Recent advances in diagnosis and treatment of microscopic colitis.

Microscopic colitis, comprising collagenous colitis and lymphocytic colitis, is a common cause of chronic diarrhea. It is characterized clinically by chronic watery diarrhea and a macroscopically normal colonic mucosa where diagnostic histopathological features are seen on microscopic examination. The annual incidence of each disorder is 4-6/100,000 inhabitants, with a peak incidence in individuals 60-70 years old and a noticeable female predominance in collagenous colitis. The etiology is unknown. Chronic diarrhea, abdominal pain, weight loss, fatigue, and fecal incontinence are common symptoms that impair the health-related quality of life of the patient. There is an association with other autoimmune disorders, such as celiac disease, thyroid disorders, diabetes mellitus, and arthritis. Budesonide is the best-documented treatment, both short-term and long-term. Recurrence of symptoms is common after withdrawal of successful budesonide therapy, and the optimal long-term treatment strategy needs further study. The long-term prognosis is good, and the risk of complications including colon cancer is low. We review the epidemiology, clinical features, diagnosis and treatment of microscopic colitis.

Introduction

Chronic diarrhea, reported by 4-5% of individuals of a Western population, is a common cause for consulting a physician in general practice or in internal medicine and for referral to a gastroenterologist [1]. Microscopic colitis (MC), previously regarded as rare, and certainly overlooked, now has emerged as a common cause of chronic diarrhea, especially in elderly females. The condition is characterized clinically by chronic watery diarrhea and a macroscopically normal or almost normal colonic mucosa, where microscopic examination of mucosal biopsies reveals characteristic histopathological changes [2]. MC comprises two entities: collagenous colitis (CC) and lymphocytic colitis (LC), which have indistinguishable clinical presentations but are separated by histopathological characteristics. This review will present recent advances in the epidemiology, clinical features, diagnosis, and management of MC.

Epidemiology

CC and LC, first described in 1976 [3] and in 1989 [4], respectively, have mostly been reported from European or North American centers, but the disease is found worldwide [5-11]. Currently, epidemiological data have been reported from five different regions (Table 1) [5,6,12-17]. The difference between data from Spain and those reported from Northern Europe and North America may suggest that there is a North–South difference in the incidence of MC. Long-term epidemiological data from Sweden and the United States since the 1980s show rising incidences, which seem to have levelled off during the last study periods in the Swedish study. Whether the increasing incidence figures are an artefact reflecting an increased awareness and improved diagnosis of the condition, or in fact represent a true rise, is at present unknown. MC may be diagnosed in 10-20% of cases investigated for chronic watery diarrhea [5]. In 2001, the prevalence of microscopic colitis in Olmsted County, Minnesota, USA was 103/100,000 inhabitants; 39.3/100,000 for collagenous colitis and 63.7/100000 for lymphocytic colitis.

Table 1

Annual incidence/100,000 inhabitants in population-based epidemiological studies of collagenous and lymphocytic colitis

CC mainly affects middle-aged women, with a peak incidence around 65 years of age (Fig. 1) [6,18]. However, the disease can occur in all ages, including children [19]. In LC the peak incidence is in the same age group as CC, but the female predominance is less pronounced (Fig. 1) [20].

Figure 1

Age- and sex-specific incidence of (A) collagenous colitis and (B) lymphocytic colitis. Reprinted with permission from Gut 2004;53:346-50

Clinical presentation

The clinical symptoms of CC and LC are similar and the diseases cannot be differentiated on clinical grounds. Both disorders cause chronic or recurrent non-bloody, watery diarrhea, often associated with nocturnal diarrhea, diffuse abdominal pain, and weight loss, which may be substantial [18,20,21]. Although some patients may suffer from severe diarrhea, serious dehydration is rare. Fatigue, nausea, and fecal incontinence are other associated symptoms, and the disease may significantly impair quality of life of the affected patient [22-24].

The onset of disease can be sudden, mimicking infectious diarrhea [18,20]. The clinical course is often chronic, relapsing, and benign. Severe complications are rare, although there are reports of colonic perforations, spontaneous or after a colonoscopy, in CC [25-27]. No increased risk of colorectal cancer is reported in CC or LC [28-30]. However, an increased risk of lung cancer was reported in women with CC [28] probably related to smoking, which is more common among patients compared to controls [31,32].

