Microscopic Colitis In Patients With Chronic Diarrhea And Normal Colonoscopic Findings In Southern China

BackgroundMicroscopic colitis (MC), comprising lymphocytic colitis (LC) and collagenous colitis (CC), is a syndrome with chronic diarrhea, normal-looking colonic mucosa at endoscopy and specific histological findings. The common histological abnormalities are characterized by intraepithelial lymphocytosis, infiltration of the lamina propria with inflammatory cells, and in CC, thickening of the subepithelial collagen band. The pathogenesis remains unknown and is often associated with autoimmune disorders, inflammatory disorders, or medication. The annual incidence of MC has been reported increasing over time. However, most epidemiologic data of MC came from European and North American studies, and limited studies on MC were reported in Asia. Microscopic colitis typically occurs in most patients during the fifth to seventh decades of life and CC is more common in female. The main symptoms are chronic watery non-bloody diarrhea, sometimes accompanied by abdominal pain and nocturnal stools, usually without dehydration or weight loss. Microscopic colitis accounted for 9.5%-14% of patients with chronic diarrhea and normal colonoscopy finding, and the quality of life is often affected. The diagnosis of MC depends on clinical symptom, endoscopy and histology of multiple colorectal biopsies. A retrospective analysis in the United Kingdom indicated that CC might be missed or misdiagnosed in up to 83% of cases and LC in up to 97%. MC may be misdiagnosed to diarrhea-predominant irritable bowel syndrome (IBS) and functional diarrhea (FD) because of the similar symptoms of diarrhea and abdominal pain. A population-based cohort study indicated that about 50% of patients with MC met the diagnosis of IBS. Since the treatment strategy of the patients with MC and IBS is different, the former with a good response to corticosteroid, the differential diagnosis of the both disorders is indispensable. Therefore, many studies proposed that patients with suspected IBS should undergo colonoscopy and mucosa biopsies to find possible MC if symptoms are not controlled by anti-diarrhea therapy.China has the largest population in the world and there are a large number of patients with functional gastrointestinal disorders (FGID). The adjusted prevalence of IBS is 5.67% in China according to the RomeⅡcriteria. However, little research on MC has been reported in China. Not positively performing colonic mucosal biopsies in patients with chronic diarrhea and negative colonoscopy may be an important reason. Many gastrointestinal clinicians and pathologists in China have not enough knowledge of the diagnosis of MC, and biopsies of colonic mucosa are not usually a subsequent work given to patients with chronic diarrhea if a colonoscopy finding is normal.ObjectivesThis study aimed to determine the prevalence of microscopic colitis in patients with chronic diarrhea and normal colonoscopy findings in Southern China, and to reveal the overlap of the diagnosis between microscopic colitis and irritable bowel syndrome or functional diarrhea in these patients. Methods1. The value of colonoscopy in patients with chronic diarrheaColonoscopy of 2449 patients with chronic diarrhea from January,1999 to December,2008 was reviewed. Two thousand one hundred and ten patients who underwent colonoscopy screening for health care in the same period were used as controls. The prevalence of different colonic organic lesions was compared between two groups and the prevalence of the colonic mucosa biopsy in two groups was also revealed.2. The value of colonoscopy in patients with suspected irritable bowel syndrome and lacking warning signsColonoscopy of 3332 patients with suspected irritable bowel syndrome and lacking warning signs from 2000 to 2009 were reviewed.1588 patients under 50 years of age who underwent colonoscopy screening for health care in the same period were used as controls. The prevalence of different colonic organic lesions was compared between two groups.3. Screening microscopic colitis in patients with chronic diarrhea and normal colonoscopic findings in Southern ChinaThis prospective study was conducted at three hospitals in Guangdong province, China (Nanfang hospital, Southern Medical University; Tungwah Hospital; Dong Guan People's hospital) from January,2009 to June,2010. Among the outpatients who underwent colonoscopy, cases with chronic diarrhea and normal colonoscopy finding were enrolled in this research. All the patients enrolled in the study underwent colonoscopy through the total colon by experienced endoscopists (having completed more than 1000 case of colonoscopy). Two biopsies were obtained randomly from each ascending, transverse, descending and sigmoid colons of all patients, and the specimens from different sites of colon were placed in a bottle with 10% buffered formalin