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INTRODUCTION — Microscopic colitis is a chronic, inflammatory disease of the colon that is characterized by chronic, watery diarrhea. It typically occurs in middle-aged patients and has a female preponderance. The colon appears normal on colonoscopy in patients with microscopic colitis. The diagnosis is established by biopsy of the colonic mucosa.
This topic will review the clinical manifestations, diagnosis, and management of microscopic colitis. The clinical manifestations, diagnosis, and management of inflammatory bowel disease including ulcerative colitis and Crohn disease are discussed in detail, separately. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults" and "Management of mild to moderate ulcerative colitis in adults" and "Management of severe ulcerative colitis in adults" and "Clinical manifestations, diagnosis and prognosis of Crohn disease in adults" and "Overview of the medical management of mild to moderate Crohn disease in adults" and "Overview of the medical management of severe or refractory Crohn disease in adults".)
SUBTYPES — Microscopic colitis is comprised of two well-defined subtypes based on their histological features :
EPIDEMIOLOGY — The estimated incidence of collagenous colitis and lymphocytic colitis are 1.1 to 5.2 and 3.1 to 5.5 per 100,000 per year, respectively [9,13-18]. The mean age at diagnosis of microscopic colitis is approximately 65 years . However, approximately 25 percent of patients with microscopic colitis are diagnosed before the age of 45 years. Although microscopic colitis has been reported in children, it is rare [19-21]. Microscopic colitis has a female preponderance, which appears to be more pronounced in collagenous as compared with lymphocytic colitis [1,6,11-17,22-30].
ETIOLOGY AND RISK FACTORS
Medications — Nonsteroidal anti-inflammatory drugs (NSAIDs) have been implicated as being causative or triggering flares of microscopic colitis in some observational studies, while others have found no association [1,31,32]. In one study that included 31 patients with microscopic colitis, use of NSAIDs for more than six months was reported in 19 subjects with microscopic colitis as compared with 4 of 31 controls . Among subjects with microscopic colitis and a history of NSAID use, the onset of diarrhea followed NSAID use by a mean duration of 5.5 years. In three subjects with collagenous colitis, diarrhea improved after they stopped taking NSAIDs. One subject, who later resumed taking an NSAID, developed recurrent diarrhea that resolved when the NSAID was again discontinued.
Collagenous colitis and lymphocytic colitis have also been linked to several other medications (table 1). However, convincing evidence is still lacking, and most of the drugs that have been associated with microscopic colitis are also known to be associated with the development of chronic diarrhea as a side effect [31,34-46].
Smoking — Smoking may play a role in the development of microscopic colitis due to its effect on colonic blood flow. In a case-control study that included 340 patients with microscopic colitis, cigarette smoking (past or present) was associated with a significantly increased risk of microscopic colitis (odds ratio 2.1, 95% CI 1.6-2.9) [47-49]. Smokers also develop microscopic colitis more than 10 years earlier than nonsmokers [48,49].
PATHOGENESIS — The pathogenesis of microscopic colitis is unclear; however, it is likely to be multifactorial, involving mucosal immune responses to luminal factors in a genetically predisposed individual [11,12,22-25]. Although lymphocytic and collagenous colitis have a similar inflammatory cell response, it is uncertain whether they are related (table 2) [1,6,29,50].
Genetics — The extent to which there may be a genetic predisposition to microscopic colitis is unclear. However, familial cases have been described [26-28]. Interestingly, different members of the same family developed either lymphocytic or collagenous colitis, supporting a similar underlying pathophysiology. Studies have also demonstrated an association between microscopic colitis and HLA-DQ2 or DQ1/3, as well as a higher frequency of HLA-DR3DQ2 haplotype and tumor necrosis factor (TNF) 2 allele carriage in microscopic colitis, as compared with controls [51-53].