Some patients have mild symptoms that may be misinterpreted as irritable bowel syndrome [33]. Morphologic findings of MC have been reported even in constipated or asymptomatic patients [34]. The natural history of the condition in these patients is unknown.

Patients with MC often have concomitant autoimmune diseases [18,20,21]. The most common are thyroid disorders, celiac disease, diabetes mellitus, and rheumatoid arthritis. The occurrence of such associations, reported in up to 40-50% of patients, is variable depending on the study, and differences between LC and CC with respect to associated conditions have been described [18,20,21,35]. Bile acid malabsorption can often coexist with MC, leading to worsening of symptoms [36]. An interchange between ulcerative colitis or Crohn’s disease and MC has been reported occasionally [37,38]. Whether this is merely a chance association of two fairly common disorders occurring in the same individual or due to common genetic predisposition or shared immunologic pathways remains unknown thus far.

Etiology and pathogenesis of mucosal inflammation

The cause of microscopic colitis is multifactorial and largely unknown. CC and LC are presently considered to represent specific mucosal responses to various noxious luminal agents, in predisposed individuals. As CC and LC have many clinical similarities and share histopathological features, except for the subepithelial collagen layer found in CC, it has been discussed whether LC and CC are in fact the same disease seen in different stages of development. Conversion of LC to CC or the opposite has been reported, but occurs infrequently. However, in clinical practice the management is not determined by histological type.

Data on the mucosal inflammation in MC are increasing but still limited. In the epithelium mainly CD8+ T-lymphocytes are found that carry the α/β form of the T-cell receptor, and in the lamina propria there are largely CD4+ T-lymphocytes [39]. CD25+FOXP3+ T reg cells are a common feature in the lamina propria of both CC and LC patients [40]. By means of segmental colorectal perfusion technique, increased luminal levels of eosinophilic cationic protein (ECP), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) were found in CC [41-43]. Likewise, Wagner et al Microscopic colitis found an increased number of activated eosinophils in the colonic mucosa in CC, which became normal after budesonide treatment [44]. By immunohistochemistry technique, others verified increased mucosal levels of VEGF that were not affected following therapy with budesonide [45]. A study of cytokines in MC found a TH1 mucosal cytokine profile with IFNγ, TNFα, and IL-15 as the predominantly upregulated cytokines [46]. Using Ussing chamber technology, increased transcellular and paracellular mucosal permeability were found in patients with CC that persisted after treatment with budesonide [47,48]. The excess subepithelial collagen in CC may be due to an imbalance of collagen turnover. An increased collagen synthesis is supported by findings of an increase in the number or the activity of myofibroblasts [49]. Among degrading enzymes, matrix-metalloproteinases (MMPs) have a central role that is regulated by tissue endogenous inhibitors of metalloproteinases (TIMPs) [50]. Impaired collagen degradation in CC was supported by findings of restricted MMP-1 RNA expression and increased TIMP expression [51].

Genetics

It is uncertain whether there is a genetic predisposition to MC. Familial cases have been reported, but it is unclear whether these reflect shared familial traits or random associations [52-55]. HLA-studies have earlier shown an association between MC and HLA-DQ2 or DQ1,3, and recently an association was reported between MC and HLA-DR3-DQ2 haplotype, and with TNF2 allele carriage, irrespective of presence of concomitant celiac disease [56,57]. Variants of MMP-9 gene associated with CC have been reported [58]. No association with NOD2/CARD15 polymorphisms and susceptibility to CC has been found [59].

Luminal factor

Mucosal inflammation with an increased number of intraepithelial T-lymphocytes has suggested that MC may be caused by an immunological response to a luminal agent in predisposed individuals. This theory is supported by the observation that diversion of the fecal stream by an ileostomy normalized or reduced the characteristic histopathologic changes in CC [60]. After closure of the ileostomy, recurrence of symptoms and histopathologic changes occurred.

Drug-induced MC

There are several reports of drug-induced MC and a strong likelihood of association has been found with acarbose, aspirin, Cyclo3 Fort, non-steroidal anti-inflammatory drugs, lansoprazole, ranitidine, sertraline, and ticlopidine [61]. Assessment of concomitant drug use in patients with MC is therefore important to identify and consider withdrawal of drugs that might cause or worsen the condition.

