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Cancer risk in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are at increased risk for developing cancer of the gastrointestinal tract, particularly colorectal cancer. Because of the relative rarity of IBD in the general population, it has been difficult to quantify this risk. Efforts to reduce the risk have included both prophylactic surgery and endoscopic screening programs. Because of the potential impact on quality of life and life expectancy, the optimal strategy for reducing this risk has not been defined. This article reviews the current literature relating to the risk of cancer for patients with IBD and methods to reduce this risk.

Adenocarcinoma↗

Colorectal cancer in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are subject to increased risks for the development of colorectal cancer (CRC), risks that are attributed to the duration and anatomic extent of disease in patients with ulcerative colitis and Crohn's disease. Although IBD contributes only 1%-2% to all cases of CRC, the mortality rate in patients with a diagnosis of CRC in the setting of IBD is higher than for those afflicted with sporadic cases of CRC. Given the length of time from IBD onset to the development of CRC, surveillance continues to be widely practiced. Although still under development, novel techniques for the earlier detection of dysplastic lesions have moved to the forefront in an attempt to optimize surveillance strategies and decrease the risk of CRC development.

Biomarkers, Tumor↗

[Bactericidal permeability increasing protein (BPI-ANCA marked chronic inflammatory bowel diseases and hepatobiliary diseases].

BACKGROUND: Bactericidal permeability increasing protein (BPI) is an antibacterial product of neutrophilic granulocytes that can serve as target antigen for antineutrophil cytoplasmic antibodies (ANCA). The clinical associations of autoantibodies against BPI (BPI-ANCA) are essentially unclear. PATIENTS AND METHODS: 587 sera from patients with chronic inflammatory bowel diseases, inflammatory hepatobiliary diseases, primary systemic vasculitides and other rheumatological diseases were examined for BPI-ANCA by mono-specific ELISA and a standard indirect immunofluorescence test for ANCA. (ACD-CPR versus S-CPR). The treatment groups were similar with respect to age, sex, time interval from collapse to CPR, defibrillation and first epinephrine medication. There was no difference between the ACD group and the standard CPR group in terms of survival rates and neurologic outcome. No differences occurred concerning complications of CPR. CONCLUSION: In our two-tiered EMS system with physician-staffed ambulances ACD-CPR neither improved nor impaired the survival rates and the neurological prognosis in patients with out-of-hospital cardiac arrest. Our results are in accordance with other studies carried out in EMS systems, with first tier call-response intervals between 4 and 6 min. RESULTS: The prevalence of BPI-ANCA was 43% in ulcerative colitis, 23% in Crohn's disease, 35% in primary sclerosing cholangitis, 25% in primary biliary cirrhosis and 29% in autoimmune hepatitides. In a spectrum of systemic vasculitides, inflammatory joint diseases and collagen vascular diseases the prevalence was only 3 to 11%. In contrast to PR3-ANCA and MPO-ANCA, BPI-ANCA was not associated with a particular pattern of fluorescence in the immuno-fluorescence test on ethanol- and formalin-fixed neutrophils. CONCLUSION: This study shows that BPI-ANCA is the third ANCA specificity, besides PR3-ANCA and MPO-ANCA, with a limited spectrum of clinical associations. The diagnostic and prognostic relevance of BPI-ANCA in the above clinical conditions is being examined prospectively.

Antibodies, Antineutrophil Cytoplasmic↗

Saliva Interleukin-6 in patients with inflammatory bowel disease.

OBJECTIVE: The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions that affect the gastrointestinal tract. In regulation of this inflammatory process, Interleukin-6 (IL-6) has a major role. Overproduction of IL-6 by immunocompetent cells contributes to development of the inflammatory condition. Elevated levels of IL-6 in saliva could be expected, because the saliva-producing cells are part of the digestive system. MATERIAL AND METHODS: IL-6 concentrations in saliva and plasma were studied in patients with CD (n=15), UC (n=7) and reference persons (RP) (n=19) by use of an ELISA method. RESULTS: A significant difference in saliva IL-6 concentration between CD patients (median 16.9 ng/L; p<0.05) and RP (median 6.3 ng/L) was found. A significant difference in plasma IL-6 concentration between CD (median 10.3 ng/L; p<0.001) or UC (median 7.8 ng/L; p<0.001) and RP (median 0.8 ng/L) was observed. In patients with CD, plasma IL-6 correlated significantly with C-reactive protein (CRP) as well as albumin. In patients with UC, saliva IL-6 and plasma IL-6 correlated significantly with AI (activity index) scores as well as albumin. In patients with UC, a significant correlation between the saliva and plasma IL-6 concentrations was found. CONCLUSIONS: IL-6 was found in saliva in patients with IBD, documenting the general involvement of the gastrointestinal tract extending to the mouth cavity, and measuring IL-6 may be an additional method for evaluating and monitoring the disease activity.