for each case. Paraffin sections were stained with hematoxyin and eosin (H & E), Masson's trichrome and immunohistochemistry for tenascin expression, and were reviewed with routine microscope. Histological slides stained with H & E were also reviewed with fluorescence microscope. The additional methods including Masson's trichrome, immunostaining and fluorescence microscopy were used to look for the presence of a thickened subepithelial collagen. The histological review was carried out by an expert gastrointestinal pathologist to confirm the diagnosis.4. Clinical and pathological features of microscopic colitisEighty-seven patients with microscopic colitis screened (59 patients with LC and 28 patients with CC) were enrolled and ninety chronic diarrhea patients with normal colonoscopic and histological finding were used as controls. The demographic, clinical symptom and the prognosis of the patients were analyzed to reveal the clinical and pathological features and risk factor of microscopic colitis. The number of the patients meeting Rome III criteria of IBS and FD were recorded.Results1. The value of colonoscopy in patients with chronic diarrheaDuring the mentioned period, a total of 40,578 patients performed colonoscopy and 2,449 patients with chronic diarrhea were enrolled in this study. The chronic diarrhea group was younger than controls, mean age 41.6 (9-86) vs.46.6 (7-84), P<0.001. There was no significant difference on the gender ratio between two groups,37.4% vs.35.0% female, P<0.001.Organic colonic lesions were found in 44.1% of patients with chronic diarrhea (1,080/2,449) and 41.7% of controls (870/2,110). No significant difference was found between two groups on the abnormality colonoscopic finding,χ2=2.756, P=0.097).The five most common organic diseases in chronic diarrhea group were non-IBD and noninfectious colitis (14.6%), non-adenomatous polyps (9.5%), adenomatous polyps (8.0%), IBD (5.3%), malignant tumor (3.8%). And the five most common organic diseases in control group were non-adenomatous polyps (15.2%), adenomatous polyps(11.3%), non-IBD and noninfectious colitis(7.4%), diverticular disease (4.4%) and terminal ileitis (1.9%). Compared with controls, patients with chronic diarrhea had higher prevalence of non-IBD and noninfectious colitis (χ2=58.578, P<0.001), IBD (χ2=59.609, P<0.001), malignant tumor (χ2=21.649, P<0.001), terminal ileitis (χ2=6.275, P=0.012), infectious colitis (χ2=17.019, P<0.001), intestinal tuberculosis(χ2=7.021, P=0.008), melanosis coli (χ2=6.040, P=0.014) and parasitic infection (χ2=4.245, P=0.039), however, had lower prevalence of adenomatous polyps (χ2=14.124, P<0.001), non-adenomatous polyps (χ2=33.427,P<0.001) and diverticular disease (χ2=9.921, P=0.002).There was no significant difference on the benign tumor (χ2=1.627,P=0.202) and angiodysplasia(χ2=0.231,P=0.631)on the colonoscopic finding between two groups. The prevalence of the colonic mucosa biopsy was 24.5%(601/2449) in chronic diarrhea group and 21.2%(446/2110) in control group.The rate of biopsy for patients with chronic diarrhea and normal colonscopy finding was 0.2%(3/1369)2. The value of colonoscopy in patients with suspected irritable bowel syndrome and lacking warning signsDuring the mentioned period, total of 4050 patients performed colonoscopy due to suspected IBS and 3332 patients without warning signs were enrolled in this study. The demographic and clinical features of suspected IBS group and control group were listed in table 1. The suspected IBS group was younger and had lower male patients than controls (mean age 34.1±7.8 vs.38.4±7.3, P<0.001,53.7% vs.67.0% male, P<0.001, respectively). IBS with diarrhea was the prominent subgroup in the suspected IBS group and accounted for 72.5%.The colonoscopy finding of patients with suspected IBS and controls were listed in Table 2. Organic colonic lesions were found in 30.3% of suspected IBS patients (1010/3332). The five most common organic diseases were IBD (6.9%), non-adenomatous polyps (6.7%), non-IBD and non-infectious colitis (5.7%), terminal ileitis (4.3%), and adenomatous polyps (2.5%). The total colonic lesions rate of controls was 39.0%, which was higher than that of suspected IBS patients (χ2= 36.141,P<0.001). The five most common organic diseases in controls group were non-adenomatous polyps (14.7%), adenomatous polyps (6.7%), IBD (6.1%), diverticular disease (3.6%) and terminal ileitis (2.2%). Compared with controls, patients with suspected IBS had higher prevalence of non-IBD and non-infectious colitis (χ2= 63.371, P<0.001) and terminal ileitis (χ2= 13.757, P<0.001), however, had lower prevalence of diverticular disease (χ2=8.596, P<0.05, adenomatous polyps (χ2=49.986, P<0.001) and non-adenomatous polyps (χ2= 81.437,P<0.001).There was no difference in the prevalence of IBD, malignant tumor, benign tumor, parasistic infection, infectious colitis, angiodysplasia and intestinal