Infection

An infectious cause has been suspected, especially in patients with a sudden onset of disease. An association with MC and Campylobacter jejuni, Yersinia enterocolitica or Clostridium difficile has been reported occasionally [62-65]. LC shares many features with “Brainerd diarrhea”, which refers to outbreaks of acute watery diarrhea with long duration, first reported among 122 residents of Brainerd, Minnesota [66]. Colonic biopsies of these patients show epithelial lymphocytosis similar to LC, but not crypt distortion or epithelial destruction [67]. Investigations of several outbreaks of “Brainerd diarrhea” have established an incubation period of 10-30 days and median duration of illness of 16 months [68]. Although an infectious agent is thought to be the cause of “Brainerd diarrhea”, no microorganism has as yet been identified. Furthermore, a seasonal pattern of onset of LC [20,69] may support an infectious cause. However, in most cases of MC with a sudden onset, stool cultures remain negative.

Bile acids

Bile acid malabsorption can coexist with MC, leading to worsening of symptoms. Concurrent bile acid malabsorption was found in 27-44% of patients with CC and in 9-60% of patients with LC [36,70,71]. These observations are the rationale for recommendations of bile acid binding treatment in MC. The treatment is especially effective in patients with concomitant bile acid malabsorption, but improvement has also been shown in patients without bile acid malabsorption.

Autoimmunity

The association with other autoimmune diseases such as thyroid disease, celiac disease, diabetes mellitus, or arthritis has suggested an autoimmune process. However, no specific autoantibody or marker has been identified.

Nitric oxide

Colonic nitric oxide (NO) production is greatly increased in active MC, caused by an upregulation of inducible nitric oxide synthase (iNOS) in the colonic epithelium [72-75]. A major transcriptional inducer of iNOS gene expression is the transcription nuclear factor κB (NFκB). In active CC colonic mucosal NFκB was found activated in epithelial cells, but not in lamina propria macrophages, in contrast to ulcerative colitis [76]. The levels of NO correlate to clinical and histological disease activity [73]. It has been suggested that NO is involved in the pathophysiology of diarrhea in CC, as infusion in the colon of NG-monomethyl-L-arginine, an inhibitor of NOS, reduced colonic net secretion by 70%, and the addition of L-arginine, a precursor in NO synthesis, increased colonic net secretion by 50% [74]. Further support for NO being involved in the pathogenesis of CC comes from therapy studies. Treatment with budesonide, in contrast to placebo, resulted in a significant reduction in iNOS mRNA that correlated with clinical and histopathological improvement [77].

Secretory or osmotic diarrhea

The exact mechanism of diarrhea in MC is not fully clarified. In CC, diarrhea has been regarded as secretory, caused by reduced net absorption of Na+ and Cl- ions due to epithelial cell lesions, and the thickened collagenous layer as a co-factor causing a diffusion barrier, and by an additional active chloride secretion [78]. Fasting, on the other hand, seems to reduce diarrhea, which would indicate an osmotic component in some patients, as well [79].

Diagnosis

The diagnosis of MC relies solely on findings of typical microscopic changes in colonic mucosal biopsies [80]. In CC a thickening of the subepithelial collagen layer is seen, together with a chronic mononuclear inflammation in the lamina propria, and epithelial cell damage with occasionally increased number of intraepithelial lymphocytes (Fig. 2). The thickened subepithelial collagen layer in CC is ≥10µm on well-orientated sections, in contrast to a normal basal membrane of <3µm. The thickening of the collagen layer may be variable and is most prominent in the ascending or transverse colon, and may be absent in biopsies from the sigmoid colon or rectum, emphasizing the importance of obtaining biopsies from the proximal colon when diagnosing CC [81]. Generally, the histopathologic changes are restricted to the large bowel, but a thickened collagen layer has infrequently been found in the stomach, duodenum, or terminal ileum. In addition to conventional histological staining, the use of tenascin immunostaining has been suggested in uncertain cases of CC (Fig. 3) [49,82].

Figure 2

Biopsy from colon showing (A, B) typical findings of collagenous colitis - increased subepithelial collagen layer, inflammation of lamina propria, and epithelial cell damage with intraepithelial lymphocytes; (C) typical findings of lymphocytic colitis - epithelial cell damage with intraepithelial lymphocytes, inflammation in the lamina propria but no increased collagen layer

Figure 3

Tenascin immunostaining in collagenous colitis

The diagnostic features of LC (Fig. 2) are an increased number of intraepithelial lymphocytes (≥20/100 surface epithelial cells) in conjunction with surface epithelial cell damage and an infiltration of lymphocytes and plasma cells in the lamina propria, but the collagen layer is normal, in contrast to CC [80]. In uncertain cases, immunostaining of CD3+ T-lymphocytes facilitates the assessment of intraepithelial lymphocyte count (Fig. 4).

