Lymphocytic (Microscopic) Colitis

Background

Lymphocytic colitis is closely related to collagenous colitis. Both are characterized by a syndrome of watery diarrhea, usually occurring in young to middle aged women. The etiology is unknown but an autoimmune basis has long been suspected. However, an infectious etiology has not been excluded. In favor of an infectious etiology are cases associated with an outbreak of Brainerd diarrhea aboard a cruise ship. Brainerd diarrhea has been applied to cases of diarrhea of unknown etiology with an acute onset and prolonged duration. Like collagenous colitis, a chronic watery diarrhea is present, but this lasts longer than 6 months and frequently for many years. Biopsies show similar features to lymphocytic colitis except there may a lesser degree of lymphocytic infiltration.

Outline

Epidemiology
Disease Associations
Laboratory
Histopathological Features and Variants
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS Microscopic colitis

INCIDENCE

Incidence of collagenous and lymphocytic colitis: a 5-year population-based study.

Fernandez-Banares F, Salas A, Forne M, Esteve M, Espinos J, Viver JM.

Department of Gastroenterology, Hospital Universitari Mutua de Terrassa, Barcelona, Catalonia, Spain.

Am J Gastroenterol 1999 Feb;94(2):418-23 Abstract quote

OBJECTIVE: The incidence of collagenous and lymphocytic colitis is not well known. We sought to assess the incidence of collagenous and lymphocytic colitis in a well-defined population during a 5-yr study period.

METHODS: From January 1, 1993, to December 31, 1997, all new patients diagnosed with collagenous or lymphocytic colitis living in the catchment area of the Hospital Mutua de Terrassa (Barcelona, Spain) were identified. Since 1993 all patients with chronic diarrhea were referred for a diagnostic colonoscopy. Multiple biopsy sampling of the entire colon was performed when appearance of the colonic mucosa was grossly normal.

RESULTS: Twenty-three cases of collagenous colitis and 37 of lymphocytic colitis were diagnosed. The female:male ratios were 4.75:1 and 2.7:1 for collagenous and lymphocytic colitis, respectively. The mean age at onset of symptoms was 53.4+/-3.2 (range, 29-82) yr for collagenous colitis, and 64.3+/-2.7 (range, 28-87) yr for lymphocytic colitis (p = 0.012). The mean annual incidence per 100,000 inhabitants based on the year of onset of symptoms was 1.1 (95% confidence interval [CI], 0.4-1.7) for collagenous colitis, and 3.1 (95% CI, 2.0-4.2) for lymphocytic colitis. A peak incidence was observed in older women in both diseases. A rate of microscopic colitis of 9.5 per 100 normal-looking colonoscopies performed in patients with chronic watery diarrhea was observed. Normal rectal biopsies were found in 43 % and 8% of patients with collagenous and lymphocytic colitis, respectively.

CONCLUSIONS: The incidence of lymphocytic colitis is three times higher than that of collagenous colitis. Microscopic colitis should be considered as a major possibility in the work-up of chronic diarrhea in older women.

DISEASE ASSOCIATIONS CHARACTERIZATION

COLLAGENOUS GASTRITIS

Collagenous gastritis associated with lymphocytic colitis.

Groisman GM, Meyers S, Harpaz N.

Department of Pathology, Mount Sinai School of Medicine of the City University of New York, New York, USA.

J Clin Gastroenterol 1996 Mar;22(2):134-7 Abstract quote

Collagenous sprue and collagenous colitis are two well-recognized idiopathic enteritides whose defining histologic attribute is fibrous thickening of the subepithelial basement membrane. Analogous changes in gastric mucosa seem to be quite rare. The term "collagenous gastritis" was recently applied for the first time to an isolated case of refractory gastritis in which distinctive subepithelial gastric fibrosis was noted.

We report an additional case of this entity in a 35-year-old woman with refractory dyspepsia. In contrast to the earlier case of collagenous gastritis, our patient also had lymphocytic colitis, a type of colitis associated with watery diarrhea.

Collagenous gastritis appears to be a distinct clinicopathologic entity, the histologic changes of which should be sought in patients with unexplained dyspepsia. Increased awareness of this condition and its possible clinical correlates may provide clues to its etiology and pathogenesis.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

LABORATORY MARKERS

FECAL LEUKOCYTES

Collagenous colitis: mucosal biopsies and association with fecal leukocytes.

Zins BJ, Tremaine WJ, Carpenter HA.

Division of Gastroenterology, Mayo Clinic Rochester, MN 55905, USA.

Mayo Clin Proc 1995 May;70(5):430-3 Abstract quote

OBJECTIVE: To determine the frequency of patchy colonic involvement, fecal leukocytosis, and association with celiac sprue in a large cohort of patients with collagenous colitis.

DESIGN: We conducted a retrospective review of the medical records of 172 consecutive Mayo Clinic patients in whom collagenous colitis had been diagnosed between 1982 and 1993.

METHODS: For each of the 172 patients, the medical record was reviewed to determine the frequency of (1) fecal leukocytosis; (2) characteristic histologic findings in the rectum and the sigmoid, descending, and ascending colon; and (3) small bowel biopsy findings consistent with celiac sprue.

RESULTS: The presence of fecal leukocytes was noted in 64 of 116 patients (55%) who had undergone assessment for fecal leukocytosis. On analysis of histologic findings, 113 of 123 rectal, 116 of 121 sigmoid, and 68 of 70 descending colon biopsy specimens were diagnostic of collagenous colitis. Small bowel biopsies were performed in 45 patients who did not have a history of small intestinal disease: 1 had celiac sprue and 44 had normal findings. Two other patients had previously diagnosed celiac sprue.

CONCLUSION: The finding of fecal leukocytes in 55% of patients with collagenous colitis confirms the inflammatory basis of this disease. Biopsy specimens obtained by flexible sigmoidoscopy seem sufficient to establish the diagnosis in most patients, and colonoscopic biopsy of the more proximal area of the colon is usually unnecessary. Celiac sprue infrequently accompanies collagenous colitis; thus, routine small bowel biopsy is not warranted.

P-ANCA

Perinuclear antineutrophil cytoplasmic antibodies in collagenous or lymphocytic colitis with or without celiac disease.

Freeman HJ.

Department of Medicine (Gastroenterology), University of British Columbia, Vancouver.

Can J Gastroenterol 1997 Jul-Aug;11(5):417-20 Abstract quote

Microscopic forms of colitis, including lymphocytic and collagenous colitis, have been observed in both those with and without celiac disease. Although perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) occur in most patients with ulcerative colitis, investigations in microscopic, particularly lymphocytic, colitis are still needed.

