GASTROENTEROLOGY 2011;140:11551165

REVIEWS IN BASIC AND CLINICAL GASTRO AND HEPATOLOGY

REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY AND HEPATOLOGY

John P. Lynch and David C. Metz, Section Editors

Microscopic Colitis
DARRELL S. PARDI* and CIARN P. KELLY
*Inammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota; and Gastroenterology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Podcast interview: www.gastro.org/gastropodcast. Microscopic colitis is a common cause of chronic watery diarrhea, especially among older persons. Diagnosis requires histologic analysis of colon biopsy samples in the appropriate clinical setting. Recent studies have shown an increase in the incidence of microscopic colitis, and several have addressed potential mechanisms. We review recent ndings about the clinical features, diagnosis, epidemiology, pathophysiology, and treatment of microscopic colitis. Keywords: Collagenous Colitis; Lymphocytic Colitis; Celiac Disease; Budesonide; Diarrhea; Inammatory Bowel Disease; pANCA. icroscopic colitis is a general term that encompasses 2 forms of idiopathic colitis: collagenous colitis and lymphocytic colitis.1,2 Microscopic colitis is characterized, clinically, by chronic or recurrent watery diarrhea without bleeding. The colonic mucosa appears normal on visual inspection by colonoscopy. Results from radiographic studies, including barium enemas and abdominal computed tomography, are also normal. Histologic analysis of colon biopsy specimens is required to reveal colitis. Microscopic colitis was described by Read et al in 1980 in patients with chronic watery diarrhea and no other evident etiologies despite extensive investigation.3 However, mild colitis was initially discounted; it was considered to be irrelevant to patients symptoms.3,4 Patients with lymphocytic colitis have increased numbers of intraepithelial lymphocytes in the colonic epithelial layer and increased numbers of subepithelial chronic inammatory cells compared with healthy individuals.2 The term collagenous colitis was coined in 1976 in a report of a patient with chronic diarrhea whose colonic biopsy specimens revealed a thickened subepithelial collagen layer, similar to that observed in patients with collagenous sprue.5 The colonic collagen band observed

in patients with collagenous colitis varies substantially in its thickness (from 7 to 100 m).6 8 The changes in inammatory cell populations, such as increased numbers of intraepithelial lymphocytes, observed in patients with lymphocytic colitis also occur in patients with collagenous colitis.2 It is not clear whether lymphocytic and collagenous colitis are 2 separate entities or part of a single disorder.2,9 There is substantial overlap in histopathologic ndings, and each disorder has similar inammatory inltration.8 Reports of patients transitioning from one to another histologic pattern indicate a common basis.9 11 However, the thickening of the collagen band that is associated with collagenous colitis can be patchy, leading to disparate histologic diagnoses in a single patient based on sampling differences. However, most patients consistently maintain one histologic type or the other.12,13 In clinical practice, the presentation, investigation, and management of microscopic colitis is not determined by histologic type. Microscopic colitis can occur in patients of any age but typically presents in late middle age and in the elderly. Nonbloody diarrhea is the predominant symptom. Abdominal discomfort and weight loss can also occur. The disease follows a chronic and unpredictable course of remission and relapse but usually responds to antidiarrheal and anti-inammatory therapies. Serious colonic or extracolonic complications are rare, and surgical intervention is seldom necessary.14 Microscopic colitis is associated with other autoimmune disorders, most notably celiac disease. Microscopic colitis is a relatively common nding among patients who undergo colonoscopy with biopsy analysis to evaluate chronic or recurrent nonbloody diarrhea.1519 In one study, microscopic colitis was identied in 9.5% of patients (97 of 1018) referred for colonoscopy because of watery diarrhea and in almost 20% of those older than 70 years.15 Thus, microscopic colitis
2011 by the AGA Institute

0016-5085/$36.00 doi:10.1053/j.gastro.2011.02.003

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Figure 1. Increasing incidence of lymphocytic and collagenous colitis from 1985 to 2001. Reprinted with permission from Pardi et al.21

should be considered in the evaluation of chronic nonbloody diarrhea, especially in older patients.16