Figure 4

Immunostaining of CD3+ T-lymphocytes in lymphocytic colitis

Barium enema and colonoscopy are usually normal, although subtle mucosal changes can be seen, such as edema, erythema, and abnormal vascular pattern [18,20]. Tears of colonic mucosa have occasionally been seen during colonoscopy, which might be a sign of increased risk of colonic perforation during the procedure [27,83-85]. In the future, the use of confocal laser microscopy may enable in vivo diagnosis of MC [86-88].

Laboratory tests are non-diagnostic and only non-specific abnormalities, such as moderately elevated C-reactive protein, ESR, or mild anemia are found. Stool tests generally reveal no pathological microorganisms. The diagnostic accuracy of fecal calprotectin and lactoferrin is low [89]. In a small pilot study, fecal eosinophil markers such as eosinophil cationic protein (F-ECP) and eosinophil protein X (F-EPX) were positive in 92% and 67%, respectively, of 12 patients with active CC, and a rapid fall of both markers was seen after budesonide treatment [90].

“Atypical” microscopic colitis

In addition to CC and LC, other rare subtypes of MC have been described, including microscopic colitis with giant cells [91,92], paucicellular lymphocytic colitis [93], cryptal lymphocytic colitis [94], pseudomembranous collagenous colitis [95], microscopic colitis with granulomatous inflammation [96], and microscopic colitis not otherwise specified [80]. The clinical features of these conditions are similar to classical MC, but histopathologic appearance differs. Further studies are required to address the relationship and clinical significance of these “atypical” types of MC [40,97].

Therapy

No curative therapy currently exists for MC. The primary goals of medical therapy are to achieve and maintain remission of symptoms, and to improve the patient’s quality of life. Whether histological remission is an essential objective is currently unknown. A careful assessment of concomitant drug use and dietary factors such as excess use of caffeine, alcohol, and dairy products that might worsen the condition is important. Concomitant bile acid malabsorption or celiac disease should be considered.

Antidiarrheals

Although loperamide or cholestyramine have not been formally studied in randomized placebo-controlled trials, they are generally recommended as the first step of treatment in the patient with mild symptoms. Clinical experience suggests a symptomatic benefit in a proportion of patients, mainly in those with mild symptoms. However, sustained clinical remission is rarely achieved and an impact on colonic inflammation is unlikely.

Budesonide

Budesonide is the best-documented treatment and significantly improves the clinical symptoms and the patient’s quality of life. Three short-term, randomized controlled trials in CC have consistently shown that budesonide 9 mg daily for 6-8 weeks is superior to placebo (Table 2) [98-100]. About 80% of patients responded to budesonide and had a decrease in the number of loose stools after 2-4 weeks of therapy. In a Cochrane meta-analysis, the pooled odds ratio for clinical response with budesonide compared to placebo was 12.32 (95% CI 5.53-27.46) and number needed to treat was two patients [101]. In a placebo-controlled trial including 41 patients, budesonide treatment was effective also in LC [102]. After 6 weeks of treatment, 18 of 21 patients (86%; 95% CI 65-96%) in the budesonide group achieved a clinical response compared to 8 of 20 patients (40%; 95% CI 22-61%) in the placebo group, yielding an odds ratio of 9.00 (95% CI 1.98-40.93; P = 0.004) [103]. The number needed to treat to achieve a clinical response in LC with budesonide was 3 patients.

Table 2

Data from four randomized, placebo-controlled trials of oral budesonide in collagenous colitis and lymphocytic colitis

The relapse rate is high after cessation of successful short-term budesonide therapy in CC, and 61-80% of treated patients will have an early recurrence of symptoms [98-100]. In clinical practice tapering doses of budesonide to 3-6 mg/day have been used as maintenance therapy and may well control clinical symptoms. The evidence for such a strategy in CC now exists, and two studies have proven that maintenance therapy with budesonide 6 mg/day for six months is well tolerated and superior to placebo [104,105]. A total of 80 patients, who had responded to open-label budesonide, were randomized to budesonide 6 mg daily or placebo for 6 months. Clinical response was maintained in 33/40 (83%) patients who received budesonide compared to 11/40 (28%) patients who received placebo (P=0.0002). Pooled odds ratio for maintenance of clinical response with budesonide compared to placebo, was 8.40 (95% CI 2.73-25.81) with a number needed to treat of 2 patients. Histological response was seen in 48% of patients who received budesonide compared to 15% of patients who received placebo (P = 0.002) [101]. However, six-month maintenance therapy did not alter the subsequent disease course, as the relapse risk after withdrawal of 24-week maintenance treatment was similar to that observed after 6-week induction therapy, and the median time to relapse was equal in the two groups (39 days versus 38 days) [104].