In this study atypical p-ANCA was evaluated in 55 patients, including 27 with celiac disease alone, 13 with celiac disease and concomitant lymphocytic colitis, and 15 with microscopic forms of colitis, including lymphocytic and collagenous colitis. Nine patients (16.3%) had atypical p-ANCA, including six with celiac disease and three with a microscopic form of colitis alone. Although five of the six positive celiac disease patients had lymphocytic colitis, all three celiac disease patients with associated primary sclerosing cholangitis--a separate risk factor for a positive assay result--were serologically positive for atypical p-ANCA.

These results indicate for the first time that this serological marker may occur in histologically defined celiac disease with or without concomitant lymphocytic colitis. Furthermore, these results suggest that the pathogenesis of ulcerative colitis differs from that of lymphocytic colitis and further emphasizes the heterogeneous nature of these newly recognized types of colonic inflammatory mucosal disorders.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

GENERAL

Lymphocytic colitis. A definable clinical and histological diagnosis.

Mills LR, Schuman BM, Thompson WO.

Laboratory Service, VA Medical Center, Augusta, Georgia 30904-6285.

Dig Dis Sci 1993 Jun;38(6):1147-51 Abstract quote

We reviewed colorectal biopsies and clinical records from 36 patients with chronic watery diarrhea who had been diagnosed as having microscopic colitis and compared their histologic features with the more detailed and precise criteria for lymphocytic colitis.

Published pathologic criteria for lymphocytic colitis were applied to the biopsies and compared. Focal or diffuse nature of the lymphoid infiltrate were noted separately. The focal lymphoid infiltrate was related to lymphoid aggregates in the lamina propria of the mucosa. Eighteen cases had focal lymphoid cell infiltration, and 16 of them had associated diverticula, polyps, or both. Eighteen cases had diffuse lymphoid cell infiltration, and six of them had diverticula or polyps.

Results indicate that focal cellular infiltration strongly predicts associated diverticula or polyps. The group with no diverticula or polyps most closely conformed to histologic criteria for lymphocytic colitis (Kruskal-Wallis P < 0.02).

We conclude that lymphocytic colitis comprises a well-defined group of cases within the large and less-defined group of microscopic colitis.

Colonic epithelial lymphocytosis without a thickened subepithelial collagen table: a clinicopathologic study of 40 cases supporting a heterogeneous entity.

Wang N, Dumot JA, Achkar E, Easley KA, Petras RE, Goldblum JR.

Department of Anatomic Pathology, The Cleveland Clinic Foundation, Ohio 44195, USA

Am J Surg Pathol 1999 Sep;23(9):1068-74 Abstract quote

Lymphocytic colitis (LC) is classically described as a triad of chronic nonbloody, watery diarrhea, normal or nearly normal endoscopy findings, and colonic epithelial lymphocytosis without a thickened subepithelial collagen table (SECT). It is unknown how often patients with colonic epithelial lymphocytosis without a thickened SECT actually present with this classic triad.

Cases diagnosed histologically as lymphocytic or microscopic colitis were reviewed. Criteria for inclusion were the presence of at least 15 surface lymphocytes per 100 epithelial cells and the absence of a thickened SECT (<12 microm). Clinical features and course were recorded by chart review and telephone follow-up. Forty patients met the inclusion criteria, including 25 women and 15 men with a mean age of 63.2 years (range, 25-83 years). Twenty-eight patients had the classic triad and were designated as having classic LC. The other 12 patients fulfilled the histologic criteria but not the clinical or endoscopic criteria for classic LC and were classified as having atypical LC (constipation, five patients; macroscopic colitis at endoscopy, five patients; hematochezia, one patient; and incidental finding, one patient). Clinically, patients with classic LC were predominantly women and had a higher incidence of autoimmune disease (p = 0.03) than did those with atypical LC.

Histologically, surface eosinophilia was significantly greater in patients with classic LC (p = 0.04). Twenty patients were using nonsteroidal antiinflammatory drugs at the time of their colonic biopsy. Surface epithelial lymphocyte counts were higher in these patients, particularly in the distal sigmoid colon (p = 0.02). Fourteen patients had associated autoimmune disease, including three patients with sprue diagnosed by small bowel biopsy, all of whom responded to gluten withdrawal. Diarrhea present in 25 patients, without documented evidence of celiac sprue, was self-limited in five, resolved with treatment in three, required intermittent treatment in eight, daily treatment in five, and was refractory to treatment in four. All eight patients who experienced spontaneous or treatment-related symptom resolution had classic LC.

No histologic feature correlated with clinical course. In conclusion, our study shows that colonic epithelial lymphocytosis without a thickened SECT is a histologic finding seen in a heterogeneous group of patients. Within this heterogeneous group is a distinct subset of patients who have the classic clinicopathologic triad of LC. This subset of patients has striking similarities to patients with collagenous colitis, lending further support to a close relationship between these two entities.

Atypical LC comprises a heterogeneous group and includes patients with idiopathic constipation, coexisting LC and inflammatory bowel disease, and possibly infectious colitides. Because of the clinical heterogeneity among our study population, the descriptive term colonic epithelial lymphocytosis may be a more prudent diagnosis than lymphocytic colitis in the absence of adequate clinical information.

Prevalence and Significance of Inflammatory Bowel Disease-Like Morphologic Features in Collagenous and Lymphocytic Colitis

Gamze Ayata, M.D.; Sarathehandra Ithamukkala, M.D.; Heidi Sapp, M.D.; Beth H. Shaz, M.D.; Tom P. Brien, M.D.; Helen H. Wang, M.D., Dr.Ph.; Donald A. Antonioli, M.D.; Francis A. Farraye, M.D., M.Sc.; Robert D. Odze, M.D., F.R.C.P.C.
Am J Surg Pathol 2002; 26(11):1414-1423 Abstract quote

Collagenous colitis (CC) and lymphocytic colitis (LC) are clinical syndromes characterized by the presence of chronic watery diarrhea, few or no endoscopic abnormalities and biopsies that typically show normal crypt architecture, increased mononuclear inflammation in the lamina propria, absence of neutrophils, and increased intraepithelial lymphocytes. Patients with CC also have a thickened subepithelial collagen layer.

We have noted, anecdotally, that biopsy specimens from some patients with CC or LC contain certain histologic features, such as Paneth cell metaplasia (PM), that are normally seen in inflammatory bowel disease (IBD), or other types of healed colitis, and thus may cause diagnostic difficulty.

Therefore, the purpose of this study was to evaluate the prevalence and significance of IBD-like morphologic features in colonic mucosal biopsies from patients with CC or LC. Five hundred thirty-one routinely processed hematoxylin and eosin-stained colonic mucosal biopsies from 150 patients with clinically, endoscopically, and histologically confirmed CC (79 patients, male/female ratio: 14/65, mean age: 60 yr) or LC (71 patients, male/female ratio: 13/58, mean age: 55 yr) were evaluated in a blinded fashion for a variety of histologic features, including active crypt inflammation (cryptitis ± crypt abscess), surface ulceration, Paneth cell metaplasia, crypt architectural irregularity, number of intraepithelial lymphocytes, and thickness of the subepithelial collagen layer (CC only). The results were compared between CC and LC and correlated with the clinical and endoscopic data. None of the patients had or developed IBD during the study period.

