Ingested matter affects intestinal lesions in Crohn's disease

BACKGROUND: Environmental factors of the modern Western lifestyle may trigger Crohn's disease (CD) in susceptible individuals. Because such factors could be part of ingested matter, we intended to improve intestinal Crohn's lesions by exclusion thereof. METHODS: At first we tested a highly restricted diet (based on spelt bread and red meat, both derived from intensively monitored organic farming) in 5 pilot cases. In a subsequent controlled trial, 18 patients with mild-to-moderate CD were randomly assigned to receive either this active diet or a control diet (low-fiber, low-fat, and high-carbohydrate). Mucosal improvement was assessed by magnetic resonance imaging (MRI) and endoscopy. Secondary endpoints included sonography, the Crohn's Disease Activity Index (CDAI), and the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: Four of 5 pilot patients showed significant improvement within 4 weeks. From 18 patients in the controlled trial, 8 were randomized to the active and 10 to the control group; 4 decided to quit immediately after dietary counseling, 3 in the active and 1 in the control group (P = 0.183). At 6 weeks MRI and endoscopy showed improvement of intestinal lesions in 3 of 4 assessable patients of the active group and 1 of 9 patients of the control group (P = 0.027). Sonography showed improvement in 4 of 5 patients of the active group and in 1 of 8 assessable patients of the control group (P = 0.016). CDAI and IBDQ improved in both groups to a similar extent. CONCLUSIONS: Ingested matter as part of the modern Western lifestyle may cause persistence of intestinal Crohn's lesions.     

Kallikrein-kinin system activation in Crohn's disease: differences in intestinal and systemic markers

OBJECTIVES: Observations in experimental models and in human ulcerative colitis suggest that activation of the kallikrein-kinin system plays a role in the pathogenesis of inflammatory bowel disease. The aim of this study was to assess activation of the plasma and tissue kallikrein-kinin system in Crohn's disease. METHODS: We studied plasma inflammatory and contact system parameters in 36 patients with Crohn's disease and in 36 control subjects with noninflammatory GI diseases. We also obtained tissue samples from the involved intestine of 12 patients with Crohn's disease, and from normal peritumoral tissue (12 patients) and diverticulitis tissue (seven patients) as controls. Full-thickness sections were tested for intestinal tissue kallikrein reactivity with a specific antibody. RESULTS: In Crohn's disease patients and controls, plasma levels of prekallikrein, factor XI, high molecular weight kininogen and its cleaved form were normal. Crohn's disease patients had significantly higher levels of antigen and functional Cl-inhibitor (+22%, +12%) than did controls (p = 0.005, p = 0.004). After surgical resection, antigen and functional Cl-inhibitor significantly decreased in Crohn's disease patients (-22%, -15%; p = 0.035, p = 0.006). Intestinal tissue kallikrein immunoreactivity was absent (75%) or weak (25%) in the goblet cells from Crohn's disease tissue sections but was normal in controls, with a highly significant difference in the staining score (p = 0.0001). Intestinal tissue kallikrein immunoreactivity in the interstitium was higher in Crohn's disease than in normal and diverticulitis samples (p = 0.0001 and p = 0.001, respectively). CONCLUSIONS: Our observations suggest that intestinal tissue kallikrein is involved in the inflammatory process in Crohn's disease. The lack of contact system activation in peripheral blood might be related to the high plasma levels of Cl-inhibitor, the most important inhibitor of the contact system in the circulation.     

Association of inflammatory bowel disease and large vascular lesions.

A case of inflammatory bowel disease with associated multiple large vessel vascular lesions similar to that seen in Takayasu's arteritis is described in a 15-year-old female. It is suggested that this type of vascular lesion may represent another rare systemic manifestation of inflammatory bowel disease.     

Immunohistochemical identification of lysozyme in intestinal lesions in ulcerative colitis and Crohn's disease.

Lysozyme (LZM) was identified in ulcerative colitis in granulocytes, monocytes, and macrophages of the intestinal lamina propria. In contrast with findings in normal colon or rectum, in ulcerative colitis LZM was also detected in some mucosal crypt cells and metaplastic Paneth cells. In both ulcerative colitis and Crohn's disease LZM was present in inflammatory cells of crypt abscesses. In Crohn's disease intense LZM staining was seen in epitheloid cell granulomas. The present observations permit one explanation for the raised concentration of serum-LZM in patients with ulcerative colitis and Crohn's disease.     