Prednisolone

Other oral corticosteroids, such as prednisolone, are associated with more frequent side effects, and the efficacy seems inferior to budesonide, although no formal comparative studies are available [106].

Bismuth subsalicylate

Bismuth subsalicylate has been shown effective in a small, placebo-controlled study including 9 patients with CC and 5 with LC [107]. This drug is not available in a number of countries because of concerns regarding drug toxicity.

Aminosalicylates

Sulfasalazine or mesalazine have been extensively used in MC, but not strictly evaluated in randomized, placebo-controlled trials. In a recent trial, 64 patients with MC were randomized to mesalazine 2.4 g/day or mesalazine 2.4 g/day + cholestyramine 4 g/day for 6 months. A high remission rate was seen in both treatment arms, and 85% of patients with LC and 91% of patients with CC were in remission at the study’s end. Combined therapy was superior in CC and induced an earlier clinical response in both diseases [108]. The benefit of mesalazine with or without cholestyramine needs to be confirmed in a placebo-controlled trial.

Antibiotics, probiotics, Boswellia serrata

Antibiotics such as metronidazole or erythromycin have been used, but not in a controlled fashion. Probiotic treatment shows uncertain results and needs further evaluation [109]. Boswellia serrata extract has been tried in a placebo-controlled trial, showing a nonsignificant trend in favor of active treatment [110].

Immunosuppressive therapy

In patients with unresponsive or steroid-resistant disease, immunosuppressive therapy may be considered, although the evidence is virtually absent. An open study with azathioprine gave partial or complete remission in eight of nine patients with MC [111]. There are conflicting data on the efficacy of methotrexate. Riddell et al reported that of 19 patients with CC treated with methotrexate orally, a good response, generally within 2-3 weeks of treatment, was seen in 14 patients, and a partial response in 2 patients. The dose of Microscopic colitis methotrexate ranged from 5-25 mg/week and was in median 7.5-10 mg/week [112]. Divergent data were reported in nine patients with CC refractory to budesonide treatment. After 12-week treatment with subcutaneous methotrexate 15-25 mg/week, no patient improved [113]. Determining the best therapeutic alternative for patients who are intolerant or fail therapy with budesonide is thus an important goal for future clinical trials.

Surgery

Surgical therapy may be considered for patients with severe, unresponsive MC. Both split ileostomy and subtotal colectomy have been performed and reported successful [60,114]. The indication for surgical therapy today is limited, considering the improvement in medical therapy.

Prognosis

The long-term prognosis of MC is generally good [115-117]. In a follow-up study of CC, 63% of patients had a lasting remission after 3.5 years [115,116]. In another cohort study all 25 patients were improved 47 months after diagnosis, and only 29% of them required ongoing medication [115,116]. After a mean follow-up time of 6.4 years, others reported that about half the patients with MC had no diarrhea and only a minority had diarrhea more than once a week [117]. However, others reported that abdominal pain may persist even after diarrheal symptoms have disappeared [32]. A benign course was reported in 27 cases with LC, with resolution of diarrhea and normalization of histology in over 80% of patients within 38 months [118]. Others reported that 63% of patients with LC had a single attack with a median duration from onset of symptoms to remission of 6 months [20].

Conclusions

Microscopic colitis is a fairly common cause of chronic watery diarrhea, especially in elderly women.

The correct diagnosis depends on the awareness of the condition by the clinician (referring the patient with chronic diarrhea to colonoscopy), by the endoscopist (obtaining mucosal biopsies, even though the colonic mucosa is endoscopically normal), and by the pathologist (recognizing the histopathological features of MC).

Budesonide is an effective treatment, both short- and long-term, and improves the patient’s symptoms and quality of life.

The relapse risk after discontinuation of therapy is high, and the optimal long-term management needs further study.

The long-term prognosis is good and the risk of complications, including colonic cancer, is low.