Epidemiology
Population-based studies have found the incidence of microscopic colitis to vary between 1 and 12 per 100,000 persons per year.6,15,16,20 22 In Europe, the incidence of collagenous colitis has been reported to vary from 1.1 to 5.2 per 100,000 persons per year and the incidence of lymphocytic colitis from 3.1 to 4.0 per 100,000 persons per year.6,15,16,20 In North America, the reported incidence of collagenous colitis (3.1 and 4.6 per 100,000 per year) and of lymphocytic colitis (5.4 and 5.5 per 100,000 per year) overlap with those reported in Europe.21,22 The number of cases of lymphocytic colitis is generally similar to that of collagenous colitis.6,1518,20,21,23 The overall incidence of microscopic colitis (collagenous and lymphocytic) appears to have increased substantially in recent years. In a US study covering the period from 1985 to 2001, the incidence of microscopic colitis increased from 1.1 per 100,000 person-years early in the study to 19.6 per 100,000 person-years at the end (Figure 1).21 At the termination of the study, in December 2001, the prevalence of microscopic colitis was 103.0 (39.3 for collagenous colitis and 63.7 for lymphocytic colitis) per 100,000 persons.21 Similarly, a European study found that the incidence of microscopic colitis increased from 6.8 per 100,000 in 19931995 to 11.8 per 100,000 in 1996 1998.15 The reasons for these apparent increases in disease incidence are not clear, but increased clinical awareness, more frequent performance of diagnostic colonic biopsies, and increased use of medications that cause microscopic colitis have been proposed.15,21,24,25 Regardless of the reasons for the apparent increases, the recent

higher estimates of disease incidence are the most relevant to current clinical practice. Although microscopic colitis can be diagnosed in patients of any age, it is more common among older individuals. The average age of patients diagnosed with microscopic colitis (lymphocytic and collagenous) ranges from 53 to 69 years.6,1517,20,26 One study found that patients older than 65 years were 5.6-fold more likely to be diagnosed with microscopic colitis than younger subjects.22 Although microscopic colitis is mainly a disease of late middle age and of the elderly, it should not be discounted in younger patients. Pediatric cases have been reported, and in one study, 25% of patients were less than 45 years of age.26 28 Microscopic colitis appears to be more frequent in women than in men. The ratio of female to male patients with collagenous colitis is consistently high, ranging from 3:1 to 9:1.6,16,22,29 The ratio of women to men with lymphocytic colitis is lower, ranging from 6:1 to no signicant difference.16,17,21,22,29 However, a review of all published cases of lymphocytic and collagenous colitis showed no signicant difference in sex of patients with either disease.30 Disease activity decreases during pregnancy, suggesting a hormone- or immune-mediated effect, such as in inammatory bowel diseases (IBD).26 It is unclear whether there is a genetic basis or predisposition to microscopic colitis. Familial cases have been described, but it is not clear whether these reect shared familial traits or random associations.3133 HLA associations have been described, but no uniform pattern has emerged.6,10,34,35 There is no evident increase in the risk of colorectal malignancy associated with microscopic colitis.21,29,36 Cases of lung cancer have been reported in patients with collagenous colitis,16,26,36,37 possibly because cigarette smoking is more common among patients with collagenous than lymphocytic colitis.31,36 38 In one study, 25% of patients with collagenous colitis smoked cigarettes compared with 14% of patients with lymphocytic colitis; only 8% of patients with collagenous colitis had stopped smoking compared with 23% of patients with lymphocytic colitis.37

Mechanism of Diarrhea
A variety of mechanisms have been proposed to cause diarrhea in patients with microscopic colitis. The severity of diarrhea appears to be related to the intensity of the inammatory response, as opposed to the thickness of the subepithelial collagen band, indicating that the diarrhea is predominantly inammatory in origin.8,39 41 Several studies have reported that patients with microscopic colitis have impaired electrolyte absorption or increased secretion.40,42 Studies of epithelial resistance and electrolyte movement in colonic biopsy samples collected from patients with microscopic colitis indicated

