho-cytic colitis (LC) (Figure 2) are uncommonchronic relapsing diarrheal illnesses. The major-

ity of patients are women in their fifth to sixth decadewho complain of profuse, watery diarrhea, and crampy

abdominal pain. Both conditions have normal mucosawhen viewed endoscopically, however biopsy speci-mens show chronic mucosal inflammation. In CCthere is a subepithelial collagen band of varying thick-ness in association with an inflammatory cell infiltratein the lamina propria (1). The collagen band is absentin LC (2,3). The term microscopic colitis (MC) wasoriginally used to describe patients with chronic diar-rhea and normal endoscopic and barium enema stud-ies, but who had evidence of mucosal inflammationwhen examined microscopically (4). This term issometimes used interchangeably with collagenous and

Microscopic Colitis: CollagenousColitis and Lymphocytic Colitis

A SPECIAL ARTICLE

Brennan A. Scott, MD, Clinical Fellow, Division of Gas-troenterology, University of California, Davis MedicalCenter. Thomas P. Prindiville, MD, FACG, Professor ofMedicine, Division of Gastroenterology, University ofCalifornia, Davis Medical Center, Sacramento, CA.

Collagenous colitis and lymphocytic colitis are chronic relapsing diarrheal illnesses,which are often referred to together as microscopic colitis. It most commonly occurs inwomen in their fifth to sixth decade. The symptoms usually include profuse waterydiarrhea and crampy abdominal pain. Laboratory and endoscopic studies are gener-ally normal but microscopic inflammation is seen when colonic biopsies are performed.In collagenous colitis there is a subepithelial collagen band in addition to chronicinflammation in the lamina propria. The etiology is not known but multiple theoriesexist including autoimmune, infectious, and medication-induced. Although the courseis generally benign, patients may have multiple relapses over many years. Treatmentregimens vary and have included anti-diarrheals, antibiotics, 5-aminosalicylates,steroids, and immunosuppressive agents.

Brennan A. Scott Thomas P. Prindiville

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Microscopic Colitis

lymphocytic colitis, and sometimes used as anumbrella term for all forms of microscopic inflamma-tion in the colon. In this review the term MC will beused to describe either collagenous colitis and/or lym-phocytic colitis.

EPIDEMIOLOGYMicroscopic colitis can present in any age group butthe majority of patients are in their fifth to sixthdecade. While CC has a strong female predominance,with women accounting for 85%–90% of cases, LChas a roughly equal distribution between males andfemales (2,5). The incidence of CC has been reportedas 1.0/105 in France (6), 1.8/105, in Sweden (7), and1.1/105 in Spain (8). The prevalence of CC in Swedenis 15.7/105 (7). LC has been reported to have an inci-dence of 3.1/105 in Spain (8).

CLINICAL FEATURESThe most prominent feature of MC is diarrhea. In mostpatients it is described as profuse and watery, with upto ten bowel movements a day. Abdominal pain,cramping, fecal urgency, and nocturnal stools may alsobe associated. The onset is generally insidious but maybe abrupt in up to 40% of cases (9). Neither bloodystools nor steatorrhea is usually seen, and dehydrationis not a common complication. Weight loss has beenassociated with MC(9) but, if present, may suggest amore serious condition. The physical examination isunrevealing in the majority of patients as are routinelaboratory tests, stool studies, radiology, andendoscopy (Table 1). Autoantibodies and increasedserum IgM have been noted in some patients but thesignificance is not clear (10–12).

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Figure 1. Collagenous Colitis: There is a mild increase in cel-lularity with a thickened subepithelial collagen band. (H&Estaining 400×)

Figure 2. Lymphocytic Colitis: The epithelium and laminapropria contain an increased celluarity that is predominantlylymphocytic. (H&E staining 200×)

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ASSOCIATED CONDITIONSMicroscopic colitis has been associated with otherenteropathies and autoimmune diseases. Celiac diseasehas been associated with both CC and LC, with reportsof LC patients having a 15%–27% incidence of celiacdisease (13–15). There have been reports of CC asso-ciated with Crohn’s disease (16) as well as CC pro-gressing to ulcerative colitis (17,18). There has alsobeen a case reported of synchronous CC andpseudomembranous colitis (19). Although there is noclear autoimmune etiology of MC, it has been found inassociation with many autoimmune and rheumatologicdiseases such as rheumatoid arthritis (20), systemicand discoid lupus erythematosis (21,22), spondy-loarthritis (23), CRST syndrome (24), diabetes melli-tus, pernicious anemia, Sjogren’s syndrome, autoim-mune thyroid disease, linear IgA dermatosis (25), andprimary biliary cirrhosis (26). Collagenous gastritishas been described in association with CC, suggestinga diffuse intestinal tract disorder (27). The relative riskof colorectal malignancy does not appear to beincreased in these patients (28).

DIAGNOSISIn a patient with the appropriate clinical history andunremarkable physical exam and laboratory studies, a

flexible sigmoidoscopy or colonoscopy with biopsy isnecessary to make the diagnosis. The endoscopicexamination is in most cases grossly normal, but ran-dom mucosal biopsies will show evidence of micro-scopic chronic inflammation.