Anti-TNF antibodies in the treatment of inflammatory intestinal stenoses in Crohn's disease

Stenoses are a frequent complication in patients with Crohn's disease and represent a major diagnostic and therapeutic challenge. The proper assessment of the nature of a stenosis as inflammatory or fibrotic is critical for appropriate treatment, since symptomatic fibrotic stenoses require surgical resection. Standard diagnostic procedures to assess the nature of a stenosis include endoscopy, conventional contrast radiography and magnetic resonance tomography. Recent data suggest, that the positron-emission-tomography possesses a high sensitivity and specificity to confirm inflammatory activity in the bowel. The recombinant monoclonal anti-TNF-antibody Infliximab (Remicade) has been approved for the treatment of steroid refractory and steroid dependent Crohn's disease in Germany since 9/2000 and the efficacy of Infliximab is well documented. However, few data exist about the treatment of inflammatory stenoses with Infliximab. We performed a retrospective analysis of our experience with Infliximab in patients with Crohn's disease with special reference to patients with inflammatory stenoses. Among a total of 21 patients treated with Infliximab 11 patients had an inflammatory stenosis. 9 of these patients responded well to Inflimab and became completely asymptomatic for a considerable period of time. Infliximab was tolerated well except for one patient who developed an intrabdominal abscess. The notable clinical response of patients with inflammatory stenoses to Infliximab suggests that treatment with Infliximab might be helpful to postpone or avoid surgical intervention. This finding should be further investigated in a prospective randomized study.     

Expression of urokinase-type plasminogen activator in the mucosal lesions of inflammatory bowel disease

The expression of plasminogen activators was analysed in mucosal homogenates from inflammatory bowel disease patients to determine whether the urokinase-type (u-PA) is implicated in the pathogenesis of mucosal tissue injury. Homogenates of mucosal biopsy tissue from ulcerative colitis, Crohn's disease, infectious colitis and normal control patients were subjected to polyacrylamide gel electrophoresis. The types of plasminogen activator present were detected by zones of lysis in a fibrin-agarose gel overlay. All the tissues studied displayed tissue plasminogen activator activity (t-PA). In ulcerative colitis, 18 of the 19 diseased colon biopsies, but none of six biopsies from uninvolved areas of the same colon, showed u-PA activity. Similar results were found in 12 Crohn's disease patients. Biopsies from the infectious colitis group and from radiation colitis patients also showed both u-PA and t-PA activity. The age, sex, duration of disease, and presence and type of treatment did not affect u-PA expression in the inflamed mucosa. The results suggest that u-PA may be implicated in the mediation of tissue injury in the inflamed intestinal mucosa.     

Evidence for predominant involvement of the B-cell system in the inflammatory process in Crohn's disease.

The cellular infiltrate in the walls of resected ileum and colon specimens obtained from patients with Crohn's disease was analysed. Mononuclear cells in tissue sections were characterized by the use of surface membrane markers and immuno-histochemical and enzyme histochemical techniques. It was found that: [1] B cells, as judged by the presence of surface membrane immunoglobulin and C3 receptors and the absence of alpha-naphthylacetate esterase and acid phosphatase activity, were the predominant type of cells in the intestinal infiltrate often found in close relation with smaller numbers of non-B cells; [2] all types of immunoglobulin-containing cells were increased in number with a shift in the ratio of IgA/IgG/IgM-containing cells in favour of the IgG- and IgM-containing cells; and [3] the histopathological reaction of the regional draining lymph nodes showed hyperplasia of B-cell areas (follicles and medulla) and small or absent T-cell areas (paracortex), consistent with a B-cell response. Our results indicate that the inflammatory process in the bowel wall in Crohn's disease mainly reflects stimulation of the B-cell system.     

Pathogenic factors in inflammatory bowel disease. 2. Crohn's disease.

Clues from patient and experimental animal studies suggest that events occurring early in the pathogenesis of Crohn's disease are related to an inability of the immune system to eradicate one or a number of luminal antigens resulting in persistent T cell and macrophage activation. Whether the primary abnormality rests with the nature of the luminal antigen, disturbances of antigen uptake by the mucosa, antigen handling by macrophages, or macrophage-T cell interactions remains unresolved. Given the heterogeneity of clinical presentations and experimental data, Crohn's disease may be a group of disorders associated with a number of primary defects.     