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that sodium and chloride absorption were impaired; increased chloride secretion was also evident.40 The subepithelial collagen band had a smaller effect in pathogenesis but may have acted as a diffusion barrier. The downregulation of molecules that formed the intraepithelial tight junctions also contributed to a loss of barrier function, causing passive uid and electrolyte loss.40 Inammatory mediators have been examined in microscopic colitis, including nitric oxide and prostaglandins. Increased concentrations of systemic and luminal nitric oxide have been reported, along with an increase in inducible NO synthase.43,44 Nuclear factor B, a transcription factor that mediates inammatory responses, is activated in the colonic mucosa of patients with microscopic colitis.41 Nuclear factor B binds to the promoter of inducible NO synthase to help activate its transcription. The NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) decreases uid secretion, suggesting the role of NO in the pathogenesis of diarrhea in microscopic colitis.44 Increased mucosal and luminal concentrations of prostaglandin might also promote inammatory diarrhea.42

Pathogenesis
The etiology of microscopic colitis is unknown, but leading models of pathogenesis include autoimmunity, an immune or inammatory response to luminal factors, and, for collagenous colitis, myobroblast dysfunction.45 However, information on pathophysiology is taken from small, sometimes conicting, studies and there is no single clear mechanism of disease.

Autoimmunity
There are indirect associations between microscopic colitis and several factors suggesting autoimmunity. More women than men develop collagenous colitis, a common feature of many autoimmune disorders.6,16,17,21,22,30 More importantly, microscopic colitis is associated with other autoimmune conditions; as many as 40% of patients have an autoimmune disease such as celiac disease, thyroiditis, type 1 diabetes mellitus, or rheumatoid arthritis.10,46 50 A study reported that patients with collagenous colitis had a signicant increase in mean serum concentration of immunoglobulin M and a nonsignicant trend toward increased concentrations of antinuclear antibodies compared with controls.51 A few patients with microscopic colitis test positive for perinuclear antineutrophil cytoplasmic antibody.51,52 However, there is no distinct or clinically useful autoimmune marker for microscopic colitis.5154

Luminal Factors
A variety of luminal factors have been implicated in the pathogenesis of microscopic colitis, including dietary antigens, drugs, bile salts, and bacterial products and toxins. The observation that histologic features as-

sociated with microscopic colitis resolve if the fecal stream is diverted by ileostomy indicates the role of luminal factors.12,55 Dogs develop a histologically similar form of lymphocytic colitis that responds to treatment with a hypoallergenic diet, further implicating luminal dietary substances in pathogenesis.56 The best evidence for the role of luminal factors in human microscopic colitis is that, among patients with microscopic colitis who also have celiac disease, enteritis and colitis may each respond to a gluten-free diet. There is also evidence for a causal or exacerbating effect of certain medications.24,25,57 60 Medications. In a literature review, a scoring system was used to determine the strength of evidence that associated individual drugs or drug classes with microscopic colitis.25 Nonsteroidal anti-inammatory drugs (NSAIDs), aspirin, proton pump inhibitors, ranitidine, selective serotonin reuptake inhibitors, ticlopidine, acarbose, and statins had high or intermediate levels of association with the disease. Carbamazepine, utamide, and paroxetine had less well-established associations with microscopic colitis. The best evidence for an association between medication use and microscopic colitis exists for NSAIDs, although some studies have not conrmed this association.12,37,59,61 63 One of the more compelling studies matched patients with collagenous colitis to those with irritable bowel syndrome or colonic diverticular disease (as controls).59 Long-term use of NSAIDs (for more than 6 months) was reported in 19 of 31 subjects with microscopic colitis, compared with only 4 of 31 controls. Among subjects with colitis and a history of NSAID use, the onset of diarrhea followed drug use by a mean interval of 5.5 years (range, 0.515 years). In a retrospective review of 163 patients in Sweden with collagenous colitis, 34% were taking NSAIDs.26 Conversely, a smaller study of 30 patients found no association between microscopic colitis and NSAID use.12 One potential confounding factor is the presence of coexisting arthralgia in patients with microscopic colitis, which could increase their use of NSAIDs. A study reported that 18 of 31 (56%) patients with collagenous colitis had some form of arthritis; 22 (71%) of those were using NSAIDs regularly at the time of diagnosis. NSAIDs induce small intestinal and colonic injury and inammation and possibly exacerbate IBD.63 Their ability to cause or at least exacerbate microscopic colitis is therefore not altogether unexpected. Furthermore, patients with collagenous colitis who took NSAIDs were more likely to require corticosteroid therapy.64 It has been proposed that NSAID-associated colitis is a distinct disease that encompasses protein-losing enteropathy, hypoproteinemia, and histopathologic features of collagenous colitis. Unlike other forms of microscopic colitis, mucosal ulcerations and even perforation can develop.65

