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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e31823d7705
Review Articles

Lymphocytic Colitis and Collagenous Colitis: A Review of Clinicopathologic Features and Immunologic Abnormalities

Mahajan, Dipti MD*; Goldblum, John R. MD*; Xiao, Shu-Yuan MD; Shen, Bo MD; Liu, Xiuli MD, PhD*

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*Department of Anatomic Pathology

Department of Gastroenterology, Digestive Disease Institute, The Cleveland Clinic Foundation, Cleveland, OH

Department of Pathology, University of Chicago, Chicago, IL

The authors have no funding or conflicts of interest to disclose.

Reprints: Xiuli Liu, MD, PhD, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue/L25, Cleveland, OH 44195 (e-mail: Liux3@ccf.org).All figures can be viewed online in color at http://http://www.anatomicpathology.com.

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Abstract

Lymphocytic colitis (LC) and collagenous colitis (CC), 2 histologic forms of microscopic colitis, were recognized as rare disease entities 4 decades ago. An increasing body of evidence accumulated in the past 40 years reveals increasing incidence and prevalence rates, a wide spectrum of clinical presentations, and several histologic variants. Although several recent randomized clinical trials confirmed the efficacy of oral budesonide in treating LC and CC, disease relapse after a short-duration treatment is common. Despite their common clinical presentations and well-defined histologic diagnostic criteria, there are only few studies on the immunologic abnormalities in colonic tissue. The aim of this review is to (1) familiarize the pathologists in general practice with histomorphology of LC and CC, including the rare histologic variants and the clinical implication associated with these 2 diagnoses, (2) summarize the data from recent randomized clinical trials of oral budesonide, and (3) review immunological studies on colonic tissue. Overall, immunologic abnormalities of colonic tissue seem to explain for the histomorphologic features and the clinical symptomatology of LC and CC. Advances in the understanding of the underlying immunologic abnormalities in the colonic tissue may help develop novel and effective therapies for these 2 diseases.

Microscopic colitis is a clinicopathologic term to describe a condition characterized by a usually normal endoscopic appearance of colonic mucosa, yet clearly the presence of histologic colitis.1 Two histologic forms of microscopic colitis have been characterized, namely, lymphocytic colitis (LC) and collagenous colitis (CC).2–4 These 2 entities were thought to be rare. However, an increasing incidence has recently been reported.5 Few studies have shown that 9.5% to 10.2% of the patients with nonbloody diarrhea undergoing colonoscopy had either CC or LC on histologic examination of the biopsies.6–8

The etiology and pathogenesis of LC and CC remain unclear. The seasonal pattern of onset in LC suggests a potential link to an infectious source.9 However, familial clustering of LC and CC also indicates a genetic predisposition.10,11 Autoimmunity and immune dysregulation may also play a significant role as multiple observational studies suggested an association between microscopic colitis with various autoimmune diseases, such as autoimmune thyroiditis, rheumatoid arthritis, celiac disease, and inflammatory bowel diseases (IBDs).2,4,12–18 LC was noted in 38% of the patients with common variable immunodeficiency.19 CC has been reported to be associated with infectious colitis, such as persistent Clostridium difficile infection.20 In addition, LC or CC has been reported to be attributed to medications.21 An increasing number of medications are reported to be associated with or cause microscopic colitis in many published case reports or case-control studies as summarized in Table 1.5,7,22–40

Table 1
Table 1
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Histologic examination of biopsies from the endoscopically normal colonic mucosa plays an essential role in the diagnosis and differential diagnosis. In general, recognition of typical LC and CC can be achieved in the majority of cases by gastrointestinal pathologists with excellent interobserver and intraobserver agreements.41 However, challenging cases with unusual or subtle changes with patchy distribution exist and they pose diagnostic difficulties. The aim of this review is to familiarize the pathologists in general practice with the histomorphology of LC and CC, including the rare variants and the clinical implication associated with these 2 diagnoses, summarize the data from several recent randomized clinical trials with oral budesonide, and review the immunologic studies on colonic tissue.

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LYMPHOCYTIC COLITIS

Incidence, Prevalence, and Demographics

Several European studies reported that the incidence of LC was approximately 1.1 to 3.1 per 100,000 per year with a prevalence of 10 to 15.7 per 100,000.6 A recent study from North America showed that the incidence rate for LC was 5.5 per 100,000 and the rate significantly increased from 1985 to 2001 with a prevalence of 63.7 per 100,000 persons at the end of 2001.42 LC usually occurs in patients with a wide age range from 19 to 98 years. The reported mean age at the time of diagnosis ranged between 53.8 years in the initial report4 and 60.7 years in 1 recent large study.4,13 Rare cases of LC have also been reported in pediatric population.43,44 The sex distribution of LC ranges from an initially reported equal female-to-male ratio to a female predominance with a female-to-male ratio of 2.4 to 2.7.4,6,7,13 LC has been reported to be associated with other diseases, particularly autoimmune diseases, including autoimmune thyroid disease, rheumatoid arthritis, fibromyalgia, and Raynaud/CREST syndrome.7,13,16,40 Also noted is the association of celiac disease with LC.7,13,16,18 The reported prevalence of celiac disease in LC patients ranged from 3.5% to 15%.7,13,16,18 In 1 report, celiac disease was seen in 3.5% of patients with LC and about 54% of these patients had a diagnosis of celiac disease after the diagnosis of LC.13

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Symptomatology

Patients with LC present with chronic, watery, and nonbloody diarrhea.4,7 The average duration of diarrhea before diagnosis is 3 to 30 months and the daily stool number averages from 4 to 6 as reported.4,40 Associated symptoms include abdominal pain (47% to 70%), incontinence (9% to 59%), urgency (65%), flatulence (15% to 59%), and weight loss (41% to 48%).7,40

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Endoscopic Findings

The majority of patients with LC have essentially normal endoscopic appearance. Uncommonly, a mild, nonspecific pattern of erythema, edema, and abnormal vessel pattern may be observed.3,7