Abnormal collagen metabolism — Abnormal collagen metabolism may be responsible for the thick collagen band in collagenous colitis. The prominent subepithelial matrix deposition has been attributed to increased expression of the main fibrogenic genes, procollagen I and metalloproteinase inhibitor (TIMP-1), by myofibroblastic cells and inadequate fibrinolysis [54-57]. Patients with collagenous colitis also have increased expression of transforming growth factor (TGF) beta-1, which has been associated with the accumulation of collagen in tissues . TGF beta-1 and vascular endothelial growth factor (VEGF) may influence the balance of local fibrogenesis and fibrinolysis, leading to a net accumulation of immature subepithelial matrix [58,59]. The modification of collagen metabolism has also been explained by the expression of endogenous histamine, prostaglandins, and/or nitric oxide (NO). Increased transcriptional activity of nuclear factor kappa B causes upregulation of inducible NO synthase activity and, subsequently, increased production of NO in the colonic epithelium, which might be a direct cause of secretory diarrhea in patients with collagenous colitis .
Altered epithelial barrier function — An alternative hypothesis is that a defect in epithelial barrier function may lead to transmucosal permeability of antigens and bacteria, leading to intestinal inflammation seen in microscopic colitis .
Synchronous collagenous and pseudomembranous colitis have also been described, suggesting a possible etiologic role for Clostridium difficile in some patients [62-64]. Infection with Yersinia sp has also been suggested as an inciting event for collagenous colitis . Resolution of collagenous colitis has been described following treatment for Helicobacter pylori, but the association remains unclear . A role for bacteria in the pathogenesis of this disorder is also supported by the observation that symptoms and histology may improve in patients with lymphocytic colitis after treatment with bismuth. (See 'Initial approach' below.)
Mechanism of diarrhea — Diarrhea in microscopic colitis is likely caused by mucosal inflammation [6,29,67]. The severity of diarrhea correlates with the inflammatory changes in the lamina propria and not with collagen table thickening. Colonic perfusion studies have demonstrated that secretory diarrhea in microscopic colitis results from decreased absorption of sodium chloride accompanied by a component of active chloride secretion [6,68]. The subepithelial collagenous band acts as a diffusion barrier. Down-regulation of tight junction molecules, but not epithelial apoptoses, is a structural correlate of barrier dysfunction that contributes to diarrhea by a leak flux mechanism . The observation that fasting can reduce stool volume in microscopic colitis suggests that the diarrhea in microscopic colitis also has an osmotic component .
Concurrent bile acid malabsorption frequently coexists in patients with collagenous colitis. In one study, for example, 12 of 27 patients (44 percent) had an abnormal (75) Se-homocholic acid taurine (75SeHCAT) test . Treatment with a bile-acid binding resin was associated with rapid, marked, or complete improvement in 21 patients (78 percent). The cause of bile acid malabsorption in patients with microscopic colitis is unclear since morphologic alterations in the terminal ileum are usually absent [8,70].
ASSOCIATED CONDITIONS — Microscopic colitis has also been associated with celiac disease, autoimmune thyroiditis, type 1 diabetes mellitus, and nonerosive, oligoarticular arthritis [71-75]. In one report, concomitant autoimmune diseases were more common in patients with collagenous colitis as compared with lymphocytic colitis (53 versus 26 percent), while the prevalence of celiac disease did not differ (20 versus 15 percent) . Whether these associations reflect an autoimmune pathogenesis of microscopic colitis is unclear.
While patients with celiac disease have an increased risk of microscopic colitis, celiac disease is relatively uncommon among patients with microscopic colitis [76-84]. In a large cohort study of 1009 patients with celiac disease, 44 (4.3 percent) were diagnosed with microscopic colitis, corresponding to a 72-fold increased risk of microscopic colitis in patients with celiac disease, as compared with the general population . The prevalence of celiac disease-like changes in the small bowel of patients with microscopic colitis ranges from 2 to 9 percent. The HLA-DR3-DQ2 haplotype that predisposes to celiac disease is also associated with microscopic colitis [51,52]. Microscopic colitis demonstrates a T(H)1 mucosal cytokine profile with upregulated interferon gamma and interleukin 15, tumor necrosis factor, and nitric oxide synthase, a pattern similar to that in celiac disease . (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'Other associations'.)
Focal areas of microscopic colitis have also been described in patients with established inflammatory bowel disease (IBD) [87-91]. They may also precede the development of overt clinical and histopathologic evidence of IBD, particularly Crohn disease, although colonoscopic abnormalities of IBD are frequently present, providing a clue toward the diagnosis [87-91]. In rare cases, cocurrent lymphocytic and collagenous gastritis have been reported . (See "Endoscopic diagnosis of inflammatory bowel disease", section on 'Endoscopic findings in ulcerative colitis' and "Endoscopic diagnosis of inflammatory bowel disease", section on 'Endoscopic findings in Crohn disease'.)