tuberculosis between suspected IBS group and control group. Colorectal cancer was the main malignant disease in both groups. There were seven and six colorectal adenocarcinoma found in suspected IBS group and control group. A patient with lymphoma was found in control group. No carcinoid was found in both groups.3. Screening microscopic colitis in patients with chronic diarrhea and normal colonoscopic findings in Southern ChinaDuring the study period,841 patients with complaint of chronic diarrhea underwent full colonoscopy with terminal ileal visualization. Of these patients,631 had normal or near normal finding at colonoscopy and were enrolled in this study. Three hundred and seventy patients were females, and 243 males. Mean age was 39.7 years with rang of 15-84 years. One hundred and four patients met irritable bowel disease (IBS) and 157 met functional diarrhea (FD) according to RomeⅢcriteria. Normal colonoscopic findings were found in 515 patients and near normal colonoscopic findings were found in 98 patients.Randomly mucosal biopsies were performed in 613 patients with negative colonoscopic findings. In 453 cases the histology was entirely normal. There were 87 cases of microscopic colitis (14.2%),64 cases of microscopic colitis NOS (10.4%) and 9 cases with a significant mucosal eosinophils infiltrate (1.5%). Among 87 cases of microscopic colitis,59 patients were found with lymphocytic colitis (LC) and 28 patients were found with collagenous colitis (CC). Eighteen cases of CC were detected by using the routine test Masson's trichrome, and each 25 cases of CC were found with the use of fluorescence microscopy and immunohistochemical detection of tenascin.4. Clinical and pathological features of microscopic colitisThe mean ages of patients with CC, LC and controls were 42.3 years,37.4 years, and 41.0 years, respectively. There was no significant difference on the composition of different ages among three groups with Pearson Chi-Square test. The male to female ratio of LC group and the CC group was 1.8:1 and 1.5:1, respectively and there was no significant difference with Pearson Chi-Square test,χ2=0.326, P=0.850.There was no significant difference among three groups with Chi-Square test on the factors as below:history of smoking (χ2=5.055, P=0.080), NSAID intake (χ2=1.598, P=0.450), PPI intake (χ2=0.984, P=0.321), with Diabetes mellitus (χ2=0.209, P=0.647). However, there was significant difference among three groups on history of rheumatoid arthritis,χ2=7.641, P=0.022. The ratios of rheumatoid arthritis in LC group (15.4%) and CC group (14.3%) were higher than in control group (2.2%). Rheumatoid arthritis was the possible risk factors of microscopic colitis.There was no significant in the colonoscopic finding among LC group, CC group and control group,χ2=3.141, P=0.208. The most common lesion was polyps (9.2%).The average frequency of bowel movements in LC group and the CC group was 4.2/day and 4.5/day, respectively, and the median duration of illness was 12 and 4 months.Most common symptoms accompanied were abdomen pain (28.7%) and distention(11.5%).There were 13.8% of patients with MC fulfilled RomeⅢcriteria of IBS and 42.5% fulfilled the criteria of FD. In total,46.3% of patients with MC fulfilled the criteria of functional gastrointestinal disorders.Among 87 cases with microscopic colitis,71 accetpted a telephone follow-up one year after the diagnosis.16 lost. In 71 patients who received follow-up,54 was confirmed with complete remission,6 patients with symptomatic partial remission, and 11 patients with symptoms not relieved. The rate of natural symptomatic remission in MC was 76.1%.ConclusionsOrganic colonic lesions were found in 44.1% of the patients with chronic diarrhea. Colonic polyps, diverticulitis, benign tumors and angiodysplasia may not be the cause of chronic diarrhea. The rate of biopsy for patients with chronic diarrhea and normal colonscopy finding was low and merely 0.2%.The diagnostic sensitivity of symptom criteria on irritable bowel syndrome without colonoscopy is not more than 69.7% in patients with suspected irritable bowel syndrome lacking warning signs. Though the method of colonoscopy is hard to screen tumor in this type of patients, it is beneficial to uncover some other relevant organic lesions such as terminal ileitis. Colonoscopy should not be refused to suspected irritable bowel syndrome patients without warning signs.MC is not an uncommon disorder in Chinese population. There were 14.2% of patients were confirmed with MC in patients with chronic diarrhea and negative colonoscopic findings. It is reasonable to obtain multiple biopsies in patients with chronic diarrhea when the mucosa grossly normal at colonoscopy.Microscopic colitis has a symptomatic overlap with IBS and FD. The clinical symptom-based criteria for the diagnosis of functional gastrointestinal disorders are not specific enough to rule out MC.