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Histologic Findings

LC is characterized by increased intraepithelial lymphocytes (IELs >20/100 colonic surface epithelial cells) in an architecturally normal colonic mucosa, accompanied by surface epithelial damage and a mixed mononuclear inflammatory infiltrate in the lamina propria3 (Fig. 1) (Table 2). The intraepithelial lymphocytosis in LC usually is evident without the need of counting. In cases in which the number of lymphocyte is borderline, a manual counting may be needed and only IELs in the intercryptal spaces should be counted.3 IELs have a small (~5 μm in diameter) dark, round or slightly irregular nucleus, and are often surrounded by a clear halo. The surface epithelium infiltrated by lymphocytes shows evidence of damage, characterized by loss of mucin, with flattened or syncytial appearance instead of the tall columnar cells. In subtle cases, the surface epithelial cells may show only mild loss of mucin. Occasionally, surface sloughing may be seen but it should not be a predominant feature. Few neutrophils in the lamina propria may be present in some cases, but they should not be prominent.3 There should be no significant eosinophilic or neutrophilic cryptitis. In a mild form of the disease, mononuclear cellular inflammation is mainly present in the upper half of the lamina propria. However, in profound cases, this can extend to the lower half of the lamina propria but basal lymphoplasmacytosis should not be present. In most cases, Paneth cell metaplasia is not a feature of LC. However, a recent study showed that some IBD-like morphologic features such as active crypt inflammation, Paneth cell metaplasia, and crypt architectural irregularity were present in 38%, 14%, and 4.2% of LC,45 but these features should be focal. In addition, in this study, active crypt inflammation seemed to be correlated with antibiotic use at the time of clinical presentation and was present in the only 2 patients who had positive stool culture.45 Nevertheless, if these features are seen diffusely, a differential diagnosis from IBD, or early presentation of IBD, should be seriously entertained (see below).

Figure 1
Figure 1
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Table 2
Table 2
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Differential Diagnosis

The histologic diagnosis is usually straightforward for most cases with typical clinical presentation. However, some entities such as CC, refractory celiac disease and its closely related entity (the so-called “lymphocytic enterocolitis”),46 autoimmune enteropathy, IBD, acute colitis, and lymphoma composed of small to medium-sized lymphocytes with a component of intraepithelial lymphocytosis (such as enteropathy-associated T-cell lymphoma, or EATL) may enter into the differential diagnosis. Accurate assessment of the subepithelial collagen table helps distinction between LC and CC. However, rare cases may be with borderline features, and a Masson trichrome stain may be of help. Colonic biopsy from patients with refractory celiac disease and lymphocytic enterocolitis may show changes resembling LC. However, past clinical history of celiac disease will point to the correct diagnosis. Autoimmune enteropathy usually occurs in infancy or in pediatric population, although cases of adult autoimmune enteropathy have been reported in the literature. The clinical presentation of autoimmune enteropathy is usually that of protracted and severe diarrhea with protein loss and requiring parenteral nutrition. Histologically, it is characterized by total villous blunting, crypt hyperplasia or hypoplasia, dense lymphoplasmacytic inflammation in the lamina propria, lymphocytic satellitosis at the base of the crypts (defined as lymphocytic infiltration of crypt epithelium accompanied by increased crypt epithelial apoptosis), loss of Paneth cells and goblet cells, distortion of crypt architecture, and formation of crypt abscess in small bowel biopsies.47–51 Colonic involvement by autoimmune enteropathy may show diffuse mild colitis with mild increase in inflammatory cells (lymphocytes, plasma cells, and a discrete presence of eosinophils) to severe colitis with goblet-cell depletion, lymphocytic infiltration of the crypts, distortion of crypt architecture, and formation of crypt abscess.49–51 However, there is a relative paucity of surface IELs. In difficult case, correlation with serologic testing for autoantibodies, especially, the antienterocyte antibody may be helpful. The differentiation of LC from acute, self-limited colitis relies on the presence of neutrophilic inflammation in the latter.3 As for IBD, in rare cases, differentiation can be difficult due to the presence of focal IBD-like features in LC, or true coexistence of both conditions. The overall assessment and identification of a predominant injury pattern help to differentiate these 2 entities. In cases with focal LC and significant endoscopic findings (including diffuse erythema, terminal ileal aphthous ulcers, active/patchy ileitis/colitis), a descriptive term of “LC pattern of injury” may be used and a comment added to suggest appropriate clinical correlation and follow up, as focal LC and CC has been reported to be patterns of Crohn colitis.52

Surface intraepithelial lymphocytosis is also microscopic feature of EATL.53,54 Development of this type of lymphoma is closely related to celiac disease, although a subset of patients have no such prior history. Although EATL predominantly affects the small bowel, it uncommonly involves colon. Histologically, a diffuse infiltrate of lymphocytes occupies the bowel wall; the infiltrating lymphocytes are small and medium-sized and mildly atypical. Immunohistochemically, the cells are CD45+, cytoplasmic CD3+, and CD7+, are both CD4 and CD8 negative in most cases.53,54 In addition, the neoplastic cells express T-cell-restricted intracellular antigen 1 (TIA-1) and granzyme B and perforin.53,54 Molecular genetics studies show clonal rearrangement of the TCR β-chain and γ-chain genes.53,54 In these cases, attention to clinical history, morphologic atypia and infiltrative nature of the lymphocytes may be helpful. In equivocal cases, immunohistochemical stain for CD3, CD20, CD4, CD8, TIA, granzyme B, perforin, and molecular genetics study for TCR γ-chain gene arrangement may be indicated.

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VARIANTS OF LC

Paucicellular LC

This was originally described in a group of patients who present with typical clinical symptoms of LC, have endoscopically normal or near normal colon, but histologically, foci of mildly increased lamina propria lymphoplasmacytic inflammation and increased surface IELs separated by foci or tissue fragments of normal mucosa (patchiness and a lower density of surface intraepithelial lymphocytosis) are identified55 (Table 2). A recent study showed a mean annual incidence rate of 3.24 per 100,000 inhabitants for paucicellular LC, higher than that for LC and CC,56 using a set of more subtle histological criteria including increased chronic inflammatory infiltrate in the lamina propria, increased number of IELs (>7% but <20%), and absence of both a thickened subepithelial collagen layer and epithelial injury (ie, flattening of epithelial cells, epithelial loss, and detachment) (Table 2). In this study, patients with LC were younger at presentation (58 vs. 65 y) and less likely to have weight loss (19.2% vs. 48%). Overall, the diagnostic criteria of paucicellular LC are variable, subjective, and still evolving. Additional large studies are needed to further define this variant both histologically and clinically.

