Increased HLA A1 and diminished HLA A3 in lymphocytic colitis compared to controls and patients with collagenous colitis

Lymphocytic colitis is a newly described chronic diarrheal disorder. Although its etiology is unknown, the possibility has been raised that autoimmunity may play a role in both lymphocytic and collagenous colitis, a similar clinicopathologic illness. The frequencies of HLA class I and class II antigens were examined in 24 white patients with lymphocytic colitis and in 47 white patients with collagenous colitis. Frequencies in these two disorders were compared to control white populations and to each other. An increased frequency of HLA-A1 was noted in 16 of 24 lymphocytic colitis patients (66.6%) compared with 1089 of 3942 controls (27.6%) (P<0.005; relative risk 5.2). Furthermore, HLA-A3 was found in decreased frequency in lymphocytic colitis patients: 0 of 24 (0%) compared with 1017 of 3942 controls (25.8%) (P<0.05; relative risk 0.0). Collagenous colitis patients had no significant deviation from control frequencies of HLA antigens. In lymphocytic colitis, there was no significant increase in B8 or DR3 antigens, which are found in linkage disequilibrium with A1 and associated with many autoimmune diseases. Moreover, the frequency of autoimmune-associated class I HLA antigens was not increased in lymphocytic colitis. Statistically significant differences existed between lymphocytic and collagenous colitis in HLA-A1, A3, Bw6, and B7 antigen frequencies. The HLA patterns noted previously in other gastrointestinal disorders, including ulcerative colitis and Crohn's disease, were not apparent in lymphocytic or collagenous colitis. HLA typing provides further evidence that lymphocytic colitis is a distinct form of chronic intestinal inflammatory disease associated with HLA class I phenotypes.Presented in part at the American Gastroenterological Association in May 1988 and published with preliminary data in a previous article (reference 1).Supported in part by The National Foundation for Ileitis and Colitis, by an institutional grant from The Johns Hopkins School of Medicine, and by outpatient GCRC grant RR00722.     

嗜酸性粒细胞在溃疡性结肠炎患者中的临床及病理学意义

目的:探讨嗜酸性粒细胞(EG)与评判溃疡性结肠(UC)病情的其他指标的一致性,病理组织学特征与EG的关系.方法:选取2007-11/2008-12就诊于湘雅二医院并诊断为UC患者45例,将患者分为:活动组(n=45)与好转组(n=39,在治疗6wk到最后1d,经DAI、EAI组织病理学评分,完全缓解和部分缓解的患者).采用CAI积分、EAI积分及组织病理学积分评价疾病活动度,并进行EG计数.结果:UC患者结肠黏膜组织中的炎症细胞浸润以中性粒细胞、淋巴细胞、浆细胞以及EG为主,活动组较好转组为重.固有层小血管病变和腺体病变以及隐窝脓肿的出现均以活动组为重.间质改变好转组较多.EG计数与中性粒细胞计数在好转组呈负相关(r=0.568,P=0.001).EG浸润的出现在活动组与淋巴组织增生、淋巴滤泡形成呈正相关(r=0.755,0.524,均P<0.01),与灶性出血呈负相关(r=.0.385,P=0.010).而好转组患者中,仅有杯状细胞消失与EG浸润呈正相关(r=0.349,P=0.046).结论:EG可能为判断UC活动或好转的指标.     

Increased arachidonic acid composition of phospholipids in colonic mucosa from patients with active ulcerative colitis.

The long chain fatty acid composition of phospholipids in colonic mucosa was determined by high performance liquid chromatography in nine patients with active ulcerative colitis and eight healthy controls. The arachidonic acid composition was 12.5 +/- 1.4 mol % (mean +/- 2 SEM) in the inflamed colonic mucosa from the patients with active ulcerative colitis and 6.8 +/- 1.2 mol % in the intact mucosa from healthy controls (p less than 0.001). In the inflamed colonic mucosa, oleic acid and palmitoleic acid were concomitantly decreased (p less than 0.001 and p less than 0.02, respectively), while docosahexaenoic acid was increased (p less than 0.05). Histopathological examination showed that there was a three fold increase in the cell density of inflammatory infiltrate in the lamina propria of the inflamed colonic mucosa (p less than 0.001). The cell density of inflammatory infiltrate correlated with the arachidonic acid composition of phospholipids in colonic mucosa (r = 0.89, p less than 0.005). These findings indicate that inflammation alters the long chain fatty acid composition of phospholipids in colonic mucosa. The observed increase in the arachidonic acid composition of phospholipids in inflamed colonic mucosa may contribute to the enhanced arachidonic acid metabolism in patients with active ulcerative colitis.     