Active crypt inflammation was a common finding in both groups, seen in 24 of 79 CC patients (30%) and 27 of 71 LC patients (38%). Surface ulceration was not seen in any of the LC biopsies but was present in 2 of 79 (2.5%) CC patients. Paneth cell metaplasia was frequent in both groups and significantly more common in CC compared with LC patients. Forty-four percent of CC patients, but only 9 of 63 (14%) of LC patients had Paneth cell metaplasia (p <0.001). Crypt architectural irregularity, although rare, was present in 6 of 79 patients with CC (7.6%) and 3 of 71 (4.2%) patients with LC. In patients with CC, the presence of Paneth cell metaplasia was associated with more severe disease characterized by the presence of abdominal pain (p <0.001) and a higher frequency of bowel movements (>3 bowel movements/day) (p = 0.06). Also, active crypt inflammation correlated with antibiotic use at the time of clinical presentation (p = 0.04) and was present in the only two patients who had positive stool cultures (one each for Campylobacter jejuni and Salmonella). However, none of the other histologic findings correlated with any of the other clinical or endoscopic features, such as type of symptoms, stool consistency, type of medical treatment, associated autoimmune diseases or outcome (complete, partial, or no resolution) in either group of patients.

Pathologists should be aware that some histologic features normally associated with IBD such as crypt irregularity and neutrophilic cryptitis and crypt abscesses are not uncommon in patients with CC or LC and that the presence of one or more of these features should not necessarily be interpreted as evidence against either of these diagnoses.

The Terminal Ileum Is Affected in Patients With Lymphocytic or Collagenous Colitis

Heidi Sapp, M.D., F.R.C.P.C.; Sarathehandra Ithamukkala, M.D.; Tom P. Brien, M.D.; Gamze Ayata, M.D.; Beth Shaz, M.D.; David M. Dorfman, M.D., Ph.D.; Helen H. Wang, M.D., Dr.Ph.; Donald A. Antonioli, M.D.; Francis A. Farraye, M.D., M.Sc.; Robert D. Odze, M.D., F.R.C.P.C.

Am J Surg Pathol 2002; 26(11):1484-1492 Abstract quote

Lymphocytic colitis (LC) and collagenous colitis (CC) are diseases characterized by the presence of marked intraepithelial lymphocytosis. Both of these disorders affect primarily the colon. However, involvement of the distal small intestine has not been systematically studied.

The purpose of this study was to evaluate the type and degree of intraepithelial lymphocytosis in the terminal ileum of patients with LC or CC. Terminal ileal mucosal biopsies from 22 patients with LC (male/female ratio 0.22, mean age 47 years) and 23 with CC (male/female ratio 0.43, mean age 54 years) were evaluated for the number of intraepithelial lymphocytes (IEL) per 100 epithelial cells (EC) both in the villi and crypts.

The results were compared with 30 patients with inflammatory bowel disease (16 with Crohn's disease [CD], 14 with ulcerative colitis [UC]) and 24 patients (male/female ratio 0.33, mean age 44 years) without colonic pathology as normal controls. None of the patients had celiac sprue. Paired terminal ileum and colonic mucosal biopsies from 6 patients with LC, 4 with CC, 5 with CD, 5 with UC, and 10 normal controls were also immunohistochemically stained with monoclonal antibodies to CD3, CD8, CD20, and a class II MHC antigen (LN3-HLA-DR). In the villi the IEL count/100 EC was 11.8 ± 1.8 in LC and 10.3 ± 1.9 in CC (p = 0.3).

These values were both significantly higher than in CD (2.8 ± 0.4, p <0.001), UC (3.1 ± 0.4, p <0.001), or normal controls (2.2 ± 0.2, p <0.001). In the crypts the IEL count was 3.8 ± 0.5 in LC and 3.2 ± 0.5 in CC (p = 0.3). These values were also significantly higher than in CD (2.3 ± 0.4, p = 0.02), UC (2.1 ± 0.3, p = 0.02), or normal controls (1.5 ± 0.2, p <0.001).

The presence of >5 IELs/100 EC in terminal ileum biopsies was highly specific for LC and CC (specificity 98%, sensitivity 73% and 56% for LC and CC, respectively). The IEL phenotype was similar in all groups of patients and in the ileum and colon of individual patients. Intraepithelial lymphocytes were CD3+, CD8+, CD20-, and LN3-HLA-DR-, indicative of a suppressor T-cell phenotype. Intraepithelial lymphocytosis occurs in the terminal ileum in patients with LC or CC and may be helpful in diagnosing these conditions and distinguishing LC or CC from CD or UC in diagnostically difficult cases.

The results suggest that the terminal ileum may be involved by a similar pathogenic process as the colon in LC and CC.

VARIANTS

BRAINERD DIARRHEA

Colonic epithelial lymphocytosis associated with an epidemic of chronic diarrhea.

Bryant DA, Mintz ED, Puhr ND, Griffin PM, Petras RE.

Department of Anatomic Pathology, Cleveland Clinic Foundation, OH 44195, USA.

Am J Surg Pathol 1996 Sep;20(9):1102-9 Abstract quote

The term Brainerd diarrhea has been applied to outbreaks of chronic watery diarrhea of unknown etiology characterized by acute onset and prolonged duration. Our aim was to describe the histologic changes in gastrointestinal biopsy specimens from patients with Brainerd diarrhea.

We examined 52 colonic and 12 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. Small bowel biopsy specimens from seven patients were histologically normal. One patient had a duodenal biopsy specimen that resembled celiac sprue. Colonic biopsy specimens from 20 patients revealed surface epithelial lymphocytosis without distortion of mucosal architecture, surface degenerative changes, or thickened subepithelial collagen plates. The degree of surface epithelial lymphocytosis was greater than that seen in control groups of persons with normal colons, acute colitis, and ulcerative colitis (p < 0.001), similar to that seen with collagenous colitis, and less than that seen with lymphocytic colitis (p < 0.001). Three patients showed focal active colitis similar to that described in acute infectious-type colitis in addition to the epithelial lymphocytosis. Two patients had colonic biopsy specimens that were histologically normal.

In summary, histologic abnormalities in the small bowel are generally absent in Brainerd diarrhea. Colonic biopsy specimens in Brainerd diarrhea frequently show epithelial lymphocytosis similar to that seen in collagenous and lymphocytic colitis.

Although currently Brainerd diarrhea can be diagnosed only with epidemiologic data indicating an epidemic and a point source, the lack of surface degenerative changes and the relatively lower lymphocyte counts seen in our cases of Brainerd diarrhea may serve to distinguish it from lymphocytic colitis, and the lack of a thickened subepithelial collagen plate distinguishes it from collagenous colitis.