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The case for a cause-and-effect relationship between NSAID use and microscopic colitis was strengthened by reports of clinical and histologic improvement among NSAID users when the medication was discontinued.59,62,65,66 In the controlled study of 31 patients with collagenous colitis described previously, 3 subjects reported reduced diarrhea after they stopped taking NSAIDs. One subject, who later resumed taking an NSAID, developed recurrent diarrhea that resolved when the NSAID was again discontinued.59 Thus, sustained use of NSAIDs can predispose to or exacerbate microscopic colitis; patients should be advised to discontinue NSAIDs once this diagnosis is made. Lansoprazole and other proton pump inhibitors, including omeprazole and esomeprazole, have been associated with lymphocytic colitis.57,58,67 69 Blockers of histamine-2 receptors have also been implicated.70,71 As for NSAIDs, many drugs that are associated with microscopic colitis, including proton pump inhibitors, induce watery diarrhea as a common adverse effect. Thus, by causing or worsening diarrhea, use of these drugs can result in identication of microscopic colitis, rather than being the primary etiologic agents.58 Furthermore, cases of microscopic colitis associated with medications may differ from idiopathic cases in their natural history and response to therapy, indicating a separate disease entity, especially in the context of controlled clinical trials.60 Because of the associations between microscopic colitis and NSAIDs, proton pump inhibitors, and other medications, drug use should be carefully reviewed in patients with watery diarrhea or newly diagnosed microscopic colitis. Agents that cause symptoms might be identied based on the relationship between the timing of drug use and symptom onset and information from published reports.25 However, the growing list of medications potentially associated with microscopic colitis, and of the nding that an average of 5 years elapses between the start of regular NSAID use and the onset of microscopic colitis symptoms, indicates that it is a challenge to associate specic agents with the disease.59 Bacterial infection and products. Several studies have proposed that bacterial infection or toxin production can cause microscopic colitis. Cholestyramine might bind bacterial toxins to alleviate diarrhea in patients with microscopic colitis. In one case report, cholestyramine resulted in symptomatic and histologic improvement. Cytotoxic activity was observed in a fecal extract before therapy, disappeared during cholestyramine treatment, and then returned, together with symptoms, when cholestyramine was discontinued.72 The efcacy of fecal diversion could also indicate provocation by bacterial or dietary luminal factors.55 Oral bismuth, which has antibacterial activity, is a potential rst-line agent for treating mild to moderate microscopic colitis, further suggesting that bacterial infection is an etiologic factor.73 Furthermore, antibiotic

