Collagenous and Lymphocytic Colitis
University of Alabama School of Medicine
Collagenous colitis is a clinicopathologic syndrome characterized by
In 1976, Lindstrom described the first case. Lindstrom coined
the term collagenous colitis because of the histopathologic similarity to
collagenous sprue, in which a collagen deposit is seen in a similar subepithelial location but in jejunal
mucosa. Several studies have addressed the prevalence of collagenous colitis. In persons with chronic
diarrhea, the frequency of collagenous colitis ranges from 0.3% to 5.0%. The incidence of this disorder
has been estimated to range from 1.8 to 5.2 cases per 100,000 population. This disease is found mainly
in "Western" countries in Europe, Australia, and North America, but rare cases have been reported from
Japan and Africa.
- chronic watery diarrhea and crampy abdominal pain
- distinctive colorectal histopathology that includes a subepithelial collagen band, prominent chronic inflammation in the lamina propria, and increased intraepithelial lymphocytes.
As the name implies, there are two main histologic components to
The increased collagen can be recognized on
conventional hematoxylin and eosin stains as an eosinophilic band localized just beneath the surface
epithelium and has been reported to contain collagen of many types. Recent reports show primarily types
I, III, and VI collagen, and tenascin. In normals, the subepithelial basement membrane is no greater
than 3 µm but can be thicker in hyperplastic polyps and with tangential sectioning. In collagenous
colitis, the width of the band averaged 15 µm in one series. In many patients, band thickness varies
throughout the colon with the transverse colon usually having the thickest bands. The rectum can lack a
thick subepithelial collagen band in up to 25% of cases and in a small percentage, the rectum can be
normal with no increase in inflammation. Consequently, multiple biopsy specimens should be taken in
areas proximal to the rectosigmoid sampled to establish or exclude the diagnosis of collagenous colitis.
In rare cases, subepithelial collagen has also been noted in duodenal and gastric mucosa in patients with
- Increased collagen deposition
- Colitis. A main histologic component is the presence of increased subepithelial collagen.
The increased subepithelial collagen has qualitative and quantitative changes from normal colon. In
normal colonic epithelium, the basement membrane has sharp, well-defined edges. In collagenous colitis,
the increased collagen imparts a shaggy appearance to the lower border of the basement membrane with
tendrils of collagen extending down into the upper lamina propria. To delineate mild increases in
subepithelial collagen, a trichrome stain is helpful. Immunoperoxidase stains for tenascin have also
been touted as a sensitive and specific marker for the subepithelial collagen band. Any increase in
subepithelial collagen, in the proper inflammatory and clinical context, is diagnostic of collagenous
colitis. Hence, measurement of the thickness of subepithelial collagen layer is not necessary to
diagnose collagenous colitis.
The second histologic component in collagenous colitis involves increases in inflammation both in the
lamina propria and within the epithelium. The lamina propria is expanded by a mixture of inflammatory
cells, including plasma cells, lymphocytes, eosinophils, and mast cells. Increased eosinophils can be
striking in some cases. Eosinophil granule component as well as TGF beta made by the eosinophils, may be
involved in the pathophysiology of the disease. Crypt distortion is rare, but Paneth cell metaplasia is
not uncommon, and a sprinkling of neutrophils can be seen in up to 25% of case. Extensive neutrophils
and pseudomembranes are rare but have been described in a few cases, potentially in acute or early stage
of the illness or concomitant C. difficile infection.
A distinctive component of collagenous colitis is increased intraepithelial lymphocytes. An increase
in these cells is present in the majority, but not all, cases of collagenous colitis. Prominent
intraepithelial lymphocytes are not a feature of other forms of colitis or enteritis except for celiac
disease and lymphocytic colitis. The intraepithelial lymphocytes of collagenous colitis are
predominantly CD8+ T cells and express the alpha beta form of the T cell receptor. Surface epithelial
damage (flattening, detachment) may also be present.
Misdiagnosis of collagenous colitis can occur by focusing exclusively on the thickness of the
subepithelial collagen band. Collagenous colitis is an inflammatory
disorder of the colon, and thus increased mucosal inflammation is a prerequisite to the diagnosis. The
basement membrane can appear artificially increased in size. For example, tangential sectioning of the
basement membrane creates a thicker basement membrane than when correctly oriented.
The cause of collagenous colitis is unknown, and thus it can be considered a
type of chronic idiopathic IBD, albeit of a "gentler and more subtle form." Hypotheses for the etiology
of collagenous colitis include
- Immune dysregulation
- Abnormalities in pericryptal fibroblasts
- Intraluminal bacterial agents or toxins
- Plasmatic vasculosis
- Drug induced damage.
Some of the most intriguing recent findings relate to the possible role of infectious agents in
collagenous colitis. Swedish investigators found that diverting the fecal stream caused clinical and
histological remission in nine patients and that clinical symptoms and an abnormal collagen table
returned after ostomy takedown. This, of course, suggests that some luminal agent or toxin is involved.