LYMPHOCYTIC VENULITIS

Lymphocytic venulitis: an unusual association with microscopic colitis.

Arora DS, Mahmood T, Wyatt JI.

Department of Histopathology, St James's University Hospital, Leeds, UK.

J Clin Pathol 1999 Apr;52(4):303-4 Abstract quote

A 79 year old man presented with occult gastrointestinal bleeds and anaemia for two years. He had received 40 units of blood over a period of one year, following which he had a subtotal colectomy as no definite cause of the bleeding was apparent. Macroscopically the colon appeared unremarkable.

Light microscopy showed prominent lymphocytic venulitis in the proximal portion, gradually merging into lymphocytic and collagenous colitis distally.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

COLLAGENOUS COLITIS

Lymphocytic colitis: a distinct clinical entity? A clinicopathological confrontation of lymphocytic and collagenous colitis.

Baert F, Wouters K, D'Haens G, Hoang P, Naegels S, D'Heygere F, Holvoet J, Louis E, Devos M, Geboes K.

Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.

Gut 1999 Sep;45(3):375-81 Abstract quote

BACKGROUND AND AIMS: It is not known whether lymphocytic colitis and collagenous colitis represent different clinical entities or constitute part of a spectrum of disease.

METHODS: Detailed clinical features and histological findings were compared in a large series of patients with confirmed lymphocytic and collagenous colitis.

RESULTS: Histological diagnosis was confirmed in 96 patients with collagenous colitis and 80 with lymphocytic colitis. Twenty eight per cent of patients with collagenous colitis and 26% of patients with lymphocytic colitis had overlapping but less pronounced histological features. Both groups were equal in terms of age, use of aspirin and non-steroidal anti-inflammatory drugs, associated autoimmune conditions, arthritis, diarrhoea, and abdominal pain. The male:female ratio was 27:73 for collagenous colitis and 45:55 for lymphocytic colitis (p=0.013). Twenty five per cent of patients with collagenous colitis compared with 14% of patients with lymphocytic colitis were active smokers; only 8.3% of patients with collagenous colitis had stopped smoking compared with 23% of patients with lymphocytic colitis (p=0.013). Drug induced disease was suspected for ticlopidine (two collagenous colitis, four lymphocytic colitis) and flutamide (four lymphocytic colitis). Mean duration of symptoms before diagnosis was two months for lymphocytic colitis and four months for collagenous colitis. Overall prognosis was generally mild; 84% of patients with lymphocytic colitis and 74% of patients with collagenous colitis reported resolution or significant improvement (p=0.033).

CONCLUSIONS: Collagenous and lymphocytic colitis are similar but not identical. Patients with lymphocytic colitis present somewhat earlier and are less likely to be active smokers. Symptoms are milder and more likely to disappear in lymphocytic colitis. Ticlopidine and flutamide should be added to the list of drugs inducing colitis.

SPRUE

Colonic lymphocytosis in patients with celiac sprue.

Wolber R, Owen D, Freeman H.

Division of Anatomic Pathology, University of British Columbia Hospitals, Vancouver, Canada.

Hum Pathol 1990 Nov;21(11):1092-6 Abstract quote

We examined colonic biopsies from 39 patients with clinical and small bowel biopsy changes of celiac sprue.

In 12 of 39 patients (31%), striking lymphocytic infiltration of the superficial colonic epithelium and chronic inflammation of the lamina propria were identified. These 12 cases had a mean of 30.4 lymphocytes per 100 superficial colonic epithelial cells, compared with means of 8.4 in sprue cases without colonic epithelial lymphocytosis, 4.8 in normal controls, and 32.4 in nine cases of lymphocytic colitis without concurrent celiac sprue. No case showed subepithelial collagen layer thickening. Four patients with celiac sprue and colonic lymphocytosis also had gastric biopsies; two showed gastric lymphocytosis. Intraepithelial lymphocytes at all sites were positive for the T-cell marker MT-1.

These findings indicate that sprue-associated colonic lymphocytosis and lymphocytic colitis are histologically, quantitatively, and immunohistochemically indistinguishable, that the epithelial T-cell infiltration of celiac sprue occurs in glandular mucosa at all levels of the gastrointestinal tract, and that colonic subepithelial collagen deposition in patients with celiac sprue is an infrequent occurrence. These findings also suggest that gastrointestinal epithelial T-cell infiltration may be an immunologic response that is common in individuals sensitized to absorbed lumenal antigens, and that colonic lymphocytosis may occur as a response to a number of antigens, including gluten.

Colonic histopathology in untreated celiac sprue or refractory sprue: is it lymphocytic colitis or colonic lymphocytosis?

Fine KD, Lee EL, Meyer RL.

Department of Pathology, Baylor University Medical Center, Dallas, TX 75246, USA.

Hum Pathol 1998 Dec;29(12):1433-40 Abstract quote

Colonic histopathology in some patients with untreated celiac sprue and refractory sprue has been said to be indistinguishable from lymphocytic colitis, but there have been no objective comparisons on which this is based.

The purpose of this study was to determine the prevalence and to characterize the nature of colonic histopathology at the time of diagnosis in patients with celiac or refractory sprue. Colonoscopic biopsy specimens obtained at the time of diagnosis from 16 patients with celiac sprue, six patients with refractory sprue, nine patients with lymphocytic colitis, and five normal controls were analyzed blindly by histological and morphometric methods, quantitating the number and specific subtypes of inflammatory cells within the lamina propria and epithelium. Immunoperoxidase staining of intraepithelial lymphocytes with a monoclonal antibody to CD8 also was performed.

Three of 16 patients with untreated celiac sprue (19%) were thought to have colonic histological abnormalities, which by morphometry consisted of slightly increased numbers of lymphocytes in the surface epithelium and lamina propria, many of which were CD8-positive. These abnormalities were distinguishable from lymphocytic colitis by the lack of increased overall lamina propria cellularity and surface epithelial abnormalities, and by fewer intraepithelial lymphocytes.

In refractory sprue, colonic histological abnormalities were more frequent than in celiac sprue, occurring in four of six patients (67%), more pronounced, and identical to those in the lymphocytic colitis syndrome. However, colonic intraepithelial lymphocytes in lymphocytic colitis were mostly CD8-positive, whereas those in the colitis of refractory sprue rarely were.

Mild colonic lymphocytosis in patients with untreated celiac sprue should be distinguished from lymphocytic colitis by the lack of surface epithelial abnormalities, the lack of increased cellularity of the lamina propria, and the lack of ongoing watery diarrhea after treatment with a gluten-free diet. In contrast, colonic histopathology in refractory sprue is indistinguishable from lymphocytic colitis, although immunohistochemical differences do exist.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

COLLAGENOUS COLITIS

Microscopic colitis progressed to collagenous colitis: a morphometric study.