Major histocompatibility class II expression on the small intestinal nervous system in Crohn's disease.

Widespread alterations of the gut autonomic nervous system have been described in Crohn's disease. Immunohistochemistry shows that these alterations are associated with the expression of major histocompatibility (MHC) class II antigens (HLA-DR) on enteroglial cells in the ganglia of the submucous and myenteric plexuses and on the enteroglial sheaths of the nerve extensions. Neuronal cell bodies and extensions do not express MHC class II antigens. The class II expression is associated with the presence of UCHL1-positive T lymphocytes. MHC class II expression can also be found on endothelial cells and vascular smooth muscle cells but not on smooth muscle cells of the muscularis mucosae or propria. The intensity of MHC class II expression on the glial cells of the enteric nervous plexus and on endothelial cells correlates well with the intensity of class II expression on epithelial cells.     

The role of the plasminogen activation system in cancer.

Hemostatic disorders are frequently observed in patients with malignancy with a significant proportion developing thrombotic and/or hemorrhagic complications including disseminated intravascular coagulation (DIC), deep venous thrombosis (DVT), and thrombocytopenia. Together, these abnormalities are the second most common cause of mortality in cancer patients, which has led many investigators to try to unravel the pathogenesis of thromboembolic disease, in the eventuality that this will lead to novel therapeutic treatments. The plasminogen activation system is one pathway that has been consistently implicated in cancer. Its relevance to cancer extends from being responsible for many of the hemorrhagic episodes that occur in cancer patients to being fundamental to many, if not all of the molecular mechanisms that define tumor progression. Recent developments of clinical significance shall be reviewed with respect to the role of the plasminogen activation system in tumor growth and metastasis dissemination and in the thrombophilic state in the cancer patient.     

Clinical course and magnifying endoscopic findings of fine lesions of the large intestinal mucosa in Crohn's disease

"Worm-eaten" appearance (WEA) is a fine lesion of Crohn's disease observed in apparently normal rectal mucosa by magnifying endoscopy. Magnifying endoscopy has now been performed following application of methylene blue on 37 occasions in 27 patients with Crohn's disease, and the occurrence of WEA was reviewed in relation to the duration and extent of disease. The frequency of WEA was 75% in patients with a history of less than five years and 77% in those who had had the disease for more than five years. In the active stage, the frequency was 85% and 100% respectively, and the degree of WEA also increased. The detection rate of granulomata in regions of WEA was 53% when the clinical history was less than five years and 33% when five years or more. In active disease, granulomata were found in 70% and 67% respectively. The large intestine other than the rectum was reviewed in eight patients with ileitis. WEA and granulomata were observed throughout the large intestine including the cecum, especially when the ileal disease was active.     

Crohn's disease and adenocarcinoma of the intestinal tract

Four patients with intestinal adenocarcinoma complicating Crohn's disease are reported. The youngest of the four patients was a 21-year-old female with a 9-year history of Crohn's disease of the terminal ileum as well as of the entire colon. She developed mucus-producing moderately differentiated adenocarcinoma in the cecum. Of the remaining three patients with Crohn's disease, one presented an adenocarcinoma in the ascending colon, one in the rectum and the remaining one in the duodenum. All three colorectal adenocarcinomas originated in areas of high-grade dysplasia and all four in areas with chronic transmural inflammation. The review of the literature indicates that a total of 174 small and large bowel cancers occurring in Crohn's disease have been recorded (including the four reported herein). The vast majority of the reported cases have been found in the North American subcontinent. Only in a few instances were bowel adenocarcinoma and Crohn's disease observed in the European continent. It is therefore remarkable that three of our four cases were seen within a period of 12 months. Interestingly, six patients having colorectal adenocarcinoma in association with Crohn's disease were recently reported from a single hospital in England. The question therefore arises whether our cases and those reported recently from England are unrelated and merely coincidental or whether carcinomas are now also affecting European CD patients. If the latter is the case, the surveillance policy for patients with CD should be reconsidered at this hospital.This study was supported by grants from the Karolinska Institute and Cancer Fonden.     

Evidence for activation of coagulation in Crohn's disease.