Clinical presentation — Microscopic colitis is characterized by chronic, nonbloody diarrhea that is typically watery [1,8,11,93]. The onset of diarrhea is often insidious, but may be sudden in approximately 40 percent of patients . Patients with microscopic colitis usually have between four and nine watery stools per day, but in rare cases may have in excess of 15 bowel movements or up to 2 liters per day [8,94]. Patients may have associated fecal urgency (70 percent), incontinence (40 percent), and nocturnal episodes (50 percent). Abdominal pain may occur in up to 50 percent of patients with microscopic colitis with active disease (≥3 stools or ≥1 watery stool daily) [95,96]. Patients may have associated weight loss due to fluid loss or decrease in oral intake. Extraintestinal symptoms, such as arthralgia, arthritis, or uveitis, can occur. (See 'Associated conditions' above.)
Laboratory findings — Laboratory findings in microscopic colitis are nonspecific. Mild anemia, elevated erythrocyte sedimentation rate, and autoantibodies are found in approximately one-half of patients [8,10,73,97,98]. These autoantibodies include rheumatoid factor (RF), antinuclear (ANA) and antimitochondrial antibodies (AMA), antineutrophilic cytoplasmic antibodies (ANCA), anti-Saccharomyces cerevisiae antibodies (ASCA), and antithyroid peroxidase antibodies (TPO). In rare cases, patients may have a protein-losing enteropathy and associated hypoalbuminemia. (See "Protein-losing gastroenteropathy", section on 'Clinical manifestations'.)
Increased levels of the inflammatory markers, eosinophil protein X (EPX), myeloperoxidase (MPO), and tryptase, have been detected in stool from patients with collagenous colitis . Studies that have evaluated fecal calprotectin excretion as a marker of active microscopic colitis have been conflicting [100,101]. Additional studies are needed to validate these findings and to clarify the role of fecal markers in the diagnosis and management of microscopic colitis.
DIAGNOSIS — Microscopic colitis should be suspected in a patient with chronic diarrhea. The diagnosis of microscopic colitis is established by histology.
Diagnostic evaluation — Evaluation of a patient with suspected microscopic colitis serves to exclude other causes of diarrhea and establish the diagnosis of microscopic colitis.
Laboratory studies — Stool studies should include stool C. difficile toxin, routine stool cultures (Salmonella, Shigella, Campylobacter, Yersinia), and specific testing for Escherichia coli O157:H7. Microscopy for ova and parasites (three samples) and a Giardia stool antigen test should also be performed, particularly if the patient has risk factors such as recent travel to endemic areas. In addition, we obtain a complete blood count, electrolytes, and albumin as patients with microscopic colitis may have mild anemia and, in rare cases, a protein-losing enteropathy. (See 'Laboratory findings' above.)
Endoscopy and biopsy — A colonoscopy with mucosal biopsy is necessary to establish the diagnosis of microscopic colitis. On endoscopy, patients with microscopic colitis usually have normal-appearing colonic mucosa, although nonspecific findings including slight edema, erythema, and friability may be seen.
The inflammatory cell response is similar in lymphocytic and collagenous colitis, consisting mainly of mononuclear infiltrates, with few neutrophils and eosinophils in the lamina propria (picture 1). However, there are certain key histologic features that are used to diagnose collagenous and lymphocytic colitis (table 2).
●Collagenous colitis is characterized by a colonic subepithelial collagen band >10 micrometers in diameter (image 1 and picture 2A-B) . The band is most evident between the crypts. While assessing the thickness of the collagen band, it is important that biopsy specimens are well oriented and cut perpendicular to the mucosal surface so that the collagen band does not falsely appear to be thickened.
●Lymphocytic colitis is characterized by ≥20 intraepithelial lymphocytes (IEL) per 100 surface epithelial cells . Crypt architecture is usually not distorted, but focal cryptitis may be present.
