Microscopic Colitis (Collagenous and Lymphocytic Colitis)

Updated: Mar 25, 2021
  • Author: Harika Balagoni, MD; Chief Editor: BS Anand, MD  more...
  • Print


Microscopic colitis (MC) is a chronic inflammatory condition of the colon, predominantly subdivided into collagenous colitis (CC) and lymphocytic colitis (LC).

Microscopic colitis typically presents as chronic, nonbloody diarrhea with an endoscopically and radiologically normal colon but which demonstrates inflammatory changes on mucosal biopsies. Lymphocytic colitis is characterized histologically by chronic inflammatory infiltration in the lamina propria with lymphocyte and plasma cell proliferation. The diagnosis is confirmed when an epithelium lymphocyte count of more than 20 lymphocytes per 100 epithelial cells are observed. Collagenous colitis is characterized by thickened subepithelial collagen (>10 µm). [1]

Another variant of microscopic colitis exists, called incomplete MC; its histopathology does not fit into either of the collagenous colitis or lymphocytic colitis criteria. [1, 2] This variant is characterized by both thickening of the collagen plate and an increase in the number of intraepithelial lymphocytes.

Ever since microscopic colitis was described, its incidence has steadily increased and accounts for about 8-16% of chronic nonbloody diarrhea. [3] Microscopic colitis should be considered as a differential diagnosis in the workup of chronic diarrhea, especially in the elderly population.

Microscopic colitis is usually found in the elderly population in their sixth or seventh decade and has a significant female predominance. [4, 5]

Historical background

Collagenous colitis was described concurrently in 1976 by Lindstrom [6] and Freeman et al. [7] In 1980, Read and colleagues described microscopic colitis, which is clinically indistinguishable from collagenous colitis but is differentiated from it by specific biopsy features. [8] Later, Lazenby et al proposed the term "lymphocytic colitis" to replace the term "microscopic colitis" and to distinguish it from infectious colitis and inflammatory bowel disease (ulcerative colitis and Crohn disease). [9]

For patient education resources, see Crohns Colitis Foundation, Digestive Disorders Center as well as Common Causes of Colitis, Celiac Sprue, and Crohn's Disease.



The pathogenesis of microscopic colitis (MC) is not clearly understood. The etiology is likely multifactorial, potentially including luminal factors, immune dysregulation, and genetic predisposition. [10] It may be mediated in part by the adaptive immune system and by cytotoxic responses triggered by mucosal injury from different factors. [11] Some studies have also shown an association between microscopic colitis and human leukocyte antigen (HLA)-DQ, as noted in celiac disease. [12] A positive correlation between DQ2/DQ8 alleles and lymphocytic colitis (LC) has been noted in some studies. The odds ratio of lymphocytic colitis with positive DQ2-alleles has been found to be as high as 3. [13]

Another significant association has been observed between 5-HTTLPR (serotonin-transporter-linked polymorphic region) polymorphism and microscopic colitis. 5-HT (serotonin) plays a significant role in regulating intestinal motility and secretion. Serotonin levels have been found to be high in patients with microscopic colitis and ulcerative colitis (UC), suggesting a possible association in its pathogenesis. [14]

The interleukin (IL)-6-174 gene polymorphism also has a possible association with microscopic colitis by influencing the inflammation pathway. IL-6 promotes T- and B-lymphocyte maturation and also contributes to macrophage recruitment, causing acute to chronic immune responses and to differentiation of Th2 and Th17 lymphocytes. [15]



No definitive etiology has been determined for microscopic colitis (MC), but evidence indicates that drug consumption may trigger underlying inflammatory factors in the colon of affected individuals, whereas other agents may exacerbate diarrhea in patients with idiopathic microscopic colitis. [16] Although many drugs, either alone or in combination, may cause diarrhea as an adverse effect, [17] nonsteroidal anti-inflammatory drugs (NSAIDs) show a strong trend (P = 0.057) toward increasing the risk of collagenous colitis (CC), and rechallenge has been shown to cause recurrence of collagenous colitis.

