Collagenous and Lymphocytic Colitis

Updated: Jan 04, 2017
  • Author: Joyann A Kroser, MD, FACP, FACG, AGAF; Chief Editor: BS Anand, MD  more...
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Overview

Background

The term microscopic colitis is used to describe both collagenous colitis (CC) and lymphocytic colitis (LC). [1] Both are relatively rare conditions that are diagnosed when a patient with chronic watery nonbloody diarrhea has an endoscopically or radiographically normal colon, but colonic mucosal biopsies show unique inflammatory changes. Because the mucosa is not ulcerated or otherwise disrupted, the diarrhea generally does not contain blood or pus. CC and LC primarily affect the colon, but the terminal ileum can also be involved.

CC was described concurrently in 1976 by Lindstrom and by Freeman. [2] In 1980, Read described microscopic colitis, which is clinically indistinguishable from CC but is differentiated from it by specific biopsy features. Later, the term LC was proposed by Lazenby to replace the term microscopic colitis and to distinguish it from infectious colitis and inflammatory bowel disease (ulcerative colitis and Crohn disease).

CC and LC should be considered in any patient with unexplained nonbloody diarrhea. Patients undergoing either sigmoidoscopy or colonoscopy for unexplained diarrhea who have normal endoscopic findings should have biopsy samples taken to diagnose or rule out either form of microscopic colitis. [3, 4, 1, 5]

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

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Pathophysiology

The characteristic feature of lymphocytic colitis (LC) is an infiltration by lymphocytes into the colonic epithelium. Collagenous colitis (CC) shares this feature but additionally shows a distinctive thickening of the subepithelial collagen table. LC and CC have been suggested to represent different phases of a single pathophysiologic process, with LC possibly being a precursor or earlier phase of CC; however, this has not been proven.

A mixed form, characterized by both thickening of the collagen plate and an increased number of intraepithelial lymphocytes has also been described.

The diarrhea in CC is more likely due to the inflammatory process than to the subepithelial collagen layer, although this layer may serve as a cofactor in the role of a diffusion barrier. Increased levels of immunoreactive prostaglandin E2 and nitric oxide (NO) in the colonic epithelium may contribute to a secretory diarrhea in patients with CC.

Some patients with CC and concurrent collagenous infiltration of the duodenum and/or the ileum have demonstrated altered small bowel dysfunction, diagnosed by reduced D-xylose absorption.

Some individuals have bile acid malabsorption demonstrated by the Se-75-homotaurocholate (SeHCAT) test, in which a positive test result is shown by retention of less than 11% of the administered dose of radioactivity after 7 days.

Some patients with CC may have increased mucosal secretion of transforming growth factor-1 (TGF-1) and vascular endothelial growth factor, a fibrosis-enhancing peptide.

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Etiology

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

Antidepressant agents such as selective serotonin reuptake inhibitors (SSRIs) as a group increase the risk of CC, but, in this class of medications, sertraline alone significantly increases the risk of lymphocytic colitis (LC). Anecdotal reports of a large number of additional drugs have been associated with the onset of microscopic colitides. 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.

Note the following:

  • Some patients have had histologic findings consistent with both CC and LC at different points during the course of the disease. This raises the possibility that these may be different manifestations of the same medical condition or different points along a continuum.
  • Many case reports describe patients with preexisting presumed autoimmune conditions, such as celiac sprue, psoriasis and rheumatoid arthritis, who subsequently are diagnosed with microscopic colitis. Patients diagnosed with LC also have had 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. Removal of gluten from the diet, however, is ineffective in treating microscopic colitis in the absence of celiac disease.
  • Microscopic colitis and inflammatory bowel disease (Crohn disease or ulcerative colitis) have been diagnosed concurrently or sequentially in a small number of cases, with either diagnosis preceding the other. The two conditions may have similar histologic features, making the distinction between them difficult.
  • LC was diagnosed in a patient who failed to respond to antibiotic therapy for diarrhea associated with Campylobacter jejuni infection in the stool. The infection theoretically might have stimulated an autoimmune response that resulted in LC.
  • Increased mast cells in some LC patients might indicate that degranulation products could serve as chemoattractants for inflammatory cells.
  • Although only 14% of patients with LC were smoking actively when diagnosed, 23% were former smokers, suggesting that smoking may actually be protective against the development of LC. Excessive production of nitric oxide by inducible nitric oxide synthase (iNOS) may result in cytotoxicity through the generation of peroxynitrite that is formed when nitric oxide reacts with superoxide. Corticosteroids inhibit iNOS biosynthesis in some cells, and newer inhibitors of this enzyme may have a future role in the management of LC and other forms of colitis. Nitric oxide diffuses into cells and can induce inflammatory cell damage by causing nitration reactions. Increased nitric oxide generation has been reported in CC. The absence of nitrotyrosine staining, which is an indicator of active inflammation typically seen in ulcerative colitis, may correspond to the lesser degree of inflammation in CC compared with ulcerative colitis. [6]
  • Diarrhea associated with CC has been proven to be due to reduced net Na + and Cl - absorption, with the thickened collagen layer serving as a diffusion barrier. The epithelium nearly completely loses its ability to absorb these ions. In fact, the shift in net chloride flux is to secretion rather than absorption.
  • Secretion of vascular endothelial growth factor, a fibrosis-enhancing peptide, is noted to be increased by the mucosa in some patients with CC. This may play a part in the pathogenesis.
  • In some patients with diabetes mellitus and diarrhea, evidence of an increase in the thickness of subepithelial collagen bands has been found. However, there was no correlation reported between collagen thickness, age, and the duration of diabetes. [7]
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Epidemiology

United States statistics

The true incidence of microscopic colitis is not known. The disease has been increasingly diagnosed over the past 20 years, but it is still uncommon. A population-based study found the incidence of microscopic colitis to have increased significantly from 1.1 per 100,000 persons in the late 1980s to 19.6 per 100,000 persons by the end of 2001. The rates increased with age. Prevalence at the end of the study period was 103.0 per 100,000 persons (39.3 for collagenous colitis [CC] and 63.7 for lymphocytic colitis [LC]).

International statistics

Estimates of international incidence rates of CC range from 1.1 to 5.2 per 100,000 per year; those for LC range from 3.1 to 5.5 per 100,000 per year.

Sex- and age-related demographics

LC affects similar numbers of men and women, whereas CC is up to 20 times more frequent in women than in men.

Both conditions are observed more commonly in people older than 40 years, with 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.

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Prognosis

Approximately 20% of patients with microscopic colitis may have a spontaneous remission without specific therapy.

More than half of patients treated for lymphocytic colitis (LC) experienced resolution of symptoms after 6 months of treatment, while 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 likely thought to be due to epithelial membrane sloughing and resultant altered mucosal permeability.

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

Mortality/morbidity

Morbidity is limited to the consequences of diarrhea and malabsorption, including metabolic abnormalities such as hypokalemia and dehydration, weight loss, fatigue, and vitamin deficiencies. This is not considered a life-threatening condition; however, profuse watery diarrhea may lead to severe dehydration and electrolyte abnormalities requiring intensive resuscitation.

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