eMedicine Specialties > Gastroenterology > Colon

Collagenous and Lymphocytic Colitis

Author: Eric Goosenberg, MD, Clinical Assistant Professor, Department of Medicine, Drexel University School of Medicine
Contributor Information and Disclosures

Updated: Jul 15, 2009

Introduction

Background

Collagenous colitis (CC) was described concurrently in 1976 by Lindstrom and by Freeman¹ . In 1980, Read described microscopic colitis, which is clinically indistinguishable from CC but is differentiated from it by colonic biopsy features. Later, the term lymphocytic colitis (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). The term microscopic colitis is now used to describe both CC and LC, and these conditions 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.

LC and CC are relatively rare conditions that are diagnosed when a patient with chronic watery nonbloody diarrhea has an endoscopically or radiographically normal colon, but colonic biopsies show unique inflammatory changes. Because the mucosa is not ulcerated or otherwise disrupted, the diarrhea generally does not contain blood or pus.

Pathophysiology

• The characteristic feature of LC is an infiltration of lymphocytes into the colonic epithelium. 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.
• 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 in stool water may contribute to a secretory diarrhea.
• Some patients with CC and concurrent collagenous infiltration of the duodenum and/or the ileum have demonstrated altered small bowel dysfunction, demonstrated 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 vascular endothelial growth factor, a fibrosis-enhancing peptide.

Frequency

United States

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

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.

Sex

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

Age

Both conditions are observed most 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.

Clinical

History

• A protracted course of nonbloody diarrhea occurs. Diarrhea may be of high volume; some patients may eliminate more than 1500 mL of fluid per day.
• Symptoms may have been present from several months to 2-3 years before medical attention is sought and a diagnosis is made. In fact, perhaps half of patients proven to have microscopic colitis meet the Rome, Rome II, and Manning symptom-based criteria for diarrhea-predominant irritable bowel syndrome and may be so misdiagnosed until endoscopic biopsies of the colon are taken.
• Less frequent complaints include abdominal cramping, fecal incontinence, and weight loss, although weight loss may be seen in 40% or more of patients with CC.
• Incontinence is probably more a reflection of the advanced age of those individuals who are affected, and patients with this problem may do well if treated with antidiarrheal agents.

Physical

• Physical examination usually does not reflect specific abnormalities.
• Severely affected individuals may show signs of dehydration, malnutrition, and weight loss.

Causes

No definite etiology has been determined, but evidence now indicates that drug consumption may trigger underlying inflammatory factors in the colons of affected individuals, while others may exacerbate the diarrhea in patients with idiopathic microscopic colitis. While many drugs, either alone or in combination, may cause diarrhea as an adverse effect, nonsteroidal anti-inflammatory drugs (NSAIDs) show a strong trend (p=0.057) toward increasing the risk of CC, with rechallenge having been shown to cause recurrence of CC. Antidepressant selective serotonin reuptake inhibitors (SSRIs) as a group increase the risk of CC, but, among this class of medications, sertraline alone significantly increases the risk of LC. Anecdotal reports of of a large number of additional drugs have been associated with the onset of the microscopic colitides. Among these, ranitidine (confirmed by rechallenge), aspirin, acarbose, ticlopidine, and proton pump inhibitors have high-level evidence ofcausality,whileflutamide, simvastatin, carbamazepine and lisinopril have intermediate-level evidence.

• Some patients have had histologic findings consistent with both CC and LC at different points during the course of 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 1/3 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's 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 a chemoattractant for inflammatory cells.
• While 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.
• 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.

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