●Incomplete microscopic colitis or microscopic colitis not otherwise specified has been used to describe a subgroup of patients with diarrhea, an increase in cellular infiltrate in the colonic lamina propria, and either an abnormal collagenous layer or IELs short of fulfilling the criteria for collagenous colitis and lymphocytic colitis . However, it is unclear if this represents a separate subtype of microscopic colitis as these findings may be seen in a variety of conditions (eg, adjacent to an adenoma, in ischemic colitis, irritable bowel syndrome, and chronic trauma) .
Biopsies should be obtained from the right side of the colon as the severity of histologic changes declines from the proximal to the distal colon. Collagenous colitis can be patchy, with normal mucosa being found mainly in specimens from the rectosigmoid. Rectosigmoid biopsies alone would miss the diagnosis of collagenous colitis in up to 40 percent of cases [22,104]. In a retrospective review of histologic specimens from 56 patients, the highest diagnostic yield was achieved in biopsies from the transverse colon (83 percent) and right colon (70 percent), and lowest in the rectosigmoid (66 percent) . While colonoscopy is generally safe in patients with microscopic colitis, perforations have been described in patients with significant collagen deposits ("fractured colon") [106-108].
In small case series, chromoendoscopy using indigo carmine has been used to highlight mucosal alterations that correspond to the histological distribution of microscopic colitis . However, larger studies are needed before routine use of chromoendoscopy can be recommended for the diagnosis of microscopic colitis.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of diarrhea due to microscopic colitis includes other causes of chronic secretory diarrhea. This is discussed in detail, separately. (See "Approach to the adult with chronic diarrhea in resource-rich settings", section on 'Evaluation'.)
MANAGEMENT — The primary goal of management in patients with microscopic colitis is to achieve clinical remission (<3 stools per day and <1 watery stool per day) and to improve the patient's quality of life. It is unclear if histologic remission is necessary . Management of microscopic colitis is largely based on observational data; the few controlled trials that exist have mainly evaluated budesonide [110,111]. Our recommendations are largely consistent with the American Gastroenterological Association Institute guidelines on the management of microscopic colitis .
●Patients should be advised to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and, if possible, discontinue medications associated with microscopic colitis (table 1) . For symptomatic management of diarrhea, we use the antidiarrheal agent, loperamide, particularly at night to decrease the frequency of nocturnal episodes . Antidiarrheals may be used alone in patients with mild diarrhea or in conjunction with other therapies, based on the severity of symptoms.
●In patients with active disease (≥3 stools daily or ≥1 watery stool daily) or diarrhea that persists despite the use of antidiarrheals, we recommend the addition of budesonide (9 mg daily for four weeks). If the patient is in clinical remission, we taper budesonide to 6 mg for two weeks, followed by 3 mg for another two weeks, and then discontinue therapy. If the symptoms are not controlled or if symptoms recur on tapering, the dose of 9 mg can be continued for 12 weeks or longer before tapering budesonide.
Randomized trials in patients with collagenous colitis suggest that budesonide is effective for short-term treatment of microscopic colitis and can improve quality of life [114-120]. A meta-analysis of eight randomized trials that included 248 patients randomized to glucocorticoids versus placebo found that short-term clinical response rates were significantly higher with budesonide, as compared with placebo (risk ratio [RR] 3.1, 95% CI 2.1-4.6) .
●In patients who fail to respond to budesonide, but with mild symptoms, we use concomitant therapy with loperamide and cholestyramine (4 g four times per day). In patients who fail to respond to a short, two-week trial of cholestyramine, we use bismuth subsalicylate (three 262 mg tablets three times daily) [70,122]. However, there are limited data to support either agent, and bismuth subsalicylate is not widely available. In a randomized trial, 23 patients with collagenous colitis and 41 with lymphocytic colitis were assigned to mesalazine at 2.4 g per day alone or in combination with cholestyramine at 4 g per day for six months . Clinical and histologic remission was noted in 91 percent of patients with collagenous colitis and 85 percent of patients with lymphocytic colitis. While the rates of clinical remission were slightly higher in patients with collagenous colitis who were treated with the combination of cholestyramine and mesalamine (100 versus 73 percent), this trial was unblinded, and there was no placebo group. In addition, some of the measured effect may have been due to spontaneous improvement in the disease activity.