Perri F, Annese V, Pastore M, Andriulli A.

Divisione di Gastroenterologia, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo (FG), Italy.

Ital J Gastroenterol 1996 Apr;28(3):147-51 Abstract quote

Microscopic (also called lymphocytic) colitis and collagenous colitis are two newly recognised clinicopathologic entities of unknown aetiology presenting with chronic watery diarrhoea. In both conditions, the colon appears normal by barium enema and colonoscopy, however, colonic biopsies reveal infiltration of plasma cells and neutrophils within the lamina propria and increased intraepithelial lymphocytes within the surface epithelium. Lack of a thickened collagen band beneath the surface epithelium histologically differentiates microscopic from collagenous colitis. The exact relationship between the two disorders is as yet unknown. The two entities may be variants of the same spectrum of disease or distinct conditions with and without collagen table thickening.

The present case report shows progression of microscopic colitis to collagenous colitis in sequential colonic biopsies taken from a patient during a 7-year endoscopic follow-up suggesting that progression of microscopic to collagenous colitis is a possibility and the two diseases are likely to represent variants of the same condition.

Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.

Commonly Used Terms

Collagenous Colitis

Last Updated 11/13/2002

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HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
GENERAL
Lymphocytic colitis. A definable clinical and histological diagnosis. Mills LR, Schuman BM, Thompson WO. Laboratory Service, VA Medical Center, Augusta, Georgia 30904-6285.	Dig Dis Sci 1993 Jun;38(6):1147-51 Abstract quote We reviewed colorectal biopsies and clinical records from 36 patients with chronic watery diarrhea who had been diagnosed as having microscopic colitis and compared their histologic features with the more detailed and precise criteria for lymphocytic colitis. Published pathologic criteria for lymphocytic colitis were applied to the biopsies and compared. Focal or diffuse nature of the lymphoid infiltrate were noted separately. The focal lymphoid infiltrate was related to lymphoid aggregates in the lamina propria of the mucosa. Eighteen cases had focal lymphoid cell infiltration, and 16 of them had associated diverticula, polyps, or both. Eighteen cases had diffuse lymphoid cell infiltration, and six of them had diverticula or polyps. Results indicate that focal cellular infiltration strongly predicts associated diverticula or polyps. The group with no diverticula or polyps most closely conformed to histologic criteria for lymphocytic colitis (Kruskal-Wallis P < 0.02). We conclude that lymphocytic colitis comprises a well-defined group of cases within the large and less-defined group of microscopic colitis.
Colonic epithelial lymphocytosis without a thickened subepithelial collagen table: a clinicopathologic study of 40 cases supporting a heterogeneous entity. Wang N, Dumot JA, Achkar E, Easley KA, Petras RE, Goldblum JR. Department of Anatomic Pathology, The Cleveland Clinic Foundation, Ohio 44195, USA	Am J Surg Pathol 1999 Sep;23(9):1068-74 Abstract quote Lymphocytic colitis (LC) is classically described as a triad of chronic nonbloody, watery diarrhea, normal or nearly normal endoscopy findings, and colonic epithelial lymphocytosis without a thickened subepithelial collagen table (SECT). It is unknown how often patients with colonic epithelial lymphocytosis without a thickened SECT actually present with this classic triad. Cases diagnosed histologically as lymphocytic or microscopic colitis were reviewed. Criteria for inclusion were the presence of at least 15 surface lymphocytes per 100 epithelial cells and the absence of a thickened SECT (<12 microm). Clinical features and course were recorded by chart review and telephone follow-up. Forty patients met the inclusion criteria, including 25 women and 15 men with a mean age of 63.2 years (range, 25-83 years). Twenty-eight patients had the classic triad and were designated as having classic LC. The other 12 patients fulfilled the histologic criteria but not the clinical or endoscopic criteria for classic LC and were classified as having atypical LC (constipation, five patients; macroscopic colitis at endoscopy, five patients; hematochezia, one patient; and incidental finding, one patient). Clinically, patients with classic LC were predominantly women and had a higher incidence of autoimmune disease (p = 0.03) than did those with atypical LC. Histologically, surface eosinophilia was significantly greater in patients with classic LC (p = 0.04). Twenty patients were using nonsteroidal antiinflammatory drugs at the time of their colonic biopsy. Surface epithelial lymphocyte counts were higher in these patients, particularly in the distal sigmoid colon (p = 0.02). Fourteen patients had associated autoimmune disease, including three patients with sprue diagnosed by small bowel biopsy, all of whom responded to gluten withdrawal. Diarrhea present in 25 patients, without documented evidence of celiac sprue, was self-limited in five, resolved with treatment in three, required intermittent treatment in eight, daily treatment in five, and was refractory to treatment in four. All eight patients who experienced spontaneous or treatment-related symptom resolution had classic LC. No histologic feature correlated with clinical course. In conclusion, our study shows that colonic epithelial lymphocytosis without a thickened SECT is a histologic finding seen in a heterogeneous group of patients. Within this heterogeneous group is a distinct subset of patients who have the classic clinicopathologic triad of LC. This subset of patients has striking similarities to patients with collagenous colitis, lending further support to a close relationship between these two entities. Atypical LC comprises a heterogeneous group and includes patients with idiopathic constipation, coexisting LC and inflammatory bowel disease, and possibly infectious colitides. Because of the clinical heterogeneity among our study population, the descriptive term colonic epithelial lymphocytosis may be a more prudent diagnosis than lymphocytic colitis in the absence of adequate clinical information.
Prevalence and Significance of Inflammatory Bowel Disease-Like Morphologic Features in Collagenous and Lymphocytic Colitis Gamze Ayata, M.D.; Sarathehandra Ithamukkala, M.D.; Heidi Sapp, M.D.; Beth H. Shaz, M.D.; Tom P. Brien, M.D.; Helen H. Wang, M.D., Dr.Ph.; Donald A. Antonioli, M.D.; Francis A. Farraye, M.D., M.Sc.; Robert D. Odze, M.D., F.R.C.P.C.	Am J Surg Pathol 2002; 26(11):1414-1423 Abstract quote Collagenous colitis (CC) and lymphocytic colitis (LC) are clinical syndromes characterized by the presence of chronic watery diarrhea, few or no endoscopic abnormalities and biopsies that typically show normal crypt architecture, increased mononuclear inflammation in the lamina propria, absence of neutrophils, and increased intraepithelial lymphocytes. Patients with CC also have a thickened subepithelial collagen layer. We have noted, anecdotally, that biopsy specimens from some patients with CC or LC contain certain histologic features, such as Paneth cell metaplasia (PM), that are normally seen in inflammatory bowel disease (IBD), or other types of healed colitis, and thus may cause diagnostic difficulty. Therefore, the purpose of this study was to evaluate the prevalence and significance of IBD-like morphologic features in colonic mucosal biopsies from patients with CC or LC. Five hundred thirty-one routinely processed hematoxylin and eosin-stained colonic mucosal biopsies from 150 patients with clinically, endoscopically, and histologically confirmed CC (79 patients, male/female ratio: 14/65, mean age: 60 yr) or LC (71 patients, male/female ratio: 13/58, mean age: 55 yr) were evaluated in a blinded fashion for a variety of histologic features, including active crypt inflammation (cryptitis ± crypt abscess), surface ulceration, Paneth cell metaplasia, crypt architectural irregularity, number of intraepithelial lymphocytes, and thickness of the subepithelial collagen layer (CC only). The results were compared between CC and LC and correlated with the clinical and endoscopic data. None of the patients had or developed IBD during the study period. Active crypt inflammation was a common finding in both groups, seen in 24 of 79 CC patients (30%) and 27 of 71 LC patients (38%). Surface ulceration was not seen in any of the LC biopsies but was present in 2 of 79 (2.5%) CC patients. Paneth cell metaplasia was frequent in both groups and significantly more common in CC compared with LC patients. Forty-four percent of CC patients, but only 9 of 63 (14%) of LC patients had Paneth cell metaplasia (p <0.001). Crypt architectural irregularity, although rare, was present in 6 of 79 patients with CC (7.6%) and 3 of 71 (4.2%) patients with LC. In patients with CC, the presence of Paneth cell metaplasia was associated with more severe disease characterized by the presence of abdominal pain (p <0.001) and a higher frequency of bowel movements (>3 bowel movements/day) (p = 0.06). Also, active crypt inflammation correlated with antibiotic use at the time of clinical presentation (p = 0.04) and was present in the only two patients who had positive stool cultures (one each for Campylobacter jejuni and Salmonella). However, none of the other histologic findings correlated with any of the other clinical or endoscopic features, such as type of symptoms, stool consistency, type of medical treatment, associated autoimmune diseases or outcome (complete, partial, or no resolution) in either group of patients. Pathologists should be aware that some histologic features normally associated with IBD such as crypt irregularity and neutrophilic cryptitis and crypt abscesses are not uncommon in patients with CC or LC and that the presence of one or more of these features should not necessarily be interpreted as evidence against either of these diagnoses.