therapy is effective in some patients.26,30,35,48 Mice that transgenically express human HLA-B27 and 2-microglobulin develop intestinal disease that resembles lymphocytic colitis.74 Interestingly, germ-free mice do not develop colitis, which requires bacterial colonization of the intestine. Outbreaks of acute-onset but prolonged diarrhea have been described (so-called Brainerd diarrhea) that have many clinical and histologic features of microscopic colitis.75,76 Brainerd diarrhea is presumed to be of infectious etiology, based on its epidemiologic characteristics.76 A few reports also have associated microscopic colitis with infection with specic pathogens, including Yersinia and Clostridium difcile.7779 However, despite data that indicate a bacterial cause for microscopic colitis, no specic pathogen or bacterial factors have been consistently identied in patients with the disease. Bile acids and bile acid malabsorption. Bile acids might be endogenous luminal factors that contribute to the pathogenesis of microscopic colitis.80 Bile acid malabsorption causes colonic secretory diarrhea in humans. In animal models, exposure of colonic mucosa to deoxycholic and chenodeoxycholic bile acids also induces uid secretion and microscopic histopathologic changes.81,82 The morphologic changes that occur in the intestine during bile acid malabsorption overlap with those of microscopic colitis, including inammatory cell inltration and collagen deposition.81 83 Furthermore, binding resins, such as cholestyramine, bind bile acids in addition to bacterial toxins; their ability to prevent the colonic effects of bile acid exposure might contribute to their ability to alleviate microscopic colitis.26,80 In one study, 12 of 27 patients (44%) with collagenous colitis showed objective evidence of bile acid malabsorption based on standardized testing. Therapies that bind bile acids improved symptoms in most patients (21 of 27; 78%). More subjects with abnormal bile acid absorption test results improved (11 of 12; 92%) compared with those with apparently normal absorption (10 of 15; 67%). However, because most patients with normal bile acid absorption also respond to the therapy, bile acid binding is not the only therapeutic mechanism of resins such as cholestyramine. Also, studies that used breath tests for bile acid did not provide substantial evidence of bile acid malabsorption in patients with microscopic colitis.84,85 Finally, cholecystectomy was not associated with the development of microscopic colitis.86

Myobroblast Function, Collagen Deposition, and Collagen Degradation

Several studies have focused on abnormalities in collagen production, structure and degradation, and function of myobroblasts that deposit the subepithelial matrix in patients with collagenous colitis. In 12 patients with collagenous colitis, the supercial collagen layer contained increased levels of collagen types I, III, and VI

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and tenascin but reduced levels of matrix metalloproteinase 1 and 13 messenger RNA, whereas levels of tissue inhibitor of metalloproteinases (TIMP-1) were increased. Furthermore, myobroblasts expressed increased amounts of pro-collagen -1 and TIMP-1 messenger RNA in a linear distribution underneath the collagenous band. The investigators concluded that deposition of an immature interstitial matrix, in combination with local impairment of brolysis, might promote pathogenesis of collagenous colitis.87 Another study supported the hypothesis that reduced brolysis has a role in this disease,87,88 showing that type VI collagen and tenascin were prominent in the abnormal collagen band. Because levels of collagen type VI messenger RNA did not increase in cells in and around the collagen band, the investigators concluded that the subepithelial collagen accumulation resulted from reduced degradation of matrix rather than increased synthesis.88 Transforming growth factor 1 is a growth factor that can mediate tissue collagen accumulation and brosis. In patients with collagenous colitis, inltrating eosinophils express increased levels of transforming growth factor 1 messenger RNA compared with controls.89 Vascular endothelial growth factor is another important regulator of extracellular matrix brogenesis and brolysis.90 Immunohistochemical analyses showed that vascular endothelial growth factor and tenascin were increased in the epithelium and in the lamina propria in patients with collagenous colitis compared with healthy controls. Prolonged treatment with oral budesonide reduced levels of vascular endothelial growth factor in lamina propria to normal levels, whereas levels in the epithelium remained signicantly increased.90 A separate study showed increased levels of vascular endothelial growth factor in the colonic mucosa and perfusates of patients with collagenous colitis.91 Fibroblasts and myobroblasts beneath the colonic crypt epithelium (pericryptal) normally produce and deposit collagen in the basement membrane and maintain the normal structure and function of the colonic mucosa.9294 In collagenous colitis, the subepithelial pericryptal broblast sheath appears to be increased in size and have increased cellularity.92,95 The cells show additional characteristics of myobroblasts, the proliferating cells found in granulation tissue.94 Furthermore, the pericryptal broblasts separate from their normal contact with the crypt epithelial cell basal lamina; separation of the myobroblast sheath from the epithelium is most evident in the upper portions of the crypts. In this region, normal broblast cell processes also become decient. These morphologic changes led to the theory that the excess collagen observed in collagenous colitis results from dysregulation of intestinal subepithelial myobroblasts within the pericryptal sheath.9395 The abnormal structure and function of the pericryptal myobroblast sheath in microscopic colitis is likely to be a secondary response to colonic mucosal inammatory mediators.