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LC With Giant Cells

A few case reports and small series reported LC with giant cells as a rare histologic subtype (Table 2). In 1 study including 94 cases of LC, only 1 case had subepithelial giant cells.57 Till the date, 6 cases of LC with giant cells have been reported in the literature.57–60 The currently available evidence suggests that the presence of giant cells in otherwise typical LC does not confer any adverse clinical outcome.57–60

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Slight Colonic Intraepithelial Lymphocytosis

Not uncommonly, pathologists encounter biopsy of an otherwise normal colonic mucosa except for a minimally increased number of IELs beyond 10 to 20 per 100 enterocytes (Table 2)16,21 (Fig. 2). From a practical point of view, it may be appropriate to sign out these cases descriptively as “slight colonic intraepithelial lymphocytosis” with a comment stating that this could represent an early phase or a minor form of LC, celiac disease-associated colonic change, medication-induced colonic injury, chronic constipation, Brainerd diarrhea of unknown etiology,61 resolving phase of acute colitis (such as C. difficile-associated colitis), or merely a nonspecific change as colonic lymphocytosis is not a distinct diagnostic entity and can occur in a variety of circumstances including gluten-sensitive enteropathy, various autoimmune diseases,7,62–65 or drug reactions.25,27,29,33,34,36 In pediatric population, it is worthwhile to add additional differential diagnoses such as autoimmune enteropathy, immune deficiency, allergic colitis, and idiopathic IBD.43,44

Figure 2
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Pitfalls to the Diagnosis of LC

As the surface mucosa overlying lymphoid aggregates always contains more IELs (Fig. 3); therefore, these areas should not be assessed for intraepithelial lymphocytosis or used for the diagnose LC. Changes of LC may be patchy and more severe in the right colon in 25% of the cases. Distal to the ascending colon3 but proximal to rectosigmoid are the ideal locations to biopsy for the diagnosis of LC. Multiple biopsies including 2 or more biopsies each from the transverse, descending, and sigmoid colon should be taken66 and submitted, preferably, in separate containers. However, if a flexible sigmoidoscopy approach is used, the endoscopist should take multiple biopsies from various segments of the left colon.67 Rectal biopsy alone cannot be used to confidently rule out LC as the rectum is reported to be spared in 8% of cases.6

Figure 3
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Cases presenting with typical watery diarrhea but only showing subtle surface epithelial disarray and minimal and patchy intraepithelial lymphocytosis, and minimally increased mononuclear cell inflammation, in their colonic biopsies, are perhaps best classified as “borderline for LC” as suggested in the original report.3 In addition, before diagnosing LC, the subepithelial collagen table should always be evaluated and documented that it is not thickened. As recent data seem to support that therapeutic options for LC and CC are similar,68 the differentiation of LC from a subtle CC may not be clinically critical as originally thought.

A diagnosis of LC in pediatric patients or in patients with atypical clinical presentation and/or evident endoscopic abnormality should always be reserved until other possibilities are ruled out. Significant and diffuse active crypt inflammation, architectural distortion, and basal lymphoplasmacytosis should raise a possibility of IBD. However, if these atypical features are limited to isolated foci in a background of otherwise typical LC, a diagnosis of LC can be rendered. In cases fulfilling the histologic criteria for LC, but had atypical clinical presentation or macroscopic colitis at endoscopy, the descriptive term of “LC pattern of injury” may be a more prudent diagnosis.

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COLLAGENOUS COLITIS

Incidence, Prevalence, and Demographics

The annual incidence of CC has been reported, in several European studies, to be 0.6 to 5.2 per 100,000 with a prevalence of 10 to 15.7 per 100,000.5,6 A recent study from North America showed an incidence rate of 3.1 per 100,000 and a prevalence of 39.3 per 100,000 at the end of 2001.42 The mean age at the time of diagnosis is 63.8 years, but patient age ranges from 29 to 93 years.13 CC occurs rarely in pediatric patients.69 The female-to-male ratio for CC is approximately 3 to 1.13

Patients with CC have higher rates of autoimmune thyroid disease, celiac disease, and rheumatoid arthritis.13 Other commonly seen rheumatologic and inflammatory disorders in CC are fibromyalgia and Raynaud/CREST syndrome.13 Of note, like LC, CC is also associated with celiac disease. In 1 study, 5 out of 171 patients with CC were diagnosed with celiac disease (2.9%) and 4 of these patients (80%) had the diagnosis of celiac disease after CC.13

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Symptomatology

Patients typically seek medical attention because of chronic, watery, secretory, and nonbloody diarrhea.2,6 The median duration of diarrhea before diagnosis is 24 months and the daily stool number averages 6.13 Associated symptoms include abdominal pain (73%), incontinence (43%), urgency (65%), flatulence (67%), and weight loss (49%).6

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Endoscopic Findings

The majority of patients with CC have an essentially normal colonoscopic appearance. Occasionally, a mild, nonspecific pattern of erythema, edema, intermittent granularity, and even ulceration can be seen endoscopically.70–74 In rare cases, colonic perforation may occur during colonoscopy or within 1 to 5 days after the procedure. The most notable colonoscopic findings associated with the development of perforation were bleeding linear ulcers in the right colon, several of which developed under direct visualization during endoscopy.75

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Histologic Findings

CC is characterized by the presence of a thickened “subepithelial collagen table” in addition to the features mentioned above for LC (Fig. 4). By definition, the subepithelial collagen layer is more than 10 μm thick in CC (Table 2). A simple reference to assist in estimating the thickness of the collagen layer is the size of nearby lymphocyte nuclei (usually 5 μm). In the majority of cases, the thick subepithelial collagen table is obvious, having a “dripping” appearance with uneven, noncontiguous thickening, and often entrapped capillaries, fibroblasts, and inflammatory cells (especially eosinophils) (Fig. 4A).76 The surface epithelium may peel off in strips ex vivo, leaving the collagen layer bare (Fig. 4B). In the remaining attached surface epithelium, there are typically an increased number of IELs (Fig. 4C). However, compared with LC, the surface intraepithelial lymphocytosis in CC may be less prominent.45 The background inflammatory change in CC is similar to that of LC but may show slight prominence of eosinophilic inflammation (Fig. 4D). Like LC, the crypt architecture is generally well preserved.74,76 IBD-like features such as active crypt inflammation, surface ulceration, Paneth cell metaplasia, and crypt architectural irregularity were reported to be present in 30%, 2.5%, 44%, and 7.6% of CC.45 However, these IBD-like features are focal and mild in nature.

