A PRACTICAL APPROACH TO GASTROINTESTINAL PATHOLOGY
COLLAGENOUS COLITIS AND LYMPHOCYTIC ("MICROSCOPIC") COLITIS
Robert E. Petras, M.D.
Collagenous colitis, first recognized by Lindstrom in 1976,1 describes a distinct clinicopathologic
syndrome causing watery diarrhea, predominantly in middle-aged or older (mean age = 59 years) women
(male:female = 1:7.5).2-4 Colonoscopic and barium enema examination in these patients are usually
normal. Therefore, diagnosis depends upon recognition of characteristic changes in biopsy specimens. The
primary histologic change of collagenous colitis consists of a patchy increase in the thickness of the
subepithelial collagenous plate.2,5 The normal colonic subepithelial collagen layer measures
approximately 5 um in thickness, but in collagenous colitis it may increase to 10 um or more (approximately
the diameter of two red blood cells). The collagen had been identified as types I and III but more recently
type VI collagen has been described.6 The lamina propria is expanded by a mild to moderate increase in
chronic inflammatory cells including plasma cells. Patchy injury to the surface epithelium characterized by
increased numbers of intraepithelial lymphocytes, epithelial degeneration, and sloughing also occurs.
Atrophy, mucosal architectural distortion, and acute inflammation are usually not present or are minimal.2,5,7
Differential diagnostic considerations include nonspecific changes, primary inflammatory bowel disease,
acute colitis, mucosal prolapse syndrome (solitary rectal ulcer syndrome), ischemic bowel disease,
amyloidosis, and lymphocytic ("microscopic") colitis. Features comparing and contrasting the remaining
conditions in the differential diagnosis are listed in the Table.
Lymphocytic ("Microscopic") Colitis
Read and colleagues introduced the term "microscopic colitis" to describe patients with chronic watery
diarrhea of unknown origin occurring in middle-aged (mean = 54 years) patients.8 Like collagenous
colitis, the colonoscopic appearance and the barium enema were usually described as normal. Biopsy
specimens demonstrated increased inflammatory cells in a pattern not specific for any established entity.8 Since this initial report, several additional investigators have refined the clinical and especially
the histologic diagnostic criteria.7,9,10 The histologic changes include increased chronic inflammatory
cells in the lamina propria and surface epithelium, degenerative changes of the surface epithelium, minimal
architectural changes, and minimal acute inflammation. The changes of microscopic colitis in general
resemble the surface epithelial and lamina propria changes of collagenous colitis, and indeed changes
identical to microscopic colitis are seen in biopsy specimens from patients with collagenous colitis if
areas where the collagen plate is not well developed are sampled. Because of the lymphocyte predominance in
the inflammatory infiltrate, Lazenby et al. 7 proposed the term "lymphocytic colitis" to describe this
entity. They cited that the term "microscopic colitis" could be confused with other diseases that can have
a normal gross appearance and an abnormal histology (e.g., Crohn's disease, acute self-limited colitis).
The histologic differential diagnosis of lymphocytic colitis includes changes caused by enema (bowel
preparation), the mucosal M cell zone, acute colitis, primary inflammatory bowel disease, and collagenous
colitis. Features comparing and contrasting these various conditions are also included in the table.
Collagenous and Lymphocytic Colitis: Different Names for the Same Condition?
The similarities between lymphocytic colitis and collagenous colitis are striking. They share similar
symptomatology and endoscopic findings. The histologic similarities include the increased intraepithelial
lymphocytes, the surface epithelial damage, and the increased chronic inflammatory cells within the lamina
propria.5,7,11,12 Both collagenous and lymphocytic colitis can be associated with other autoimmune
phenomenon such as thyroid disease, enteropathic arthritis, rheumatoid arthritis, myasthenia gravis and
celiac sprue.13-15 One patient with well established microscopic colitis developed collagenous colitis
three years after the initial diagnosis.7 Some cases of lymphocytic colitis demonstrate some thickening
of the subepithelial collagen plate and the distinction of lymphocytic colitis from collagenous colitis may
not be so clear cut in all cases.12 It appears likely that lymphocytic colitis and collagenous colitis
are either the same or very similar entities, perhaps representing different morphologic phases of one
There are some minor differences between lymphocytic colitis and collagenous colitis that deserved mention.