Subepithelial collagen table thickness in colon specimens from patients with microscopic colitis and collagenous colitis.

Microscopic colitis and collagenous colitis are similar conditions that are differentiated by the presence or absence of subepithelial collagen table thickening. To better understand the relationship between these two disorders and the role of collagen table thickening in the pathogenesis of diarrhea, colonic mucosal biopsy specimens from 24 patients with microscopic or collagenous colitis and 9 control subjects were analyzed using a computer-assisted morphometric method to evaluate the average thickness of the subepithelial collagen table. The collagen table thickness in colitis patients taken together formed a multimodal rather than a unimodal distribution. There was no tendency for collagen table thickening to increase with age or with duration of symptoms. In general, the types and distribution of inflammatory cells were similar in patients with normal and thickened collagen tables. Stool weight correlated with lamina propria cellularity but not with collagen table thickening. The multimodal distribution of collagen table thickening and the lack of correlation with age, duration of symptoms, or inflammation suggest that microscopic colitis and collagenous colitis are discrete conditions, although the inflammatory changes in the two conditions are similar. Moreover, because stool weight correlates with lamina propria cellularity but not with collagen table thickening, diarrhea probably is caused by the inflammatory changes and not by collagen table thickening per se.     

Fractured colon: an endoscopically distinctive lesion associated with colonic perforation following colonoscopy in patients with collagenous colitis

BACKGROUND: Collagenous colitis is characterized by collagen deposition in the superficial colonic mucosa, beneath the surface epithelium, resulting in chronic nonbloody diarrhea of variable severity. The mucosa generally appears endoscopically normal. METHODS: We report the occurrence of distinctive linear mucosal tears, unassociated with trauma, in 4 patients during diagnostic colonoscopy. The patients' tissue specimens were examined histologically, and clinical courses were recorded. OBSERVATIONS: Recognition of linear "fractures" was followed in 3 patients by colonic perforation. One patient required colectomy. Severe collagenous colitis was present in all. The resection specimen contained shallow linear ulcers overlying fibrotic submucosa, with pneumatosis and acute peritonitis. CONCLUSIONS: We theorize that the stiffness of the colon in areas of collagenous colitis with submucosal fibrosis makes it susceptible to linear "fractures" during colonoscopic air insufflation with subsequent transmural air dissection. We urge extreme caution if this lesion is recognized at colonoscopy and recommend aborting the examination and obtaining plain radiographs to detect free intraperitoneal air.     

In vitro mucus glycoprotein production by colonic tissue from patients with ulcerative colitis.

Colonic mucus production was measured in vitro by means of incorporation of tritiated glucosamine using biopsy material from patients with ulcerative colitis and compared with data from patients with Crohn's disease, colonic carcinoma, colonic polyps and patients with apparently normal colonic mucosae. Mucus production was significantly decreased (p less than 0.03) in all patients with ulcerative colitis, and in particular in patients with inactive disease when compared with normal subjects. In patients with active disease mucus production was not significantly different from normal subjects. The radiolabelled material was characterised by gel filtration and ion exchange liquid chromatography as mainly high molecular weight glycoproteins. These results indicate that the quantitative character of colonic mucus is abnormal in inactive ulcerative colitis.     

Spontaneous colonic perforation: a rare complication of collagenous colitis

Collagenous colitis is a clinicopathologic syndrome characterized by chronic watery diarrhea and unique histopathologic features. Spontaneous colonic perforation in the setting of collagenous colitis is a highly unusual complication, with only three cases reported in the literature to date. We present a fourth case and propose a potential pathologic mechanism for acute colonic perforation in this patient population.     

Different distribution of mast cells and macrophages in colonic mucosa of patients with collagenous colitis and inflammatory bowel disease