Figure 4
Figure 4
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VARIANTS OF CC

Pseudomembranous CC

This has been increasingly recognized as a rare form of CC, which is characterized by the presence of a fibrinopurulent pseudomembrane erupting from the surface of the mucosa in a background of otherwise typical CC (Table 2).74 In the largest series of pseudomembranous CC, 6 out of 7 cases carried an initial clinical diagnosis of macroscopic colitis which included Crohn disease (5) and ulcerative colitis (1). Limited follow-up suggested that patients with pseudomembranous CC had clinical course and an outcome similar to those of patients with typical CC without pseudomembranous formation.74

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CC With Giant Cell

A few case reports and small series indicated CC with giant cells as a histologic subtype of CC (Fig. 5) (Table 2). In 1 study consisted of 72 CC, 1 case (1.4%) had subepithelial CD68+ giant cells.57 Till the date, a total of 12 cases of CC with giant cells have been reported.57–60 The currently available evidence suggests that the presence of giant cells in otherwise typical CC does not confer any adverse clinical outcome.57–60

Figure 5
Figure 5
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Pitfalls to the Diagnosis of CC

CC may be patchy, and is seen more commonly in biopsies from the proximal colon.76,77 Rarely, CC may only involve the right colon.78 Therefore, multiple biopsies should be taken randomly throughout the colon with at least 2 or more each from right, transverse, descending, and sigmoid colon66, and preferably, submitted separately. Sole biopsy of the rectosigmoid colon should be discouraged as only 66% of specimens obtained from the rectosigmoid colon have diagnostic features of CC and approximately 18% of rectosigmoid colon biopsies were interpreted as normal in 1 study.79 The thickness of the subepithelial collagen layer should only be assessed in a well-oriented mucosal biopsy because tangential sectioning of colonic mucosa always renders an impression of thickened subepithelial collagen layer focally. Occasionally, a “thick subepithelial collagen layer” is noted in otherwise well-oriented, normal colonic mucosa. In this situation, a possibility of artifactual layer caused by uniform elevation of epithelial nuclei causing the basal cytoplasm to appear as a uniform pink band should be considered (Fig. 6A). Careful examination easily reveals such a band is above the true basement membrane (Fig. 6B). Other conditions associated with a thickened subepithelial collagen table without a background inflammatory change include chronic ischemia, prolapse, diabetes, and hyperplastic polyp (Fig. 6B).76,80

Figure 6
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IBD-like features include crypt architectural distortion, cryptitis, Paneth cell metaplasia, and surface erosion limited to isolated foci in a background of otherwise typical CC have been reported. In 1 study, cryptitis, Paneth cell metaplasia, and crypt irregularities were present in 30%, 44%, and 4% to 8% of CC, respectively.45 These researchers reported that Paneth cell metaplasia correlated with disease severity in CC. However, IBD and CC are not mutually exclusive. Indeed, progression of CC to ulcerative colitis, and transition of ulcerative colitis to CC have been reported.12,14,17,81,82

CC should also be considered in colonic biopsies showing a fibrinopurulent pseudomembrane, as rare cases of severe CC may have overlying necroinflammatory debris mimicking pseudomembranous colitis endoscopically and histologically.24,73,74,83 Assessment of the nearby mucosa as regard to intraepithelial lymphocytosis, subepithelial collagen table thickness, and inflammatory infiltrates in the lamina propria, crypt architectural distortion, and atrophy of glands should aid in the differentiation of pseudomembranous CC from severe ischemic colitis and severe idiopathic IBD. In addition, clinical correlation with regard to medication, stool C. difficile toxin test, and stool culture will further help to exclude medication-associated pseudomembranous colitis, C. difficile-associated pseudomembranous colitis, and severe infection colitis caused by enterotoxigenic Escherichia coli, most notably the E. coli O157:H7 serotype. Of note, rare cases of synchronous occurrence of CC and C. difficile-associated pseudomembranous colitis have been reported.84

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CLINICAL COURSE OF LC AND CC

Present data support that 20% to 48% of patients with LC undergo spontaneous clinical remission16,85 and 30% of patients had normalized histology and an additional 15% of patients with histologic improvement. Up to 44% of patients with LC experience a clinical relapse during a mean follow-up of 14 months, after a mean lapse of 2 months. These results suggest a chronic, continuous or intermittent clinical course for about 50% patients with LC.85

CC can also undergo spontaneous clinical remission in 25% of the patients,86 which is accompanied or followed by histologic improvement. Although several randomized trials have shown that oral budesonide effectively induces clinical remission in up to 85.7% of cases,86,87 this clinical remission cannot be sustained after discontinuation of budesonide treatment in at least 60% of patients.86 These data suggest that majority of patients with CC may have a chronic, continuous or intermittent clinical course.

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TREATMENT FOR LC AND CC AND HISTOLOGIC FINDINGS IN TREATED LC AND CC

General Approach

Over the last 2 decades, many therapeutic options ranging from no therapy to high-dose immune modulatory therapy to fecal diversion have been developed for patients with microscopic colitis.88 These options are used by clinicians in a stepwise manner; it usually starts with ruling out associated diseases such as celiac disease and stopping medication which may be associated with the development of microscopic colitis. In cases of truly idiopathic microscopic colitides, the patients can be empirically treated with antidiarrheal agents, budesonide or Bismuth subsalicylate, bile acid binding agents or mesalamine. In cases resistant to the above options, oral corticosteroids or azathioprine/6-mercaptopurine or methotrexate ± octreotide can be used.88 The response rate to the above options is variable.88

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Randomized Clinical Trial With Budesonide in LC

A recent randomized, double blinded, placebo-controlled study showed that oral budesonide treatment of a 6-week duration effectively induced clinical remission in 86% of patients with LC (vs. 48% patients received placebo), and normalized or significantly improved histology in 86% of patients (vs. 31% receiving placebo). However, the 6-week treatment of budesonide appeared not to reduce clinical relapse in LC.85

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Randomized Clinical Trial With Budesonide in CC

Several clinical trials showed that budesonide treatment of an 8-week duration effectively induced clinical remission in 85.7% of patients with CC,86,87,89 but with a high rate of relapse (61%) after treatment cessation.90 Clinical remission induced by short-duration budesonide therapy was associated with a significant decrease of the lamina propria infiltrate with or without a reduction in collagen table thickness in colonic biopsies repeated at week 8.86,87 Two recent randomized, double-blinded, and placebo-controlled trials have also showed that oral budesonide is efficacious for long-term maintenance of clinical remission in patients with CC90,91 and clinical remission is accompanied by histology improvement in 93.3% patients on budesonide maintenance therapy.90

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Randomized Clinical Trials With Other Agents

Only few randomized clinical trials assessed the efficacy of other agents including Bismuth subsalicylate and mesalamine with or without cholestyramine in CC and LC. Some data support that Bismuth subsalicylate with or without cholestyramine may be effective for treating CC and LC.68 Mesalazine seems to be an effective therapeutic option for LC, whereas mesalazine with cholestyramine more useful in the treatment of CC.92 In this study, the clinical relapse rates (11.7% and 15% for LC and CC, respectively) are lower than those reported after short-duration budesonide treatment. However, no randomized trial has been reported to compare mesalazine-based therapy with budesonide regarding their efficacy in reducing clinical relapse after discontinuation of treatment in microscopic colitis.