Antidepressant agents such as selective serotonin reuptake inhibitors (SSRIs) as a group increase the risk of collagenous colitis, but in this class of medications, sertraline alone significantly raises the risk of lymphocytic colitis (LC). [18] Anecdotal reports of a large number of additional drugs have been associated with the onset of microscopic colitis. Among these, ranitidine (confirmed by rechallenge), aspirin, acarbose, ticlopidine, and proton pump inhibitors have high-level evidence of causality, whereas flutamide, simvastatin, carbamazepine, and lisinopril have intermediate-level evidence.

Some patients have had histologic findings consistent with both collagenous colitis and lymphocytic colitis at different points during the course of their disease. This raises the possibility that these may be different manifestations of the same medical condition, or they may be at different points along a continuum.

Many case reports describe patients with preexisting presumed autoimmune conditions (eg, celiac sprue, psoriasis, and rheumatoid arthritis) who are subsequently diagnosed with microscopic colitis. Patients diagnosed with lymphocytic colitis have also been reported to have uveitis, idiopathic pulmonary fibrosis, juvenile diabetes mellitus, pernicious anemia, autoimmune thyroid disease, and idiopathic thrombocytopenic purpura. Approximately one third of patients with celiac disease have histologic findings consistent with microscopic colitis. For this reason, microscopic colitis should be considered in patients diagnosed with celiac disease who have diarrhea that fails to respond to a gluten-free diet. However, removal of gluten from the diet is ineffective in treating microscopic colitis in the absence of celiac disease.

Microscopic colitis and inflammatory bowel disease (IBD) (Crohn disease or ulcerative colitis) have been diagnosed concurrently or sequentially in a small number of cases, with either diagnosis preceding the other. It is hypothesized that the two diseases may be part of one disease spectrum rather than two separate entities.

Smoking increases the risk of microscopic colitis [19, 20] as well as the age at diagnosis. Active smoking is associated with a higher incidence of microscopic colitis, and it is more strongly implicated in collagenous colitis than lymphocytic colitis. [21, 22] Clinical symptoms of collagenous colitis may be worse in smokers than nonsmokers, and smokers are less likely to achieve clinical remission. [23]

In some patients with diabetes mellitus and diarrhea, there is evidence of an increase in the thickness of the subepithelial collagen bands. However, no correlation has been reported between collagen thickness, age, and the duration of diabetes. [24]



Microscopic colitis (MC) is strongly associated with other autoimmune disorders, such as celiac disease, polyarthritis, and thyroid disorders. [4]  Up to 20-60% of patients with lymphocytic colitis and 17-40% of patients with collagenous colitis (CC) have an autoimmune disease. [4, 25] In fact, histologic features of microscopic colitis in the colon are present in 30% of patients with celiac disease.

An increased risk of microscopic colitis is associated with smoking, as well as the use of certain drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), and selective serotonin reuptake inhibitors (SSRIs). [10, 19, 26, 27]

Tong et al, in their systematic review and meta-analysis of epidemiologic studies on microscopic colitis found that the incidence of collagenous colitis and lymphocytic colitis (LC) was 4.14 per 100,000 person-years and 4.85 per 100,000, respectively. [28] The study showed significant female predominance with a female-male incidence ratio of 3.05 for collagenous colitis and 1.92 for lymphocytic colitis, as well as a median age of diagnosis in the sixth decade. Overall, the investigators noticed a steady increase in the incidence of microscopic colitis across different countries since year 2000. The incidence in the United States, Sweden, and Spain appears to have stabilized since year 2000.

Both conditions are observed more commonly in individuals older than 40 years, with a peak incidence in the sixth and seventh decades of life, and the incidence of both conditions increases with age. Isolated cases have been reported in younger populations, including children.



Natural history/prognosis

The clinical course of microscopic colitis (MC) varies throughout the literature. Approximately 20% of patients with microcytic colitis may have a spontaneous remission without specific therapy. [11]

More than half of patients treated for lymphocytic colitis (LC) experienced resolution of symptoms after 6 months of treatment, whereas only 15% of patients had significant persistent symptoms.

In some patients, the diarrhea may wax and wane over many years; however, more than 80% of patients can expect diarrhea and histologic abnormalities to resolve within 3 years.

Rare cases with severe and protracted diarrhea have been fatal; these cases are thought to be due to epithelial membrane sloughing and the resultant altered mucosal permeability.

Although some small studies have suggested otherwise, microscopic colitis (either collagenous colitis [CC] or lymphocytic colitis) does not appear to increase the risk of colon cancer or adenoma. [10]