BACKGROUND/AIMS: Chronic inflammatory cells in colonic mucosa is a histopathologic feature in patients with collagenous colitis and inflammatory bowel disease. The aim of this study was to compare the distribution of mast cells and macrophages in the colonic mucosa of patients with collagenous colitis, Crohn's disease, and ulcerative colitis. METHODOLOGY: Patients with histologically confirmed collagenous colitis (n = 13), Crohn's disease (n = 20) or ulcerative colitis (n = 20) and normal control patients (n = 20) were included in this study. Biopsy specimens were obtained from the sigmoid colon of each patient, and immunostained using antibodies to tryptase (AA1) and CD68. The number of mast cells and macrophages located in upper and lower part of the lamina propria was determined. RESULTS: The number of mast cells in the upper part of lamina propria in patients with collagenous colitis (286 +/- 89/mm2, mean +/- SD), Crohn's disease (330 +/- 84/mm2) and ulcerative colitis (355 +/- 90/mm2), was higher than normal controls (201 +/- 44/mm2). The number of mast cells in the lower part of lamina propria in patients with Crohn's disease (345 +/- 87/mm2) and ulcerative colitis (363 +/- 86/mm2) was higher than collagenous colitis (266 +/- 63/mm2) and normal controls (309 +/- 60/mm2). The number of macrophages in the lower part of lamina propria in patients with Crohn's disease (330 +/- 63/mm2) and ulcerative colitis (301 +/- 60/mm2) was higher than in collagenous colitis (247 +/- 46/mm2) and normal controls (242 +/- 52/mm2), although there were no significant differences in the number of macrophages present in the upper part of the lamina propria among the four groups. CONCLUSIONS: Our data showed the presence of a different distribution of mast cells and macrophages in collagenous colitis and inflammatory bowel disease, and these suggest that because mucosal mast cells have been implicated in the development of Th2 response collagenous colitis is more of a Th2 type reaction rather than Th1.     

Detection of inflammatory markers in stools from patients with irritable bowel syndrome and collagenous colitis

OBJECTIVE: Irritable bowel syndrome (IBS) and collagenous colitis (CC) share chronically recurring symptoms of altered bowel habits associated with abdominal pain or discomfort. The aims of the present study were to investigate whether inflammatory markers could be detected in faeces from patients with IBS and CC, and to elucidate whether such analyses could be used as non-invasive tools to distinguish between these disorders. MATERIAL AND METHODS: Stool samples were obtained from 18 patients with CC, 46 patients with IBS and 20 healthy controls (HC). Eosinophil protein X (EPX), myeloperoxidase (MPO), tryptase, interleukin-1 beta (IL-1beta) and tumour necrosis factor alpha (TNFalpha) were measured in supernatants from processed faeces using immunoassays. RESULTS: EPX levels were enhanced in faeces from CC patients (median 3.8 microg/g (0.47-16.2)) compared to patients with IBS (0.44 microg/g (0.25-1.8)), p<0.001, and HC (0.46 microg/g (0.21-1.3)), p<0.001. In addition, MPO was increased in CC patients (11.7 microg/g (2.0-124)) compared to IBS patients (1.7 microg/g (0.81-5.2)), p<0.01, and HC (2.5 microg/g (1.1-6.3)), p<0.05. Tryptase was found in 9/18 patients with CC, 6/46 with IBS and 1/19 HC. IL-1beta was only enhanced in 2/11 CC patients and TNFalpha was not detected in any sample. CONCLUSIONS: Increased levels of EPX, MPO and tryptase were observed in stools from collagenous colitis patients, whereas the levels in IBS patients did not differ from healthy controls. Our data suggest that faecal markers could be used as part of the clinical work-up to determine which patients should be biopsied and evaluated for collagenous colitis.     

Ursodeoxycholic acid inhibits eosinophil degranulation in patients with primary biliary cirrhosis.

Eosinophilia is a distinctive feature of primary biliary cirrhosis (PBC), especially in its early stages. Intriguingly, treatment with ursodeoxycholic acid (UDCA) ameliorates eosinophilia as well as liver tests in patients with PBC. It remains unknown, however, whether eosinophils in PBC patients are functionally activated and whether UDCA inhibits eosinophil activation. In the present study, we systematically examined eosinophil dynamics in the blood and liver in patients with stage I to II PBC before and after UDCA treatment. We determined serum concentrations of eosinophil granule proteins (major basic protein [MBP] and eosinophil-derived neurotoxin [EDN]) by radioimmunoassay and quantitated eosinophil degranulation using computer-assisted morphometry after MBP immunohistochemistry. Before UDCA treatment, patients with PBC (n = 25) showed significantly higher circulating eosinophil counts (P <. 05) and serum concentrations of MBP (P <.0005) and EDN (P <.02) compared with patients with chronic viral hepatitis (n = 22), autoimmune hepatitis (n = 10), and obstructive jaundice (n = 12). Four-week UDCA treatment significantly reduced blood eosinophil counts (P <.0001) and serum MBP (P <.0001) and EDN (P <.0001) levels in PBC patients. MBP immunohistochemistry and computer-assisted quantitative morphometry showed infiltration and degranulation of eosinophils in the portal tract in patients with PBC and significant reductions in the number of sites and the area occupied by extracellular MBP deposits after UDCA treatment for 2 years (P <.02) but not in placebo-treated patients. Our results suggest that eosinophils in patients with PBC are not only increased in number, but also release granule proteins, and that UDCA treatment inhibits this eosinophil activation/degranulation.     