Similar abnormalities occur in patients with chronic ulcerative colitis; the severity of diarrhea in patients with collagenous colitis correlates with the intensity of inammatory cell inltration rather than thickness of the collagen band.8,95,96 In summary, several potential mechanisms have been proposed to explain the pathophysiology of microscopic colitis, although no dominant mechanism has emerged. It seems that the clinical and histologic entity referred to as microscopic colitis is caused by more than one mechanism.

Clinical Features
Microscopic colitis is characterized by chronic or intermittent watery diarrhea, ranging from mild and selflimited to severe, with dehydration and other metabolic abnormalities. Many patients also have abdominal pain or weight loss. The weight loss is typically mild but can be signicant in some cases.26,48 Quality of life is affected in proportion to the degree of diarrhea, abdominal pain, urgency, and incontinence.13,97,98 It is important to recognize that the symptoms of microscopic colitis are nonspecic. In fact, many patients with biopsy-proven microscopic colitis meet the symptom-based criteria for irritable bowel syndrome.99,100 Therefore, these criteria are not specic enough to distinguish microscopic colitis from irritable bowel syndrome. This distinction can only be made by colonic mucosal biopsy analysis. Arthralgias and various autoimmune conditions (eg, thyroid dysfunction, rheumatoid arthritis, psoriasis) often occur in patients with microscopic colitis.15,26,29,48 Some patients also have increased erythrocyte sedimentation rates or positive results on tests for antinuclear antibodies or other markers of autoimmunity.48,51,85 The association between microscopic colitis and celiac disease is of particular interest and clinical importance. As many as 33% of patients with celiac disease have histologic changes in the colonic mucosa that are consistent with microscopic colitis.101,102 In a large cohort study of patients with celiac disease, 4.3% were diagnosed with microscopic colitis, which is a rate of diagnosis that is 72-fold greater than for patients without celiac disease.103 Microscopic colitis is therefore more common among patients with celiac disease; it should be considered in the diagnosis of patients who have continued or recurrent diarrhea despite a strict gluten-free diet.104 The prevalence of celiac diseaselike changes in the small bowel of patients with microscopic colitis ranged from 2% to 9% in the largest studies of this association.15,26,29,48 However, patients with microscopic colitis did not frequently have serologic markers associated with celiac disease; antiendomysial antibodies were found in 0 to 4% of patients and antitissue transglutaminase antibodies were not detected in any patients with microscopic colitis.51,105,106 In patients with microscopic colitis, titers of these antibodies were lower than in patients with