Collagenous colitis has been reported predominantly in women, whereas lymphocytic colitis affects men and
women equally.7,16 However, the Mayo Clinic reported a similar frequency of collagenous colitis in men
and women.14 Giardiello et al have reported differences in HLA haplotypes between collagenous colitis
and lymphocytic colitis with lymphocytic colitis having a higher frequency of HLA A1 and a lower frequency
of HLA A3,16 but the number of observations was quite small. Finally, collagenous colitis and
lymphocytic colitis do differ histologically with the presence of the collagen plate in the former.
Pathogenesis of the Diarrhea
Since lymphocytic and collagenous colitis share so many features, most clinical reviews have included them
both together. In both conditions there appears to be net fluid secretion in the colon that is primarily
responsible for the diarrhea.11,18 Several investigators could find no association between the thickness
and extent of the collagen plate and the amount of diarrhea.12,14 Therefore, most investigators conclude
that it is the damage to the surface epithelial cells and the inflammation rather than the collagen deposits
that causes the diarrhea.12 The presence and thickness of the subepithelial collagen plate appears
unrelated to the patient age or duration of disease.12 Interestingly, a minority of patients have also
demonstrated evidence for small bowel dysfunction with salt wasting, fatty acid malabsorption, small bowel
net secretion, and rarely a small bowel villous lesion that resembles celiac sprue (see below).17
Treatment and Prognosis
Spontaneous resolution of collagenous colitis and lymphocytic colitis has occurred, thus rendering
evaluation of therapeutic regimens difficult.19 A distinct minority of patients with these colitides
have presented with relatively mild diarrhea and have achieved medical control with dietary restriction,
(elimination of caffeine and lactose containing foods) bulking agents, and antimotility drugs (loperamide
hydrochloride, diphenoxylate hydrochloride, atropine).17,19 This type of "symptomatic" therapy has
failed, however, in the vast majority of patients thus necessitating the addition of anti-inflammatory
agents. Approximately half of the patients with lymphocytic and collagenous colitis respond to
Sulfasalazine alone with diarrhea subsiding in one to two weeks. In non-responders or in those intolerant
of Sulfasalazine, Prednisone can be used either with or instead of Sulfasalazine. Approximately 80-90% of
patients eventually respond to this approach.3,11,17,19,20 Treatment of the often-associated thyroid
problem can also improve bowel function. There are also case reports of improvement with Pepto-Bismol,
mepacrine hydrochloride, steroid enemas, metronidazole, and 5-aminosalicylate.11,17,20
Etiology and Pathogenesis
Although NSAIDS have been reportedly linked to some occurrences of collagenous colitis,21 and lymphocytic
colitis has been reported in patients receiving the drug Cyclo 3 Fort 22 and ranitidine,23 the bulk of
the evidence suggests that lymphocytic colitis and collagenous colitis share a common immune-mediated
etiology and pathogenesis. Both conditions have a striking histologic similarity to celiac sprue, a
condition known to be autoimmune possibly having a viral or infectious trigger.7 In addition, both
lymphocytic and collagenous colitis have been linked to other conditions thought to have autoimmune
pathogenesis such as hypothyroidism, hyperthyroidism, inflammatory arthropathies, pernicious anemia, small
bowel villous atrophy, iritis, and myasthenia gravis.13,14,18,19 Finally, both conditions respond
dramatically to anti-inflammatory agents.17,19 Recently, a "lymphocytic colitis-like" histology was
reported in an epidemic outbreak of Brainerd Diarrhea linked to a water tank aboard a cruise ship supporting
an infectious trigger for some cases of lymphocytic colitis. (See below)
Association with Celiac Sprue
The association between lymphocytic colitis/collagenous colitis and celiac sprue and "sprue-like" lesions
deserves special attention.24-26 In the experience of DuBois and associates 25 and Wolber and
colleagues,26 approximately 25% of patients with "celiac sprue" who had colonic biopsies also showed
changes of lymphocytic colitis. Colonic microscopic abnormalities in patients with celiac sprue occur after
experimental exposure to wheat or gliadin enemas 25-28 suggesting that the entire intestinal tract may be
susceptible to gluten-induced injury. It is possible that in some patients with true celiac sprue
(responsive to gluten withdrawal), occult dietary gluten actually reaches the colon and induces the
histologic changes of "lymphocytic colitis." However, approximately one-half of the patients with
"sprue-like" small bowel lesions and lymphocytic colitis have not responded to gluten withdrawal. The term
"lymphocytic enterocolitis" has been coined to describe this refractory sprue-like condition associated with
The term Brainerd Diarrhea has been applied to outbreaks of diarrhea of unknown etiology characterized by
acute onset and prolonged duration.29 The disease was named after Brainerd, Minnesota, where in 1984,
122 residents developed watery diarrhea after drinking unpasteurized milk from a local dairy. A second
outbreak occurred in Henderson County, Illinois in 1987, when 72 people developed watery diarrhea associated
with drinking contaminated well water at a roadside restaurant. In each outbreak, patients underwent
extensive diagnostic evaluations including comprehensive microbiological studies of their stool and the
implicated exposure site. Despite this work up, no etiologic agent was identified. The clinical and
epidemiologic characteristics were typical for a point-source epidemic infectious diarrhea. However, unlike
typical infectious diarrhea, these patients developed a chronic watery diarrhea syndrome with symptoms
lasting longer than six months and often lasting for years.