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Histologic Findings in Treated LC and CC

Patients with LC or CC usually do not have repeat colonoscopic examination and rebiopsy after treatment. Documentation of posttreatment histology findings in LC and CC is often only found in reports of clinical trials. For LC, effective budesonide treatment is often associated with normalization of histology in a majority of cases. In CC, budesonide treatment leads to a complete normalization of the inflammatory infiltrate in the lamina propria in 69.2% cases and a partial reduction in 30.8% cases.86 The reduction in the thickness of the subepithelial collagen table seems to take longer time (in several months) than the resolution of chronic inflammation, but can be seen in a subset of patients treated with 8 weeks’ budesonide as well 27.3% of patients on placebo.86

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IMMUNOLOGIC ABNORMALITIES OF LC AND CC

Since the initial description of LC and CC, several studies have reported a strong association of LC and CC with other autoimmune diseases as well as positive ANA,4,13,64 indicating an autoimmune etiology. Like many idiopathic autoimmune diseases, a genetic predilection has been postulated for LC and CC based on their association with HLA-DR3-DQ2 haplotype, TNF2 allele [a tumor necrosis factor alpha (TNFα) allele], and HLA A1 allele,93,94 which are known to be in strong linkage disequilibrium. HLA-DR3-DQ2 haplotype is also known to be associated with celiac disease. Interestingly, the associations of LC and CC with HLA-DR3-DQ2 haplotype and TNF2 allele carriage are present also in microscopic colitis patients without celiac disease. The shared predisposing HLA-DR3-DQ2 haplotype93 and the high prevalence of celiac disease in patients with microscopic colitis,18 therefore, suggest some similarities in the pathogenesis of microscopic colitis and celiac disease.

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Colonic Immunologic Abnormalities in LC and CC

Although the association of microscopic colitis with autoimmune diseases is evident from several clinical studies/reports, studies on immunologic abnormalities in colonic tissue are few. One early study has suggested that the immune abnormalities in the colonic mucosa are similar in LC and CC and include an accumulation of CD4+ T cells within the lamina propria, an increase of CD8 TcR αβ IELs with associated surface epithelial injury, and abnormal expression of class II major histocompatibility complex (MHC) molecule on colonic epithelium.95 These findings support an MHC-restricted immune mechanism in the pathogenesis of LC and CC. Further studies have reported a T helper cell-type 1 (TH1) mucosal cytokine profile in both LC and CC which is characterized by marked upregulation of interferon gamma (IFNγ) and TNFα.96 By immunohistochemistry, TNFα immunoreactivity is noted in subepithelial macrophages.96 In contrast, IL2 and IL4, 2 cytokines of T helper cell-type 2 (TH2), are not significantly different from controls.96 The upregulation of IFNγ and TNFα in LC and CC is associated with concurrent induction of nitric oxide synthase in epithelial cells (surface and crypt) and lamina propria mononuclear cells, especially macrophages.96 Induction of nitric oxide synthase with the resultant production of nitric oxide has been shown to lead to surface epithelial injury and apoptosis and hyperpermeability97,98 in other inflammatory bowel conditions. Indeed, the IFNγ mRNA levels in LC and CC correlate with the degree of diarrhea and downregulation of E-cadherin and ZO-1, 2 cell junction proteins.96 In CC, IFNγ and TNFα may induce nitric oxide synthase in epithelium by upregulating nuclear factor kappa B.99

In animal models, IFNγ upregulates the expression of MHC class II molecule in colonic epithelial cells100 which may result in a proinflammatory status of the colonic epithelium and lead to a vicious cycle of inflammation in LC and CC. In addition to the abnormal expression of class II MHC, a decreased expression of CD1d, a member of an MHC class I-like molecule family has been reported in both LC and CC.101 However, the mechanism and significance of this change remain unclear.

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Other Inflammatory Cells and Inflammatory Mediators and in LC and C

Other types of inflammatory cells noted in colonic biopsies with LC and CC include eosinophils and to a lesser degree, neutrophils. In some cases, these inflammatory cells and their mediators may also contribute to pathogenesis of LC and CC. Indeed, rectal mucosa secretion and stool levels of eosinophilic cationic protein, eosinophil protein X, and myeloperoxidase are increased in CC.102,103 Although persistent, long-term chronic inflammation and epithelial injury are thought to stimulate collagen deposition (ie, CC), the exact underlying mechanism remains unclear. It has been suggested that increased transforming growth factor-β1 in eosinophils may contribute to the subepithelial collagen deposition.104 Other factors, such as vascular endothelial growth factor102 and connective tissue growth factor in the cells with morphology of smooth muscle cells105 may also play a role in the fibrogenesis of CC.

Overall, these studies support the notion that an upregulation in TH1 cytokine profile mediated by an MHC-restricted immune mechanism plays a major role in the evolution of histomorphology and the development of clinical symptom in LC and CC patients. The findings summarized above are in line with the clinical observation that grade of inflammation in CC correlates with stool weight, an objective and accurate assessment of diarrhea.87 Further mechanistic studies are needed to identify those key regulators involved in the pathogenesis of LC and CC to develop novel and effective therapies.

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CONCLUSIONS

Both LC and CC are no longer rare conditions. The incidence of both entities is rising. Histological diagnosis of both entities is straightforward in most patients with typical clinical presentations. Several variants or histologic subtypes of LC and CC have been recently described. Intraepithelial lymphocytosis in an otherwise normal colonic mucosa is a legitimate descriptive diagnosis associated with many circumstances. Many medications have been associated with changes of LC and CC and this list is expected to expand in the future. Although treatments are available to effectively relieve diarrhea associated with LC and CC, the etiopathogenesis of these 2 entities remains unknown. Fundamental advances in the understanding of these conditions are needed to further help develop novel and effective therapies to treat them.