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celiac disease.105 Therefore, serologic analysis does not seem to be a good diagnostic tool for celiac disease in patients with microscopic colitis. Finally, HLA types of patients with microscopic colitis are similar to those of patients with celiac disease.105 These data indicate that celiac disease is relatively uncommon among patients with microscopic colitis, and it is probably not necessary to routinely test these patients for celiac disease. However, celiac disease should be considered in treatment-refractory patients and those with signicant weight loss, any indication of steatorrhea, or other symptoms such as unexplained iron deciency anemia. There have been a few reports of patients with microscopic colitis later developing IBD107109 and of patients with IBD developing collagenous colitis.26,108 However, because of the small number of these reports, the occurrence of the 2 diseases could be random. It also is important to recognize that histologic features of IBD, such as Paneth cell metaplasia and distortion of the crypt architecture, may occur in patients with microscopic colitis who otherwise have no evidence of IBD.110 The reported natural history of microscopic colitis varies. The rate of symptomatic remission ranges from 60% to 93% among patients with lymphocytic colitis13,111 and 2% to 92% among those with collagenous colitis.26,64,111,112 A study reported remission rates of 59% among patients with lymphocytic colitis and 34% among those with collagenous colitis after a 6-month follow-up period, with an additional 25% and 40%, respectively, showing signicant improvement.37 Another study reported spontaneous remission in 15% and treatmentinduced remission in 48% of patients with collagenous colitis after a 3.5-year follow-up period.61 Of the remaining 37% with ongoing disease, only 60% (22% of the entire cohort) required prolonged therapy. In contrast, clinical trials have reported that 12% to 40% of patients respond to placebo after 6 to 8 weeks.113116 In contrast, an openlabel study of corticosteroid therapy reported that 90% of patients required some form of maintenance therapy.117

Figure 2. Lymphocytic colitis, characterized by increased numbers of intraepithelial lymphocytes and inammatory inltrate in the lamina propria. Courtesy of Thomas C. Smyrk, MD, Department of Pathology, Mayo Clinic Rochester.

neutrophils, with active cryptitis having been reported in 30% to 40% of patients119 (Figure 4), although acute inammation should not predominate the inammatory inltrate. These inammatory features are often accompanied by damage to the surface epithelium (Figure 5),2,7 including detachment of the epithelium in some cases, despite the normal appearance of the mucosa.

Treatment
In treating patients with microscopic colitis, it is important that they rst discontinue use of drugs that might have caused the disorder or other agents that might exacerbate diarrhea (eg, dairy products) if possible (Figure 6). Nonspecic antidiarrheal drugs such as loperamide or diphenoxylate/atropine can be effective15,26,48 and are often rst prescribed for mild cases (Figure 6). If these agents are unsuccessful, or for patients with moderate symptoms, bismuth subsalicylate, at a dose of 2 or 3 tablets (262 mg each) 3 or 4 times per day, can be benecial48,73 (Figure 6), although a study reported that most patients have only a partial response.48 Some patients who responded to this therapy experienced longterm remission without continuous therapy.73,120 For patients with diarrhea that does not respond to bismuth or those with severe symptoms, corticosteroids were reported to be among the best therapies in the largest uncontrolled studies.23,29,48 Budesonide is the best-studied treatment for microscopic colitis; it was assessed in 3 randomized controlled studies in collagenous colitis113115 and 2 studies in lymphocytic colitis.116,121 In each of these studies, budesonide was superior to placebo for short-term treatment. In an open-label study, budesonide was as effective as prednisone.117 Because it has fewer side effects, budesonide should be given instead of prednisone. Unfortunately, although budesonide is effec-

Diagnosis
Endoscopic evaluation reveals that the colon is typically normal or has mild nonspecic changes such as erythema or edema. Colon ulceration is uncommon, and when it occurs it is likely to be caused by NSAIDs.118 Fecal leukocytes can be present,48 but steatorrhea, fever, or hematochezia indicate an alternate diagnosis should be made. The hallmark histologic feature of microscopic colitis is intraepithelial lymphocytosis.2,37 In addition, the disease is characterized by mixed inltrate in the lamina propria, predominantly by chronic inammatory cells2,7 (Figure 2). Collagenous colitis is characterized by a thickened subepithelial collagen band (Figure 3).7 Biopsy samples from patients with microscopic colitis can contain

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Figure 3. Collagenous colitis, characterized by a thickened subepithelial collagen band with entrapped capillaries. In normal colon biopsy specimens, the collagen band is 57 m thick. Courtesy of Thomas C. Smyrk, MD, Department of Pathology, Mayo Clinic Rochester.