The Terminal Ileum Is Affected in Patients With Lymphocytic or Collagenous Colitis Heidi Sapp, M.D., F.R.C.P.C.; Sarathehandra Ithamukkala, M.D.; Tom P. Brien, M.D.; Gamze Ayata, M.D.; Beth Shaz, M.D.; David M. Dorfman, M.D., Ph.D.; Helen H. Wang, M.D., Dr.Ph.; Donald A. Antonioli, M.D.; Francis A. Farraye, M.D., M.Sc.; Robert D. Odze, M.D., F.R.C.P.C.	Am J Surg Pathol 2002; 26(11):1484-1492 Abstract quote Lymphocytic colitis (LC) and collagenous colitis (CC) are diseases characterized by the presence of marked intraepithelial lymphocytosis. Both of these disorders affect primarily the colon. However, involvement of the distal small intestine has not been systematically studied. The purpose of this study was to evaluate the type and degree of intraepithelial lymphocytosis in the terminal ileum of patients with LC or CC. Terminal ileal mucosal biopsies from 22 patients with LC (male/female ratio 0.22, mean age 47 years) and 23 with CC (male/female ratio 0.43, mean age 54 years) were evaluated for the number of intraepithelial lymphocytes (IEL) per 100 epithelial cells (EC) both in the villi and crypts. The results were compared with 30 patients with inflammatory bowel disease (16 with Crohn's disease [CD], 14 with ulcerative colitis [UC]) and 24 patients (male/female ratio 0.33, mean age 44 years) without colonic pathology as normal controls. None of the patients had celiac sprue. Paired terminal ileum and colonic mucosal biopsies from 6 patients with LC, 4 with CC, 5 with CD, 5 with UC, and 10 normal controls were also immunohistochemically stained with monoclonal antibodies to CD3, CD8, CD20, and a class II MHC antigen (LN3-HLA-DR). In the villi the IEL count/100 EC was 11.8 ± 1.8 in LC and 10.3 ± 1.9 in CC (p = 0.3). These values were both significantly higher than in CD (2.8 ± 0.4, p <0.001), UC (3.1 ± 0.4, p <0.001), or normal controls (2.2 ± 0.2, p <0.001). In the crypts the IEL count was 3.8 ± 0.5 in LC and 3.2 ± 0.5 in CC (p = 0.3). These values were also significantly higher than in CD (2.3 ± 0.4, p = 0.02), UC (2.1 ± 0.3, p = 0.02), or normal controls (1.5 ± 0.2, p <0.001). The presence of >5 IELs/100 EC in terminal ileum biopsies was highly specific for LC and CC (specificity 98%, sensitivity 73% and 56% for LC and CC, respectively). The IEL phenotype was similar in all groups of patients and in the ileum and colon of individual patients. Intraepithelial lymphocytes were CD3+, CD8+, CD20-, and LN3-HLA-DR-, indicative of a suppressor T-cell phenotype. Intraepithelial lymphocytosis occurs in the terminal ileum in patients with LC or CC and may be helpful in diagnosing these conditions and distinguishing LC or CC from CD or UC in diagnostically difficult cases. The results suggest that the terminal ileum may be involved by a similar pathogenic process as the colon in LC and CC.
VARIANTS
BRAINERD DIARRHEA
Colonic epithelial lymphocytosis associated with an epidemic of chronic diarrhea. Bryant DA, Mintz ED, Puhr ND, Griffin PM, Petras RE. Department of Anatomic Pathology, Cleveland Clinic Foundation, OH 44195, USA.	Am J Surg Pathol 1996 Sep;20(9):1102-9 Abstract quote The term Brainerd diarrhea has been applied to outbreaks of chronic watery diarrhea of unknown etiology characterized by acute onset and prolonged duration. Our aim was to describe the histologic changes in gastrointestinal biopsy specimens from patients with Brainerd diarrhea. We examined 52 colonic and 12 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. Small bowel biopsy specimens from seven patients were histologically normal. One patient had a duodenal biopsy specimen that resembled celiac sprue. Colonic biopsy specimens from 20 patients revealed surface epithelial lymphocytosis without distortion of mucosal architecture, surface degenerative changes, or thickened subepithelial collagen plates. The degree of surface epithelial lymphocytosis was greater than that seen in control groups of persons with normal colons, acute colitis, and ulcerative colitis (p < 0.001), similar to that seen with collagenous colitis, and less than that seen with lymphocytic colitis (p < 0.001). Three patients showed focal active colitis similar to that described in acute infectious-type colitis in addition to the epithelial lymphocytosis. Two patients had colonic biopsy specimens that were histologically normal. In summary, histologic abnormalities in the small bowel are generally absent in Brainerd diarrhea. Colonic biopsy specimens in Brainerd diarrhea frequently show epithelial lymphocytosis similar to that seen in collagenous and lymphocytic colitis. Although currently Brainerd diarrhea can be diagnosed only with epidemiologic data indicating an epidemic and a point source, the lack of surface degenerative changes and the relatively lower lymphocyte counts seen in our cases of Brainerd diarrhea may serve to distinguish it from lymphocytic colitis, and the lack of a thickened subepithelial collagen plate distinguishes it from collagenous colitis.
LYMPHOCYTIC VENULITIS
Lymphocytic venulitis: an unusual association with microscopic colitis. Arora DS, Mahmood T, Wyatt JI. Department of Histopathology, St James's University Hospital, Leeds, UK.	J Clin Pathol 1999 Apr;52(4):303-4 Abstract quote A 79 year old man presented with occult gastrointestinal bleeds and anaemia for two years. He had received 40 units of blood over a period of one year, following which he had a subtotal colectomy as no definite cause of the bleeding was apparent. Macroscopically the colon appeared unremarkable. Light microscopy showed prominent lymphocytic venulitis in the proximal portion, gradually merging into lymphocytic and collagenous colitis distally.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
COLLAGENOUS COLITIS
Lymphocytic colitis: a distinct clinical entity? A clinicopathological confrontation of lymphocytic and collagenous colitis. Baert F, Wouters K, D'Haens G, Hoang P, Naegels S, D'Heygere F, Holvoet J, Louis E, Devos M, Geboes K. Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.	Gut 1999 Sep;45(3):375-81 Abstract quote BACKGROUND AND AIMS: It is not known whether lymphocytic colitis and collagenous colitis represent different clinical entities or constitute part of a spectrum of disease. METHODS: Detailed clinical features and histological findings were compared in a large series of patients with confirmed lymphocytic and collagenous colitis. RESULTS: Histological diagnosis was confirmed in 96 patients with collagenous colitis and 80 with lymphocytic colitis. Twenty eight per cent of patients with collagenous colitis and 26% of patients with lymphocytic colitis had overlapping but less pronounced histological features. Both groups were equal in terms of age, use of aspirin and non-steroidal anti-inflammatory drugs, associated autoimmune conditions, arthritis, diarrhoea, and abdominal pain. The male:female ratio was 27:73 for collagenous colitis and 45:55 for lymphocytic colitis (p=0.013). Twenty five per cent of patients with collagenous colitis compared with 14% of patients with lymphocytic colitis were active smokers; only 8.3% of patients with collagenous colitis had stopped smoking compared with 23% of patients with lymphocytic colitis (p=0.013). Drug induced disease was suspected for ticlopidine (two collagenous colitis, four lymphocytic colitis) and flutamide (four lymphocytic colitis). Mean duration of symptoms before diagnosis was two months for lymphocytic colitis and four months for collagenous colitis. Overall prognosis was generally mild; 84% of patients with lymphocytic colitis and 74% of patients with collagenous colitis reported resolution or significant improvement (p=0.033). CONCLUSIONS: Collagenous and lymphocytic colitis are similar but not identical. Patients with lymphocytic colitis present somewhat earlier and are less likely to be active smokers. Symptoms are milder and more likely to disappear in lymphocytic colitis. Ticlopidine and flutamide should be added to the list of drugs inducing colitis.
SPRUE
Colonic lymphocytosis in patients with celiac sprue. Wolber R, Owen D, Freeman H. Division of Anatomic Pathology, University of British Columbia Hospitals, Vancouver, Canada.	Hum Pathol 1990 Nov;21(11):1092-6 Abstract quote We examined colonic biopsies from 39 patients with clinical and small bowel biopsy changes of celiac sprue. In 12 of 39 patients (31%), striking lymphocytic infiltration of the superficial colonic epithelium and chronic inflammation of the lamina propria were identified. These 12 cases had a mean of 30.4 lymphocytes per 100 superficial colonic epithelial cells, compared with means of 8.4 in sprue cases without colonic epithelial lymphocytosis, 4.8 in normal controls, and 32.4 in nine cases of lymphocytic colitis without concurrent celiac sprue. No case showed subepithelial collagen layer thickening. Four patients with celiac sprue and colonic lymphocytosis also had gastric biopsies; two showed gastric lymphocytosis. Intraepithelial lymphocytes at all sites were positive for the T-cell marker MT-1. These findings indicate that sprue-associated colonic lymphocytosis and lymphocytic colitis are histologically, quantitatively, and immunohistochemically indistinguishable, that the epithelial T-cell infiltration of celiac sprue occurs in glandular mucosa at all levels of the gastrointestinal tract, and that colonic subepithelial collagen deposition in patients with celiac sprue is an infrequent occurrence. These findings also suggest that gastrointestinal epithelial T-cell infiltration may be an immunologic response that is common in individuals sensitized to absorbed lumenal antigens, and that colonic lymphocytosis may occur as a response to a number of antigens, including gluten.
Colonic histopathology in untreated celiac sprue or refractory sprue: is it lymphocytic colitis or colonic lymphocytosis? Fine KD, Lee EL, Meyer RL. Department of Pathology, Baylor University Medical Center, Dallas, TX 75246, USA.	Hum Pathol 1998 Dec;29(12):1433-40 Abstract quote Colonic histopathology in some patients with untreated celiac sprue and refractory sprue has been said to be indistinguishable from lymphocytic colitis, but there have been no objective comparisons on which this is based. The purpose of this study was to determine the prevalence and to characterize the nature of colonic histopathology at the time of diagnosis in patients with celiac or refractory sprue. Colonoscopic biopsy specimens obtained at the time of diagnosis from 16 patients with celiac sprue, six patients with refractory sprue, nine patients with lymphocytic colitis, and five normal controls were analyzed blindly by histological and morphometric methods, quantitating the number and specific subtypes of inflammatory cells within the lamina propria and epithelium. Immunoperoxidase staining of intraepithelial lymphocytes with a monoclonal antibody to CD8 also was performed. Three of 16 patients with untreated celiac sprue (19%) were thought to have colonic histological abnormalities, which by morphometry consisted of slightly increased numbers of lymphocytes in the surface epithelium and lamina propria, many of which were CD8-positive. These abnormalities were distinguishable from lymphocytic colitis by the lack of increased overall lamina propria cellularity and surface epithelial abnormalities, and by fewer intraepithelial lymphocytes. In refractory sprue, colonic histological abnormalities were more frequent than in celiac sprue, occurring in four of six patients (67%), more pronounced, and identical to those in the lymphocytic colitis syndrome. However, colonic intraepithelial lymphocytes in lymphocytic colitis were mostly CD8-positive, whereas those in the colitis of refractory sprue rarely were. Mild colonic lymphocytosis in patients with untreated celiac sprue should be distinguished from lymphocytic colitis by the lack of surface epithelial abnormalities, the lack of increased cellularity of the lamina propria, and the lack of ongoing watery diarrhea after treatment with a gluten-free diet. In contrast, colonic histopathology in refractory sprue is indistinguishable from lymphocytic colitis, although immunohistochemical differences do exist.