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REFERENCES

1. Read NW, Krejs GJ, Read MG, et al. Chronic diarrhea of unknown origin. Gastroenterology. 1980;78:264–271

2. Lindstrom CG. “Collagenous colitis” with watery diarrhea-a new entity? Pathol Eur. 1976;11:87–89

3. Lazenby AJ, Yardley JH, Giardiello FM, et al. Lymphocytic (“microscopic”) colitis: a comparative histopathologic study with particular reference to collagenous colitis. Hum Pathol. 1989;20:18–28

4. Giardiello FM, Lazenby AJ, Bayless TM, et al. Lymphocytic (microscopic) colitis: clinicopathologic study of 18 patients and comparison to collagenous colitis. Dig Dis Sci. 1989;34:1730–1738

5. Olesen M, Eriksson S, Bohr J, et al. Microscopic colitis: a common diarrheal disease. An epidemiological study in Örebro, Sweden, 1993-1998. Gut. 2004;53:346–350

6. Fernandez-Banares F, Salas A, Forne M, et al. Incidence of collagenous and lymphocytic colitis: a 5-year population-based study. Am J Gastroenterol. 1999;94:418–423

7. Olesen M, Eriksson S, Bohr J, et al. Lymphocytic colitis: a retrospective clinical study of 199 Swedish patients. Gut. 2004;53:536–541

8. da Silva JGN, De Brito T, Cintra Damiao AO, et al. Histologic study of colonic mucosa in patients with chronic diarrhea and normal colonoscopic findings. J Clin Gastroenterol. 2006;40:44–48

9. LaSala PR, Chondosh AB, Vecchio JA, et al. Seasonal pattern of onset in lymphocytic colitis. J Clin Gastroenterol. 2005;39:891–893

10. Jarnerot G, Hertervig E, Granno C, et al. Familial occurrence of microscopic colitis: a report of 5 families. Scand J Gastroenterol. 2001;36:959–962

11. Abdo AA, Zetler PJ, Halparin LS. Familial microscopic colitis. Can J Gastroenterol. 2001;15:341–343

12. Chandratre S, Bramble MG, Cooke WM, et al. Simultaneous occurrence of collagenous colitis and Crohn’s disease. Digestion. 1987;36:55–60

13. Kao KT, Pedraza B, McClune A, et al. Microscopic colitis: a large retrospective analysis from a health maintenance organization experience. World J Gastroenterol. 2009;15:3122–3127

14. Giardiello FM, Jackson FW, Lazenby AJ. Metachronous occurrence of collagenous colitis and ulcerative colitis. Gut. 1991;32:447–449

15. Bohr J, Tysk C, Eriksson S, et al. Collagenous colitis: a retrospective study of clinical presentation and treatment in 163 patients. Gut. 1996;39:846–851

16. Wang N, Dumot JA, Achkar E, et al. Colonic epithelial lymphocytosis without a thickened subepithelial collagen table: a clinicopathologic study of 40 cases supporting a heterogeneous entity. Am J Surg Pathol. 1999;23:1068–1074

17. Pokorny CS, Kneale KL, Henderson CJ. Progression of collagenous colitis to ulcerative colitis. J Clin Gastroenterol. 2001;32:435–438

18. Matteoni CA, Goldblum JR, Wang N, et al. Celiac disease is highly prevalent in lymphocytic colitis. J Clin Gastroenterol. 2001;32:225–227

19. Daniels JA, Lederman HM, Maitra A, et al. Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review. Am J Surg Pathol. 2007;31:1800–1812

20. Khan MA, Brunt EM, Longo WE, et al. Persistent Clostridium difficile colitis: a possible etiology for the development of collagenous colitis. Dig Dis Sci. 2000;45:998–1001

21. Carmack SW, Lash RH, Gulizia JM, et al. Lymphocytic disorders of the gastrointestinal tract: a review for the practicing pathology. Adv Anat Pathol. 2009;16:290–306

22. Geramizadeh B, Taghavi A, Clinical Banan B. endoscopic and pathologic spectrum of non-steroidal anti-inflammatory drug-induced colitis. Ind J Gastroenterol. 2009;28:150–153

23. Riddell RH, Tanaka M, Mazzoleni G. Non-steroidal anti-inflammatory drugs as a possible cause of collagenous colitis: a case-control study. Gut. 1992:33–683-686

24. Giardiello FM, Hansen FC III, Lazenby AJ, et al. Collagenous colitis in a setting of nonsteroidal antiinflammatory drugs and antibiotics. Dig Dis Sci. 1990;35:257–260

25. Chande N, Driman DK. Microscopic colitis associated with lansoprazole: report of two cases and a review of the literature. Scand J Gastroenterol. 2007;42:530–533

26. Thomson RD, Lestina LS, Bensen SP, et al. Lansoprazole-associated microscopic colitis: a case series. Am J Gastroenterol. 2002;97:2908–2913

27. Beaugerie L, Patey N, Brousse N. Ranitidine, diarrhea, and lymphocytic colitis. Gut. 1995;37:708–711

28. Duncan H, Talbot I, Silk D. Collagenous colitis and cimetidine. Eur J Gastroenterol Hepatol. 1997;9:819–820

29. Pelizza L, Melegari M. Clozapine-induced microscopic colitis: a case report and review of the literature. J Clin Psychopharmacol. 2007;27:571–574

30. Beaugerie L, Luboinski J, Brousse N, et al. Drug induced lymphocytic colitis. Gut. 1994;35:426–428

31. Mennecier D, Saloum T, Nexon M, et al. Chronic diarrhea and lymphocytic colitis associated with Daflon therapy. Gastroenterol Clin Biol. 1999;23:1101–1102

32. Berrebi D, Sautet A, Dauge M, et al. Ticlopidine-induced colitis, a histopathological study including apoptosis. J Clin Pathol. 1998;51:280–283

33. Feurle GE, Bartz KO, Schmitt-Graff A. Lymphocytic colitis, induced by ticlopidine. Z Gastroenterol. 1999;37:1105–1108

34. Baert F, Wouters K, D’Haens G, et al. Lymphocytic colitis: a distinct clinical entity? A clinicopathological confrontation of lymphocytic and collagenous colitis. Gut. 1999;45:375–381

35. Mahajan L, Wyllie R, Goldblum J. Lymphocytic colitis in a pediatric patient: a possible adverse reaction to carbamazepine. Am J Gastroenterol. 1997;92:2126–2127

36. Piche T, Raimondi V, Schneider S, et al. Acarbose and lymphocytic colitis. Lancet. 2000;356:1246

37. Macaigne G, Boivin JF, Chayette C, et al. Oxetorone-associated lymphocytic colitis. Gastroenterol Clin Biol. 2002;26:537

38. Rassiat E, Michiels C, Sgro C, et al. Lymphocytic colitis due to Modopar. Gastroenterol Clin Biol. 2000;24:852–853

39. Chagnon J, Cerf M. Simvastatin-induced protein-losing enteropathy. Am J Gastroenterol. 1992;87:257

40. Fernandez-Banares F, Salas A, Esteve M, et al. Collagenous and lymphocytic colitis. Evaluation of clinical and histological features, response to treatment, and long-term follow-up. Am J Gastroenterol. 2003;98:340–347