Figure 5. Surface epithelial damage in collagenous colitis. In this example, the surface epithelial cells have cuboidal shapes and separation from the basement membrane. Courtesy of Thomas C. Smyrk, MD, Department of Pathology, Mayo Clinic Rochester.

tive for induction therapy, the relapse rate is high once this medication is discontinued15,117,122 and many patients become corticosteroid dependent. Therefore, before patients are given corticosteroid therapy, their diagnosis should be reevaluated and alternative diagnoses, such as coexistent celiac sprue or infection, must be excluded. Immune modiers such as azathioprine, 6-mercaptopurine, or methotrexate can be helpful to corticosteroiddependent patients.48,123125 However, many clinicians are gaining experience with long-term use of low-dose (3 6 mg/day) budesonide for these patients as an alternative to immunosuppression.126 This practice was assessed in 2 randomized controlled trials, and each found that budes-

onide was more effective than placebo for up to 6 months of therapy.127,128 In our clinical practice, if a patient with microscopic colitis experiences a relapse soon after a successful course of budesonide therapy, budesonide is given again, often at a dose of 6 mg/day. Once remission is reestablished, the dose is reduced to 3 mg/day and even further, if possible, to 3 mg every other day. After 6 to 12 months of additional therapy, another attempt is made to discontinue budesonide therapy; if a relapse occurs after a short period, budesonide is given again at the lowest effective dose. Patients who receive long-term budesonide therapy should be followed up to monitor for corticosteroidrelated adverse effects.126 For patients who do not tolerate long-term therapy with budesonide, alternative maintenance strategies, such as with an immunomodulator,

Figure 4. Acute inammation in a biopsy showing collagenous colitis. Features include cryptitis (thick arrow) and a giant-cell reaction to a damaged crypt (thin arrow). Courtesy of Thomas C. Smyrk, MD, Department of Pathology, Mayo Clinic Rochester.

Figure 6. Management of microscopic colitis. The initial approach to treatment is guided by the severity of symptoms. Alternatives to budesonide for patients who do not respond include bile acid binders, aminosalicylates, and prednisone. For recurrent disease after a successful course of budesonide, treatment options include immunomodulators or long-term low-dose budesonide. Very few patients require surgery for medically refractory microscopic colitis.

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bile acid binding agent, or aminosalicylate, should be considered (Figure 6). Few patients do not respond to corticosteroid therapy,117 but for these patients, alternate or concomitant diagnoses and noncompliance should be considered. For patients who have corticosteroid-resistant microscopic colitis, treatment options include aminosalicylates, a bile acid binding agent, or an immunomodulator. Aminosalicylates were successful in most patients in a controlled trial,129 but several large retrospective studies reported that less than 50% of patients beneted from these drugs.15,26,48 Cholestyramine can be more effective,15,26,48 although many patients do not tolerate the medication because of its texture. Bile acid binding agents in pill form, such as colesevelam, might be better tolerated. There have not been many reports of the effects of azathioprine123 or antitumor necrosis factor therapies such as iniximab130 in patients with corticosteroidrefractory microscopic colitis. Patients who are refractory to all medical therapy can be considered for surgery, although this is rarely necessary. Reported operations include an ileostomy, with or without a colectomy,48,131 or ileal pouchanal anastomosis.132,133

Summary
Microscopic colitis is a relatively common cause of chronic diarrhea, especially among the elderly, and the incidence is increasing. Biopsies of the colon are required to diagnose this disorder and should be performed for any patient undergoing sigmoidoscopy or colonoscopy to evaluate unexplained diarrhea. The 2 subtypes of microscopic colitis, collagenous and lymphocytic colitis, are similar histologically and clinically and seem to respond similarly to various medical therapies. Although there are few controlled trials of therapies for microscopic colitis, the treatment approach we present often leads to satisfactory control of symptoms.
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Received November 15, 2010; Accepted February 3, 2011. Reprint requests Address requests for reprints to: Darrell S. Pardi, MD, 200 First Street Southwest, Rochester, Minnesota 55905. e-mail: pardi.darrell@mayo.edu. Conicts of interest The authors disclose no conicts.