Lymphocytic and collagenous colitis

Opinion statement  

Hydroxycarbamide reduces eosinophil adhesion and degranulation in sickle cell anaemia patients

Inflammation, leucocyte and red cell adhesion to the endothelium contribute to the pathogenesis of sickle cell anaemia. Neutrophils appear to be important for vaso‐occlusion, however, eosinophils may also participate in this phenomenon. The role of eosinophils in the pathophysiology of sickle cell anaemia (SCA) and the effect of hydroxycarbamide (HC) therapy on the functional properties of these cells are not understood. Patients with SCA and those on HC therapy (SCAHC) were included in the study. SCAHC individuals presented significantly lower absolute numbers of eosinophils than SCA. Furthermore, SCAHC eosinophils demonstrated significantly lower adhesive properties, compared to SCA eosinophils. SCA and SCAHC eosinophils presented greater spontaneous migration when compared with control eosinophils. Baseline eosinophil peroxidase and reactive oxygen species release was higher for SCA individuals than for control individuals, as were plasma levels of eosinophil derived neurotoxin. SCAHC eosinophil degranulation was lower than that of SCA eosinophil degranulation. Eotaxin‐1 and RANTES levels were higher in the plasma of SCA and SCAHC individuals, when compared with controls. These data suggest that eosinophils exist in an activated state in SCA and indicate that these cells play a role in the vaso‐occlusive process. The exact mechanism by which HC may alter SCA eosinophil properties is not clear.     

Enteropathic arthritis in association with collagenous colitis

A 46-year-old man simultaneously developed chronic seronegative non destructive oligoarthritis and chronic watery diarrhoea. Biopsies from the colorectal mucosa showed a thickened subepithelial collagen layer consistent with collagenous colitis. Collagenous colitis should be added to the list of causes of enteropathic arthritis.     

Phlebosclerotic colitis that was difficult to distinguish from collagenous colitis

Phlebosclerotic colitis is a rare and recently known disease entity and its etiology is still to be elucidated. Some phlebosclerotic colitis cases are difficult to distinguish from collagenous colitis because of the similarity of pathological findings. In all Japanese case reports of phlebosclerotic colitis in which an association with the use of Chinese herbal medicine is suspected, sansisi (gardenia fruit) was included, suggesting pathogenesis of this disease. We report a case of phlebosclerotic colitis that wasdifficult to be distinguished from collagenous colitis, and an association with the use of Chinese herbal medicine was suspected as the cause of the disease.     

Elevated fecal levels of eosinophil granule proteins predict collagenous colitis in patients referred to colonoscopy due to chronic non-bloody diarrhea

Objective: Colonoscopy with biopsy sampling is often performed to detect collagenous colitis (CC) and lymphocytic colitis (LC) in patients with chronic non-bloody diarrhea. However, the diagnostic yield is low and incurs high costs. Fecal calprotectin (FC) and myeloperoxidase (MPO) indicate intestinal inflammation in ulcerative colitis (UC) and Crohn’s disease (CD). In CC, elevated fecal levels of eosinophil protein X (EPX) and eosinophil cationic protein (ECP) have been reported. We aimed to evaluate if F-EPX, F-ECP, FC, and F-MPO could predict the diagnostic outcome in patients with chronic non-bloody diarrhea referred to colonoscopy. We also evaluated serum (S) EPX and ECP in this regard.

Methods: Of 67 included patients, 63 (94%) underwent colonoscopy with biopsy sampling. Fecal EPX, F-ECP, FC, F-MPO, S-EPX, and S-ECP were analyzed.

Results: Diagnostic outcome: normal: n?=?46 (73%), CC: n?=?9 (14%), LC: n?=?4 (6%), UC: n?=?2 (3%), CD: n?=?2 (3%). Higher levels of F-EPX and F-ECP were found in CC compared to a normal diagnostic outcome (p?=?0.01). No change was noted in any of the fecal markers in LC. When all of the fecal markers were normal the probability of a normal diagnostic outcome was 92%. We found no differences in S-EPX and S-ECP between the groups.

Conclusion: Elevated F-EPX and F-ECP could predict CC. None of the fecal markers predicted LC. Serum-EPX and S-ECP are not useful for the diagnosis of CC, LC, UC, or CD. With normal levels in all of the analyzed fecal markers, there is a low probability of a pathologic diagnostic outcome.