41. Limsui D, Pardi DS, Smyrk TC, et al. Observer variability in the histologic diagnosis of microscopic colitis. Inflamm Bowel Dis. 2009;15:35–38

42. Pardi DS, Loftus EV, Smyrk TC, et al. The epidemiology of microscopic colitis: a population based study in Olmsted County, Minnesota. Gut. 2007;56:504–508

43. Najarian RM, Hait EJ, Leichtner AM, et al. Clinical significance of colonic intraepithelial lymphocytosis in a pediatric population. Modern Pathol. 2009;22:13–20

44. El-Matary W, Girgis S, Huynh H, et al. Microscopic colitis in children. Dig Dis Sci. 2010;55:1996–2001

45. Ayata G, Ithamukkala S, Sapp H, et al. Prevalence and significance of inflammatory bowel disease-like morphologic features in collagenous and lymphocytic colitis. Am J Surg Pathol. 2002;26:1414–1423

46. DuBois RN, Lazenby AJ, Yardley JH, et al. Lymphocytic enterocolitis in patients with “refractory sprue”. JAMA. 1989;262:935–937

47. Montalto M, D’Onofrio F, Santoro L, et al. Autoimmune enteropathy in children and adults. Scand J Gastroenterol. 2009;44:1029–1036

48. Lachaux A, Laras-Duclaux I, Bouvier R. Autoimmune enteropathy in infants: pathological study of the disease in two familial cases. Vichows Arch. 1998;433:481–485

49. Carroccio A, Volta U, Prima L, et al. Autoimmune enteropathy and colitis in an adult patient. Dig Dis Sci. 2003;48:1600–1606

50. Mitomi H, Tanabe S, Igarashi M, et al. Autoimmune enteropathy with severe atrophic gastritis and colitis in an adult: proposal of a generalized autoimmune disorder of the alimentary tract. Scand J Gastroenterol. 1998;33:716–720

51. Moore L, Xu X, Davidson G, et al. Autoimmune enteropathy with anit-goblet cell antibodies. Hum Pathol. 1995;26:1162–1168

52. Goldstein NS, Gyorfi T. Focal lymphocytic colitis and collagenous colitis: patterns of Crohn’s colitis? Am J Surg Pathol. 1999;23:1075–1081

53. Ferry JAOdze RD, Goldblum JR. Lymphoid tumors of the GI tract, hepatobiliary tract, and pancreas. Surgical pathology of the GI tract, liver, biliary tract, and pancreas. 2010 Philadelphia, PA Saunders Elsevier:701–732

54. Zettl A, Ott G, Makulik A, et al. Chromosomal gains at 9q characterizes enteropathy-type T-cell lymphoma. Am J Surg Pathol. 2002;161:1635–1645

55. Goldstein NS, Bhanot P. Paucicellular and asymptomatic lymphocytic colitis: expanding the clinicopathologic spectrum of lymphocytic colitis. Am J Clin Pathol. 2004;122:405–411

56. Fernandez-Banares F, Casalots J, Salas A, et al. Paucicellular lymphocytic colitis: is it a minor form of lymphocytic colitis? A clinical pathological and immunological study. Am J Gastroenterol. 2009;104:1189–1198

57. Brown IS, Lambie DLJ. Microscopic colitis with giant cells: a clinico-pathological review of 11 cases and comparison with microscopic colitis without giant cells. Pathology. 2008;40:671–675

58. Sandmeier D, Bouzourene H. Microscopic colitis with giant cells: a rare new histopathologic subtype? Int J Surg Pathol. 2004;12:45–48

59. Libbrecht L, Croes R, Ectors N, et al. Microscopic colitis with giant cells. Histopathology. 2002;40:335–338

60. Rotimi O, Rodrigues MG, Lim C. Microscopic colitis with giant cells—is it really a distinct pathological entity. Histopathology. 2004;44:503–505

61. Bryant DA, Mintz ED, Puhr ND, et al. Colonic epithelial lymphocytosis associated with an epidemic of chronic diarrhea. Am J Surg Pathol. 1996;20:1102–1109

62. Cindoruk M, Tuncer C, Dursun A, et al. Increased colonic intraepithelial lymphocytes in patients with Hashimoto’s thyroiditis. J Clin Gastroenterol. 2002;34:237–239

63. Fine KD, Lee EL, Meyer RL. Colonic histopathology in untreated celiac sprue or refractory sprue: is it lymphocytic colitis or colonic lymphocytosis? Hum Pathol. 1998;29:1433–1440

64. Holstein A, Burmeister J, Plaschke A, et al. Autoantibody profiles in microscopic colitis. J Gastroenterol Hepatol. 2006;21:1016–1020

65. Williams JJ, Kaplan GG, Makhija S, et al. Microscopic colitis-defining incidence rates and risk factors: a population-based study. Clin Gastroenterol Hepatol. 2008;6:35–40

66. Yantis RK, Odze RD. Optimal approach to obtaining mucosal biopsies for assessment of inflammatory bowel disorders of the gastrointestinal tract. Am J Gastroenterol. 2009;104:774–783

67. Matteoni CA, Wang N, Goldblum JR. Flexible sigmoidoscopy for the detection of microscopic colitis. Am J Med. 2000;108:416–417

68. Chande N, MacDonald JK. McDonald JWD. Interventions for treating microscopic colitis: a Cochrane inflammatory bowel disease and functional bowel disorders review group systemic review of randomized trials. Am J Gastroenterol. 2009;104:235–241

69. Gremse DA, Boudreaux CW, Manci EA. Collagenous colitis in children. Gastroenterology. 1993;104:906–909

70. Kakar S, Pardi DS, Burgart LJ. Colonic ulcers accompanying collagenous colitis: implication of nonsteroid anti-inflammatory drugs. Am J Gastroenterol. 2003;98:1834–1837

71. Sato S, Matsui T, Tsuda S, et al. Endoscopic abnormalities in a Japanese patient with collagenous colitis. J Gastroenterol. 2003;38:812–813

72. Wichbom A, Lindqvist M, Bohr J, et al. Colonic mucosal tears in collagenous colitis. Scand J Gastroenterol. 2006;41:726–729