In an open-label study, treatment with bismuth subsalicylate was associated with improvement in symptoms in 11 of 13 patients and resolution of colitis in nine . These results were confirmed in a subsequent preliminary trial in which 14 patients were randomly assigned to receive bismuth subsalicylate (three 262 mg chewable tablets three times daily) or placebo for eight weeks . As compared with placebo, treatment with bismuth was reportedly associated with a significant decrease in fecal frequency and weight, improvement in consistency, and improvement in colonic histology. However, the results of this study have not been published.
Refractory symptoms — Approximately 10 to 20 percent of patients treated with budesonide are nonresponders . Patients with an inadequate response to combination treatment with budesonide, cholestyramine, antidiarrheals, and/or bismuth should be re-evaluated for other causes of diarrhea (eg, celiac disease, hyperthyroidism, carcinoid syndrome, VIPoma, persistent NSAID use, irritable bowel syndrome) [125,126]. (See "Diagnosis of celiac disease in adults", section on 'Diagnostic approach' and "Diagnosis of hyperthyroidism" and "Diagnosis of the carcinoid syndrome and tumor localization" and "VIPoma: Clinical manifestations, diagnosis, and management" and "NSAIDs: Adverse effects on the distal small bowel and colon" and "Clinical manifestations and diagnosis of irritable bowel syndrome in adults", section on 'Diagnostic criteria'.)
●In patients with refractory microscopic colitis, we use anti-tumor necrosis factor (TNF) therapy (eg, infliximab, adalimumab) or immunomodulators (6-mercaptopurine or azathioprine). Limited evidence from small case series and retrospective studies suggest that anti-TNF agents and immunomodulators can induce remission in patients with refractory microscopic colitis [127-131].
●Surgery (ileostomy, sigmoidostomy, colectomy) should be reserved for management of microscopic colitis that is refractory to medical therapy [132-135]. Ileostomy may be the procedure of choice in older patients with resistant disease [1,134].
●Prednisone has no role in the management of patients with microscopic colitis who fail to respond to budesonide. Prednisone leads to a reduction in colonic inflammation, but not in the thickness of the collagen band [19,136,137]. As compared with budesonide, prednisone is associated with a lower response rate (53 versus 83 percent), more side effects, and a higher risk of relapse when therapy is withdrawn [137,138].
●Aminosalicylates including mesalamine appear to be ineffective in the treatment of collagenous colitis. Studies are necessary to elucidate the role of mesalamine in lymphocytic colitis. In a randomized trial in which 92 patients with active collagenous colitis were assigned to treatment with oral budesonide (9 mg daily), mesalamine (3 grams daily), or placebo for eight weeks, remission rates with mesalamine were comparable to placebo (32 and 38 percent, respectively) [8,120].
●Although a number of other agents (eg, octreotide, methotrexate, verapamil, probiotic E. coli strain Nissle, and Boswellia serrata extract) have been used to treat patients with microscopic colitis, they have not been consistently effective [7,114,139-142].
Recurrent symptoms and maintenance therapy — Patients with recurrent symptoms after an initial response to budesonide can either be retreated with budesonide as intermittent therapy or as continuous maintenance therapy at the lowest dose that maintains clinical remission [112,121,143].
However, low-dose maintenance treatment is controversial . Only limited data are available that have described the efficacy of budesonide for maintenance therapy in collagenous colitis. Long-term treatment with budesonide increases the risk of steroid-related side effects. A pooled analysis included two maintenance budesonide trials with a six-week, open-label induction phase, followed by a six-month, double-blind maintenance phase of 6 mg of budesonide daily versus placebo, in patients with collagenous colitis . In this analysis, long-term treatment with budesonide was significantly superior to placebo for maintenance of clinical response (RR 3.2, 95% CI 1.1-9.9). However, relapse occurred in 46 to 80 percent of patients within six months of treatment cessation.
NATURAL HISTORY — Microscopic colitis has a chronic, intermittent course in most patients [8,144,145]. Diarrhea may resolve within weeks with or without treatment, but relapses are common (approximately 30 to 60 percent) [22,36,115,133]. In one prospective study that included 47 patients with collagenous colitis, at 10-year follow-up, diarrhea resolved in approximately one-half of patients with anti-inflammatory treatment and persisted in approximately one-third of patients .