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Microscopic colitis
INCIDENCE
Incidence of collagenous and lymphocytic colitis: a 5-year population-based study. Fernandez-Banares F, Salas A, Forne M, Esteve M, Espinos J, Viver JM. Department of Gastroenterology, Hospital Universitari Mutua de Terrassa, Barcelona, Catalonia, Spain.	Am J Gastroenterol 1999 Feb;94(2):418-23 Abstract quote OBJECTIVE: The incidence of collagenous and lymphocytic colitis is not well known. We sought to assess the incidence of collagenous and lymphocytic colitis in a well-defined population during a 5-yr study period. METHODS: From January 1, 1993, to December 31, 1997, all new patients diagnosed with collagenous or lymphocytic colitis living in the catchment area of the Hospital Mutua de Terrassa (Barcelona, Spain) were identified. Since 1993 all patients with chronic diarrhea were referred for a diagnostic colonoscopy. Multiple biopsy sampling of the entire colon was performed when appearance of the colonic mucosa was grossly normal. RESULTS: Twenty-three cases of collagenous colitis and 37 of lymphocytic colitis were diagnosed. The female:male ratios were 4.75:1 and 2.7:1 for collagenous and lymphocytic colitis, respectively. The mean age at onset of symptoms was 53.4+/-3.2 (range, 29-82) yr for collagenous colitis, and 64.3+/-2.7 (range, 28-87) yr for lymphocytic colitis (p = 0.012). The mean annual incidence per 100,000 inhabitants based on the year of onset of symptoms was 1.1 (95% confidence interval [CI], 0.4-1.7) for collagenous colitis, and 3.1 (95% CI, 2.0-4.2) for lymphocytic colitis. A peak incidence was observed in older women in both diseases. A rate of microscopic colitis of 9.5 per 100 normal-looking colonoscopies performed in patients with chronic watery diarrhea was observed. Normal rectal biopsies were found in 43 % and 8% of patients with collagenous and lymphocytic colitis, respectively. CONCLUSIONS: The incidence of lymphocytic colitis is three times higher than that of collagenous colitis. Microscopic colitis should be considered as a major possibility in the work-up of chronic diarrhea in older women.