We examined colonic and small bowel biopsy specimens from 22 patients who were involved in an outbreak of
Brainerd Diarrhea that was linked to the water supply of a cruise ship visiting the Galapagos Islands. In
general, the small bowel biopsy specimens were histologically normal. Colonic biopsy specimens from 20
patients revealed surface epithelial lymphocytosis without distortion of mucosal architecture, surface
degenerative changes or thickened subepithelial collagen plate. The degree of surface epithelial
lymphocytosis was similar to that seen in collagenous colitis and lymphocytic colitis.7,29 We also
evaluated a limited number of colonic biopsy specimens from two other outbreaks of Brainerd Diarrhea. They
revealed similar histologic findings to the Galapagos outbreak.
We now believe that patients with the clinical syndrome of chronic watery diarrhea of unknown etiology and
patients reported as having lymphocytic colitis represent a heterogeneous group that may contain persons
with unrecognized Brainerd Diarrhea. With longer term follow-up, the "Brainerd" cases appear to be
self-limited with patients recovering in less than 3 years. From a practical standpoint, we believe surface
epithelial lymphocyte counts should be performed on all colonic biopsy specimens from patients with chronic
diarrhea, especially chronic watery diarrhea. Somewhat lower lymphocyte counts and a lesser degree of
surface degeneration may distinguish Brainerd Diarrhea from other types of "lymphocytic colitis" but more
study is required. Currently, Brainerd Diarrhea cannot be recognized outside the setting of an epidemic.
COLLAGENOUS AND LYMPHOCYTIC COLITIS: DIFFERENTIAL DIAGNOSIS
|Colitis ||Lymphocytic Colitis||Collagenous Colitis||IBD ||Acute Colitis||SRUS ||Ischemia||Amyloid||Enema ||M-cell Zone|
|Intraepithelial lymphocytes ||+++ ||+++ ||0 ||0 ||0 ||0 ||0 ||0 ||+++*|
|Lamina propria Chronic inflammation||++ ||++ ||+++ ||+ ||0 ||+||0 ||0 ||+++*|
|Surface PMN's ||0 ||0 ||+ ||+ ||0 ||+ ||0 ||+||0|
|Apoptosis ||0 ||0 ||+ ||+ ||0 ||+ ||0 ||+** ||0|
|Lamina propria PMN's ||+ ||+ ||0 ||++ ||0 ||+ ||0 ||0 ||0|
|Cryptitis/crypt abscesses ||+ ||+ ||+++ ||++ ||0 ||+ ||0 ||0 ||0|
|Surface epithelial degeneration ||++ ||+++ ||0 ||++ ||0 ||++ ||0 ||+||0|
|Mucosal architectural distortion ||+ ||+ ||+++ ||+ ||++ ||++ ||+ ||0 ||+|
|Collagen deposits ||0 ||Yes# ||0 ||0 ||Yes##||Yes## ||0 ||0 ||0|
|Positive amyloid stain ||0 ||0 ||+||0 ||0 ||0 ||+++ ||0 ||0|
|* Over lymphoid aggregate only ||** Surface only |
|IBD = Primary inflammatory bowel disease||SRUS = Solitary rectal ulcer syndrome|
|# Subepithelial ||## Throughout lamina propria |
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