The long-term course of patients with lymphocytic colitis may be more favorable than with collagenous colitis [34,146]. A retrospective study compared the natural history of 96 patients with collagenous colitis and 80 patients with lymphocytic colitis . Resolution or significant improvement occurred significantly more often in those with lymphocytic colitis, as compared with collagenous colitis (84 versus 74 percent).
Few prospective studies have examined the natural history of microscopic colitis in patients who received the medical treatment. One of the largest such studies included 37 patients with collagenous and 44 patients with lymphocytic colitis who were followed prospectively after diagnosis for an average of 37 months . Patients were treated with a variety of interventions, including withdrawal of implicated medications and the use of salicylates, cholestyramine, prednisone, and budesonide. These interventions were associated with long-term cessation of diarrhea in approximately 70 percent of patients, while 25 to 30 percent relapsed.
Although some cases have been reported, transformation between collagenous and lymphocytic colitis usually does not occur [1,146]. Microscopic colitis has not been associated with an increased risk of colorectal cancer.
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Microscopic colitis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Microscopic colitis is a chronic inflammatory disease of the colon that is characterized by chronic, watery diarrhea. Based on the histological features, microscopic colitis is divided into lymphocytic and collagenous colitis; however, it is unclear if these conditions are related. (See 'Introduction' above and 'Subtypes' above.)
●The pathogenesis of microscopic colitis is unclear, but it is likely to be multifactorial, involving mucosal immune responses to luminal factors in a genetically predisposed individual. Medications and smoking have been implicated as being causative or triggering flares of microscopic colitis (table 1). (See 'Etiology and risk factors' above and 'Pathogenesis' above.)
●Microscopic colitis has a female preponderance, with a mean age at diagnosis of 65 years. Patients with microscopic colitis typically present with insidious onset of chronic, nonbloody, watery diarrhea. Associated symptoms include fecal urgency (70 percent), abdominal pain (50 percent), fecal incontinence (40 percent), and nocturnal episodes (50 percent). (See 'Epidemiology' above and 'Clinical manifestations' above.)
●Microscopic colitis should be suspected in a patient with chronic diarrhea. Evaluation of a patient with suspected microscopic colitis should include stool cultures and a colonoscopy, with mucosal biopsy to establish the diagnosis of microscopic colitis and to exclude other inflammatory diseases. Collagenous colitis is classically characterized by colonic subepithelial collagen band >10 micrometers in thickness. Lymphocytic colitis is characterized by an intraepithelial lymphocytic infiltrate (>20 per high power field). (See 'Diagnosis' above.)
●Patients should be advised to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and, if possible, discontinue medications associated with microscopic colitis. Antidiarrheals may be used alone in patients with mild diarrhea or in conjunction with other therapies, based on the severity of symptoms. For patients with microscopic colitis with active disease (≥3 stools daily or ≥1 watery stool daily), we recommend budesonide (Grade 1B). We usually begin with 9 mg/day for four weeks. If the patient is in remission (<3 stools daily and no watery stools), we taper to 6 mg for two weeks, to 3 mg for another two weeks, and then discontinue therapy. If the symptoms are not controlled or if symptoms recur on tapering, the dose of 9 mg can be continued for 12 weeks or longer before tapering budesonide. (See 'Initial approach' above.)
Patients with recurrent symptoms after an initial response to budesonide can either be retreated with budesonide as intermittent therapy or as continuous maintenance therapy at the lowest dose that maintains clinical remission. (See 'Recurrent symptoms and maintenance therapy' above.)
In patients who do not respond to budesonide, we suggest concomitant therapy with cholestyramine (Grade 2C). If the combination of budesonide and cholestyramine is not effective, we suggest a trial of bismuth subsalicylate (Grade 2C).
●We reserve the use of anti-tumor necrosis factor (TNF) agents for microscopic colitis that is refractory to a combination of budesonide, antidiarrheals, cholestyramine and/or bismuth subsalicylate once other causes of diarrhea have been excluded. We reserve surgery for patients with microscopic colitis that is refractory to medical therapy. (See 'Refractory symptoms' above.)
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