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
FECAL LEUKOCYTES
Collagenous colitis: mucosal biopsies and association with fecal leukocytes. Zins BJ, Tremaine WJ, Carpenter HA. Division of Gastroenterology, Mayo Clinic Rochester, MN 55905, USA.	Mayo Clin Proc 1995 May;70(5):430-3 Abstract quote OBJECTIVE: To determine the frequency of patchy colonic involvement, fecal leukocytosis, and association with celiac sprue in a large cohort of patients with collagenous colitis. DESIGN: We conducted a retrospective review of the medical records of 172 consecutive Mayo Clinic patients in whom collagenous colitis had been diagnosed between 1982 and 1993. METHODS: For each of the 172 patients, the medical record was reviewed to determine the frequency of (1) fecal leukocytosis; (2) characteristic histologic findings in the rectum and the sigmoid, descending, and ascending colon; and (3) small bowel biopsy findings consistent with celiac sprue. RESULTS: The presence of fecal leukocytes was noted in 64 of 116 patients (55%) who had undergone assessment for fecal leukocytosis. On analysis of histologic findings, 113 of 123 rectal, 116 of 121 sigmoid, and 68 of 70 descending colon biopsy specimens were diagnostic of collagenous colitis. Small bowel biopsies were performed in 45 patients who did not have a history of small intestinal disease: 1 had celiac sprue and 44 had normal findings. Two other patients had previously diagnosed celiac sprue. CONCLUSION: The finding of fecal leukocytes in 55% of patients with collagenous colitis confirms the inflammatory basis of this disease. Biopsy specimens obtained by flexible sigmoidoscopy seem sufficient to establish the diagnosis in most patients, and colonoscopic biopsy of the more proximal area of the colon is usually unnecessary. Celiac sprue infrequently accompanies collagenous colitis; thus, routine small bowel biopsy is not warranted.
P-ANCA
Perinuclear antineutrophil cytoplasmic antibodies in collagenous or lymphocytic colitis with or without celiac disease. Freeman HJ. Department of Medicine (Gastroenterology), University of British Columbia, Vancouver.	Can J Gastroenterol 1997 Jul-Aug;11(5):417-20 Abstract quote Microscopic forms of colitis, including lymphocytic and collagenous colitis, have been observed in both those with and without celiac disease. Although perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) occur in most patients with ulcerative colitis, investigations in microscopic, particularly lymphocytic, colitis are still needed. In this study atypical p-ANCA was evaluated in 55 patients, including 27 with celiac disease alone, 13 with celiac disease and concomitant lymphocytic colitis, and 15 with microscopic forms of colitis, including lymphocytic and collagenous colitis. Nine patients (16.3%) had atypical p-ANCA, including six with celiac disease and three with a microscopic form of colitis alone. Although five of the six positive celiac disease patients had lymphocytic colitis, all three celiac disease patients with associated primary sclerosing cholangitis--a separate risk factor for a positive assay result--were serologically positive for atypical p-ANCA. These results indicate for the first time that this serological marker may occur in histologically defined celiac disease with or without concomitant lymphocytic colitis. Furthermore, these results suggest that the pathogenesis of ulcerative colitis differs from that of lymphocytic colitis and further emphasizes the heterogeneous nature of these newly recognized types of colonic inflammatory mucosal disorders.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
COLLAGENOUS COLITIS
Microscopic colitis progressed to collagenous colitis: a morphometric study. Perri F, Annese V, Pastore M, Andriulli A. Divisione di Gastroenterologia, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo (FG), Italy.	Ital J Gastroenterol 1996 Apr;28(3):147-51 Abstract quote Microscopic (also called lymphocytic) colitis and collagenous colitis are two newly recognised clinicopathologic entities of unknown aetiology presenting with chronic watery diarrhoea. In both conditions, the colon appears normal by barium enema and colonoscopy, however, colonic biopsies reveal infiltration of plasma cells and neutrophils within the lamina propria and increased intraepithelial lymphocytes within the surface epithelium. Lack of a thickened collagen band beneath the surface epithelium histologically differentiates microscopic from collagenous colitis. The exact relationship between the two disorders is as yet unknown. The two entities may be variants of the same spectrum of disease or distinct conditions with and without collagen table thickening. The present case report shows progression of microscopic colitis to collagenous colitis in sequential colonic biopsies taken from a patient during a 7-year endoscopic follow-up suggesting that progression of microscopic to collagenous colitis is a possibility and the two diseases are likely to represent variants of the same condition.