73. Buchman AL, Rao S. Pseudomembranous collagenous colitis. Dig Dis Sci. 2004;49:1763–1767

74. Yuan S, Reyes V, Bronner MP. Pseudomembranous collagenous colitis. Am J Surg Pathol. 2003;27:1375–1379

75. Daniela SA, Taylor SL, Bronner MP. Colonic perforation as a complication of collagenous colitis in a series of 12 patients. Am J Gastroenterol. 2008;103:2598–2604

76. Lazenby AJ, Yardley JH, Giardiello FM, et al. Pitfalls in the diagnosis of collagenous colitis: experience with 75 cases from a registry of collagenous colitis at the Johns Hopkins Hospital. Hum Pathol. 1990;21:905–910

77. Jessurun J, Yardley JH, Giardiello FM, et al. Chronic colitis with thickening of the subepithelial collagen layer (collagenous colitis): histopathologic findings in 15 patients. Hum Pathol. 1987;18:839–848

78. Thijs WJ, van BJ, Kleibeuker JH, et al. Microscopic colitis: prevalence and distribution throughout the colon in patients with chronic diarrhoea. Neth J Med. 2005;63:137–140

79. Offner FA, Jao RV, Lewin KJ, et al. Collagenous colitis: a study of the distribution of morphological abnormalities and their histological detection. Hum Pathol. 1999;30:451–457

80. Unal A, Guven K, Yurci A, et al. Is increased colon subepithelial collagen layer thickness in diabetic patients related to collagen colitis? An immunohistochemical study. Pathol Res Pract. 2008;204:537–544

81. Freeman HJ, Berean KW, Nimmo M. Evolution of collagenous colitis into severe and extensive ulcerative colitis. Can J Gastroenterol. 2007;21:315–318

82. Haque M, Florin T. Progression of ulcerative colitis to collagenous colitis: chance, evolution or association? Inflamm Bowel Dis. 2007;13:1321

83. Treanor D, Gibbons D, O’Donoghue DP, et al. Pseudomembranes in collagenous colitis. Histopathology. 2001;38:83–84

84. Vesoulis Z, Lazanski G, Loiudice T. Synchronous occurrence of collagenous colitis and pseudomembranous colitis. Can J Gastroenterol. 2000;14:353–358

85. Miehlke S, Madisch A, Karimi D, et al. Budesonide is effective in treating lymphocytic colitis: a randomized-double-blinded-placebo controlled study. Gastroenterology. 2009;136:2092–2100

86. Baert F, Schmit A, D’Haens G, et al. Budesonide in collagenous colitis: a double-blind placebo-controlled trial with histologic follow-up. Gastroenterology. 2002;122:20–25

87. Bonderop OK, Hansen JB, Birket-Smith L, et al. Budesonide treatment of collagenous colitis: a randomized, double blind, placebo controlled trial with morphometric analysis. Gut. 2003;52:248–251

88. Abdo AA, Urbanski S, Beck PL. Lymphocytic and collagenous colitis: the emerging entity of microscopic colitis. An update on pathopathysiology, diagnosis and management. Can J Gastroenterol. 2003;17:425–432

89. Miehlke S, Heymer P, Bethke B, et al. Budesonide treatment for collagenous colitis: a randomized, double-blinded, placebo-controlled, multicenter trial. Gastroenterology. 2002;123:978–984

90. Miehlke S, Madisch A, Bethke B, et al. Oral budesonide for maintenance treatment of collagenous colitis: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2008;135:1510–1516

91. Bonderop OK, Hansen JB, Teglbjærg, et al. Long-term budesonide treatment of collagenous colitis: a randomized, double-blind, placebo-controlled trial. Gut. 2009;58:68–72

92. Aalabrese C, Fabbri A, Areni A, et al. Mesalazine with or without cholestyramine in the treatment of microscopic colitis: randomized controlled trial. J Gastroenterol Hepatol. 2007;22:809–814

93. Koskela RM, Karttunen TJ, Niemelä SE, et al. Human leucocyte antigen and TNFalpha polymorphism association in microscopic colitis. Eur J Gastroenterol Hepatol. 2008;20:276–282

94. Giardiello FM, Lazenby AJ, Yardley JH, et al. Increased HLA A1 and diminished HLA A3 in lymphocytic colitis compared to controls and patients with collagenous colitis. Dig Dis Sci. 1992;37:496–499

95. Mosnier JF, Larvol L, Barge J, et al. Lymphocytic and collagenous colitis: an immunohistochemical study. Am J Gastroenterol. 1996;91:709–713

96. Tagkalidis PP, Gibson PR, Bhathal PS. Microscopic colitis demonstrates a T helper cell type 1 mucosal cytokine profile. J Clin Pathol. 2007;60:382–387

97. Ford H, Watkins S, Reblock K, et al. The role of inflammatory cytokines and nitric oxide in pathogenesis of necrotizing enterocolitis. J Pediatr Surg. 1997;32:275–282

98. Chavez AM, Menconi MJ, Hodin RA, et al. Cytokine-induced intestinal epithelial hyperpermeability: role of nitric oxide. Crit Care Med. 1999;27:2246–2251

99. Andresen A, Jørgensen VL, Perner A, et al. Activation of nuclear factor kappaB in colonic mucosa from patients with collagenous and ulcerative colitis. Gut. 2005;54:503–509

100. Steiniger B, Falk P, Lohmuller M, et al. Class II MHC antigens in the rat digestive system. Normal distribution and induced expression after interferon-gamma treatment in vivo. Immunology. 1989;68:507–513

101. Ge Y, Rampy BA, Wang HL, et al. Reduced CD1d expression in colonic epithelium in microscopic colitis. Appl Immunohistochem Mol Morphol. 2006;14:309–313

102. Taha Y, Raab Y, Larsson A, et al. Vascular endothelial growth factor (VEGF)—a possible mediator of inflammation and mucosal permeability in patients with collagenous colitis. Dig Dis Sci. 2004;49:109–115

103. Lettesjo H, Hansson T, Peterson C, et al. Detection of inflammatory markers in stools from patients with irritable bowel syndrome and collagenous colitits. Scand J Gastroenterol. 2006;41:54–59

104. Stahle-Backdahl M, Malm J, Veress B, et al. Increased presence of eosinophilic granulocytes expressing transforming growth factor-β1 in collagenous colitis. Scand J Gastroenterol. 2000;35:742–746

105. Günther U, Bateman AC, Beattie RM, et al. Connective tissue growth factor expression is increased in collagenous colitis and celiac disease. Histopathology. 2010;57:427–435

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Keywords:

colitis; lymphocytic; collagenous; budesonide; immunologic

© 2012 Lippincott Williams & Wilkins, Inc.

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