Some investigators have found clinical improvement in patients treated with antibiotics or with bismuth
subsalicylate, an agent thought to work via an antibacterial mechanism. Also, antibodies against
Yersinia virulence factors are more common in collagenous colitis than in control patients. The pattern
of inflammation, with increased intraepithelial lymphocytes, suggests polarization of the immune system
toward a luminal agent. One hypothesis is that a foreign luminal agent, possibly bacteria, initiates
colorectal inflammation that leads to an immunologic cross-reactivity with an endogenous antigen in
luminal epithelial cells leading to a self sustaining inflammatory condition.
On the other hand, collagenous colitis has been linked in rare cases to lansoprazole administration,
(the association is more common with lymphocytic colitis.) In these cases, drug was clearly associated
with onset of symptoms and resolved with lansoprazole was stopped. NSAIDs have also been linked to
collagenous colitis by a few investigators but not others.
The mechanisms of diarrhea are variable between patients. Fasting improves, but does not totally
abate the diarrhea in most patients, suggesting both an osmotic and a secretory component to the
diarrhea. Reduced Na and Cl absorption are the main mechanisms of diarrhea in collagenous colitis, but
there is also an active component of Cl secretion. Down regulation of tight junction molecules,
particularly occludin, is thought to contribute to the diarrhea. While the diarrhea is felt to be mainly
of colonic origin, some studies have also shown abnormal permeability in the small bowel as well.
Collagenous colitis is a disease primarily of women with a female to male
predominance of nine to one. This disorder is seen primarily in middle-aged patients with a mean age of
diagnosis of 59 years, but a wide age range of presentation. No well documented cases have been
described in children.
Chronic watery diarrhea is the main symptom and in most patients has been present months to years.
Nocturnal diarrhea is not uncommon. The patients often also have crampy diffuse abdominal pain, symptoms
which cause misdiagnosis with irritable bowel syndrome. Enteropathic arthritis is seen in approximately
7% of collagenous colitis patients, with the arthritis being seronegative for rheumatoid factor and
nondestructive. A variety of other immunologic disorders have been noted in this patient population,
with 17%-40% of patients having coexistent autoimmune illnesses.
Routine laboratory studies are usually normal. However, antineutrophilic cytoplasmic antibodies have
been described. Importantly, gastrointestinal radiographic and endoscopic examinations usually show
normal mucosa. Thus, it is essential for clinicians to biopsy grossly normal mucosa to establish this
While collagenous colitis is usually a chronic process, patients can have
spontaneous remissions, thus complicating evaluation of drug effectiveness. While dietary modification
(elimination of caffeine, lactose, or NSAIDs) may help some individuals, most require medication of some
sort. In the past, first line therapy was with sulfasalazine or other 5-ASA derivatives. If that
therapy failed, patients were treated with steroids or even more potent immunosuppressives. Currently,
two main therapeutic regimens are being touted, either therapy with a non-absorbable steroid (budesonide)
or high dose bismuth preparations. While patients usually respond to the above medications, it is not
infrequent for there to be flares of diarrhea after the medication is stopped.
Lymphocytic colitis has similar clinical features to collagenous colitis. Watery diarrhea is the main
symptom with most individual also noting a mild, intermittent, crampy abdominal pain. Most patients are
middle-aged, but in contrast to collagenous colitis, there is an equal male-to-female ratio. Routine
hematologic tests are usually normal, but occasionally the Westergren sedimentation is increased. Some
patients have increased titers of anti-nuclear antibodies, anti-parietal cell antibodies, and
anti-microsomal antibodies. Lymphocytic colitis patients have an increased frequency of HLA A1 and of a
diminished frequency of HLA A3 compared to controls.
The main histologic feature of lymphocytic colitis is
increased intraepithelial lymphocytes. In a normal colon, the number of intraepithelial lymphocytes
(IELs) is 5 per 100 epithelial cells, while in lymphocytic colitis, the median number of IELs is 30
lymphocytes per 100 epithelial cells (range 10 to 50). Also, surface epithelial damage and a mild
increase in chronic inflammation in the lamina propria is usually seen. There is minimal to no increase
in intraepithelial neutrophils, and crypt distortion is generally absent, which sets these cases apart
from ulcerative colitis and Crohn's disease. In contrast to collagenous colitis, there is not a
subepithelial collagen band – the basement membrane has a sharp, discrete lower border. Also, in
comparison to collagenous colitis, there are usually fewer eosinophils, and the amount of chronic
inflammation in the lamina propria is usually less.
While collagenous colitis is a tightly coherent clinicopathology entity,
lymphocytic colitis is more a histologic pattern associated with a variety of conditions. While most of
the cases are idiopathic and chronic, some are associated with celiac disease and will resolve when the
patients go on a gluten-free diet. A small group of cases is also associated with particular drugs,
including ticlopidine, carbamazepine, cimetidine, ranitidine, simvastatin, and some drugs used primarily
in France including veinotonics and vinburnine. Finally, cases have been reported following certain
infections, and thus may represent a slowly resolving infection or perhaps and abnormal persistent immune
response following an infection.
Microscopic colitis is a term introduced by Read et al to describe a group of patients with chronic
diarrhea that had normal endoscopy, but abnormal histology. Subsequent review of those cases showed them
to include collagenous colitis, lymphocytic colitis, eosinophilic colitis, and Crohn's disease. While
microscopic colitis is a fine clinical "umbrella" term, pathologists should give a more exacting and
specific diagnosis. A microscope is how we make our diagnosis – not a diagnostic entity.
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