Haemostatic changes in 16 patients with Crohn's disease were studied from active disease into clinical remission and beyond. Elevated concentrations of fibrinopeptide A (FpA) and prothrombin fragments F1 + 2 (F1 + 2) were found at times of both active (FpA median 3.2, range [0.3-40] ng/ml and F1 + 2 median 2.3, range [0.3-18] nm/l) and inactive disease (FpA median 2, range [0.4-40] ng/ml and F1 + 2 median 1.3, range [0.2-20) nm/l]. We also measured the physiological inhibitors of coagulation and fibrinolysis; there was no significant difference in the levels of antithrombin III, protein C or the Exner ratio between active and inactive disease. Free protein S levels were significantly lower in active disease (median 34, range 9-54 U/dl) than in remission (median 40, range 12-65 U/dl). Plasminogen activator inhibitor type 1 (PAI-1) was significantly raised in remission (median 11, range 3-32 ng/ml) when compared to active disease (median 7, range 3-42 ng/ml). The D-dimer correlated significantly with fibrinopeptide A (P < 0.001), suggesting reactive fibrinolysis in some patients. Most (35/52, 67%) samples showed evidence of persistent haemostatic activation (elevated FpA and/or F1 + 2) during phases of apparent clinical remission in Crohn's disease, a factor that is not reflected by clinical activity scores. This study supports the hypothesis that coagulation is activated in the mesenteric vasculature of patients with Crohn's disease.     

Mechanisms of intestinal failure in Crohn's disease

PURPOSE: The purpose of this study was to determine the mechanisms by which patients with Crohn's disease develop intestinal failure and, in particular, to assess the relative importance of severe primary disease, repeated uncomplicated elective small intestine resection, and resection performed as a consequence of intra-abdominal septic surgical complications. METHODS: This was a retrospective analysis of 41 patients with Crohn's disease referred to a specialized intestinal failure unit between January 1987 and September 1998 for permanent home parenteral nutrition. To compare the surgical activity in patient groups, a resection index was calculated by dividing the number of intestinal resections by the interval in years between the first resection for Crohn's disease and referral for management of intestinal failure. RESULTS: Extensive primary Crohn's disease was responsible for intestinal failure in 7 cases (17 percent). The remainder (n=34, 83 percent) developed intestinal failure after intestinal resection. Nine of the surgical Crohn's patients developed intestinal failure after uncomplicated sequential resection, (median small-bowel length 65 (range, 60–120) cm) after a median of 3 (range, 2–8) operations over a median of 17 (range, 3–27) years. By contrast, the other 25 surgical Crohn's patients developed intestinal failure after multiple unplanned laparotomies for intra-abdominal sepsis (median small-bowel length 70 (range, 60–200) cm), with a median of 4 (range, 2–7) laparotomies performed over a median of 0.5 (range, 0.1 to 1.5) years (P<0.001). The resection index for the 25 Crohn's patients undergoing laparotomies for intra-abdominal sepsis was significantly greater than that of the 9 patients who had planned sequential resections (2.1 (0.27–25)vs. 0.23 (0.1–1.0);P < 0.002, Mann-WhitneyU test). CONCLUSION: Intestinal failure develops in Crohn's disease primarily as a result of complications of surgical treatment. The largest group of patients at risk consists of those who are undergoing multiple unplanned laparotomies to control intra-abdominal sepsis.     

Risks of intestinal cancer in Crohn's disease

This review described the principal features of the three studies that have established clearly that patients in the U.S.A. or the U.K. who have long-standing (>7 years) Crohn's colitis are at increased risk (up to 20-fold) of developing large bowel cancer. In addition, it emphasizes that there are no data on the extent of this risk in patients in other countries, and also that the magnitude of the risk of cancer of the small intestine in Crohn's disease is unknown. Despite the increased incidence of large bowel cancer in long-standing Crohn's colitis in the U.S.A. or the U.K., the total number of such patients is small, as is the number in which the colonic carcinoma will occur. However, careful supervision is advised for the small group at risk, despite the limitations of current methods for the early detection of cancer of the large intestine.     

Marital idiopathic inflammatory bowel disease. Crohn's disease in a husband and wife

Two cases of Crohn's disease in a husband and wife are described and compared with the seven previously reported cases of chronic idiopathic inflammatory bowel disease occurring in spouses.