HISTOLOGYBoth LC and CC have evidence of chronic inflamma-tory cell deposition in the lamina propria (generally 20lymphocytes per 100 surface epithelial cells is used for diagnosis (3)). Neutrophils, plasma cells, andeosinophils are seen less commonly (1). In CC there isan eosinophilic staining subepithelial band of collagen,which measures between 7 and 100 microns in thick-ness. The band thickness varies from each area of thecolon and is an average of 9 microns (29). The super-ficial collagen layer has been shown to stain stronglyfor collagen types I, III, and VI, as well as the glyco-protein tenascin, which is involved in matrix remodel-ing (30). A labile imbalance between fibrogenesis andfibrolysis has been proposed as the mechanism thatinduces collagen band formation (31). Biopsies shouldbe done from both the proximal and distal colon inorder to most accurately classify the disorder becausethe collagen layer is generally less thick in the distalcolon (5). Immunostaining of mucosal biopsies fortenascin and type VI collagen has recently been pro-posed as a sensitive and specific method for determin-ing the presence of CC, especially in indefinite cases(32). The sensitivity of this method may allow for thediagnosis to be made from biopsies of the rectum andsigmoid colon, avoiding colonoscopy in some patients.

PATHOGENESISMultiple theories for the etiology of microscopic colitisexist: environmental, infectious, and autoimmune. Nonutritional component or medication has been directlylinked to the disorder, but NSAID use has been sug-gested to play an etiological role, with some patients’symptoms improving after the withdrawal of the med-ication (33). There have been reports of CC associatedwith lansoprazole (34), and cimetidine (35), and reportsof LC associated with ticlodipine (36–38), ranitidine

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Table 1 Diagnosis

Symtoms• Watery diarrhea• Crampy abdominal pain

Laboratory• Normal

Endoscopy• Normal

Muscosal biopsy• Chronic inflammatory infiltrate• Thickened subepithelial collagen layer (collagenous

colitis)

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(39), and acarbose (40). Fecal stream diversion surg e r yhas been shown to induce histological remission withclinical and histologic recurrence after ostomy closure(41), suggesting that noxious luminal material mayplay a role. Bile salt malabsorption has also been pos-tulated to play a role in pathogenesis (42). Others haveraised the question of bacterial endotoxins as a cause ofMC, with the toxin-binding resin cholestyramineshown to improve symptoms (43). A toxigenic strain ofB a c t e roides fragilis has been associated with MC(44),and there have been reports of CC associated withClostridium difficile (19,45) infection. A small seriesreported collagenous colitis diagnosed after Ye r s i n i ae n t e ro c o l i t i c a infection (46), and a case of lymphocyticcolitis was attributed to Campylobacter jejuni i n f e c t i o nin one patient (47), raising the question of a post-infec-tious response causing MC. Additionally, treatment ofHelicobacter pylori has been associated with improve-ment in CC (48) (Table 2).

Some authors have suggested an immune-mediatedmechanism due to the high incidence of autoantibodiesin these patients (2). Although there are associations withmany autoimmune diseases as noted above, no clearautoimmune etiology has been postulated or proven.

The mechanism of diarrhea in patients with MC isnot entirely clear. One hypothesis has been that thecollagen band in collagenous colitis is responsible forthe symptoms, but some believe that the collagen is amere consequence of mucosal inflammation (49) andnot the causative abnormality. In addition, the symp-toms are similar between LC and CC, and there is nocollagen band to alter mucosal permeability in LC.Eosinophil activation has been noted to be increased inthe mucosa of patients with collagenous colitis (50),and has been suggested to be related to altered mucosalpermeability (51). Increased numbers of mucosal mastcells and clinical response to an H1 antagonist wasnoted in one patient suggesting a role for this mecha-nism in the production of diarrhea (52). It is possiblethat bacterial toxins induce an altered host inflamma-tory cell response in some patients leading to diarrhea.

TREATMENTA variety of therapeutic agents have been used inpatients with microscopic colitis. Most regimens aresupported by case-reports or small, uncontrolled seriesonly. A recent double-blind placebo-controlled trial of9 mg of oral budesonide versus placebo in 24 patientswith CC showed both clinical and histological short-term response (53) with budesonide. This study, how-ever, used a different formulation of budesonide thanthat currently available in the United States. An openlabel trial of bismuth subsalicylate in 13 patients withmicroscopic colitis showed it to be safe and efficacious(54). Case series or case reports have noted the suc-cessful use of many other agents. Antidiarrheals andverapamil have been used to control symptoms insome cases (55,56), and bismuth subsalicylate hasbeen shown to have a prolonged response in some(54,57). The 5-aminosalicylates, sulphasalazine, andcholestyramine have been shown to be useful in somepatients with more severe symptoms (9,58,59). Somepatients may respond to variable courses of steroids(9,58), and the immunomodulatory drugs methotrexateand 6-mercaptopurine have been used with some suc-cess in patients who have refractory symptoms or whoare steroid dependent (60–63) (Table 3).

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Table 1 Proposed Etiologies

• Environmental (medications, dietary)• Bacterial toxins• Autoimmune

Table 3 Treatment Options

• Antidarrheals• Bismuth Subsalicylate• Cholestyramine• 5-Aminosalicylates• Sulphasalazine• Antibiotics• Budesonide• Prednisone• Methotrexate• 6-Mercaptopurine

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SUMMARYMicroscopic colitis is a term that is often used toencompass the two similar disorders, lymphocytic col-itis and collagenous colitis. Both disorders are charac-terized by chronic, relapsing watery diarrhea. The diag-nosis is made in patients with the appropriate clinicalpresentation, who have normal radiographic, labora-t o r y, and endoscopic findings, but have evidence ofmicroscopic inflammation on colonic biopsy. Althoughmany theories as to its cause exist, no etiology is cur-rently known. Many treatments ranging from antidiar-reals to immunosuppressants have shown eff i c a c y, butcontrolled trials are lacking. The course of microscopiccolitis is benign in the vast majority of cases. ■

AcknowledgmentThe authors wish to thank Mark Wu, MD, and KristenVa n d e w a l k e r, MD for providing the photomicrographs.

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