Adult↗

Venous thrombosis in inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) have a threefold increased risk of venous thrombosis, a major cause of morbidity and mortality. Although the exact mechanism explaining the initiation of thrombosis remains unclear, it is likely to be a multifactorial process. Reported abnormalities include activation of markers of the coagulation cascade, disturbed fibrinolysis and the activation of platelets. The contribution of thrombophilic disorders such as factor V Leiden, prothrombin gene mutations and hyperhomocysteinaemia are discussed, but their role in thrombosis associated with IBD has remained unclear. Recent research has examined elevated CD40, P-selectin levels and tissue factor-bearing microvesicles in venous thrombosis, and the relevance of these observations to IBD is reviewed.

Blood Coagulation Disorders↗

Childhood infections and the risk of inflammatory bowel disease.

Adults with inflammatory bowel disease from North Carolina were questioned during 1986 and 1987 to assess risk due to a variety of childhood infections and treatments with antibiotics. Responses were compared with those of neighbor controls. Persons with Crohn's disease were more likely to report an increased frequency of childhood infections in general (odds ratio 4.67, 95% CI 2.65-8.23) and pharyngitis specifically (odds ratio 2.14, 95% CI 1.30-3.51). This was validated by an increased frequency of tonsillectomy (odds ratio 1.53, 95% CI 1.07-2.20). Crohn's cases were more likely to report frequent treatment with antibiotics for both otitis (odds ratio 2.07, 95% CI 1.03-4.14) and pharyngitis (odds ratio 2.14, 95% CI 1.20-3.84). Although Crohn's cases were more likely to report frequent exposure to penicillin (odds ratio 1.81, 95% CI 0.98-3.31), there did not appear to be excess risk conferred by penicillin after controlling for frequency of infections. Persons with ulcerative colitis also reported an excess of infections generally (odds ratio 2.37, 95% CI 1.19-4.71), but not an excess of specific infections or treatments with antibiotics. Persons who reported an increased frequency of infections tended to have an earlier onset of Crohn's disease (P < 0.0001) and ulcerative colitis (P = 0.04). Finally, it was noted that urban living in childhood increased the risk for Crohn's disease. We conclude that childhood infections may be a risk factor for Crohn's disease and may presage the early onset of disease.

Adolescent↗

Serum lipopolysaccharide-binding protein in endotoxemic patients with inflammatory bowel disease.

BACKGROUND: In inflammatory bowel disease (IBD), enhanced inflammatory activity in the gut is thought to increase the risk of bacterial translocation and endotoxemia. By searching for signs of endotoxin-signaling cascade activation, including augmented levels of endotoxin, lipopolysaccharide-binding protein (LBP), and soluble CD14 receptor (sCD14), this prospective study sought to establish whether endotoxemia could contribute to greater clinical activity of disease. METHODS: Concentrations of plasma endotoxin, LBP, sCD14, several cytokines, acute phase proteins and clinical activity indices were determined in 104 patients with Crohn's disease (CD) and 52 patients with ulcerative colitis (UC). RESULTS: Endotoxemia was present in 48% of the patients with CD and in 28% of the patients with UC. The mean LBP was higher in patients with active CD (23.1 +/- 13.7 microg/mL) and UC (21.4 +/- 10.9 microg/mL) than in healthy controls (7.2 +/- 1.8 microg/mL; P < 0.01). Elevated serum concentrations of endotoxin and LBP were even detected in patients with inactive CD. Among the patients with active IBD, those with higher endotoxin levels had the worst clinical activity scores and the highest LBP levels. Treatment normalized LBP concentrations, from 29.1 +/- 13.0 to 15.2 +/- 7.3 microg/mL; (P < 0.05) in active CD and from 21.7 +/- 9.8 to 13.6 +/- 5.7 microg/mL; (P < 0.01) in active UC, along with normalizing endotoxin and sCD14 plasma concentrations. CONCLUSIONS: Patients with IBD show increased serum levels of endotoxin, LBP and sCD14. This alteration correlates with disease activity, with normal levels recovered after treatment, although less completely in Crohn's disease, and parallels a rise in proinflammatory cytokines, suggesting a contribution of bacterial products to the inflammatory cascade in these patients.

Acute-Phase Proteins↗

Animal models of inflammatory bowel disease: an overview.

Inflammatory bowel disease (IBD) research has been performed in human in vitro studies and in in vivo studies using appropriate animal models. Such animal models allow both the examination of inflammatory processes (both early and late events) as well as the evaluation of new therapeutic modalities. Since the first description of the immune complex colitis in rabbits in 1961, overall 63 models have been described, most of which within the last decade. These IBD animal models can be divided into 5 different categories: (1) antigen-induced colitis and colitis induced by microbials; (2) other inducible forms of colitis (chemical, immunological, and physical); (3) genetic colitis models (transgenic and knock-out models); (4) adoptive transfer models, and (5) spontaneous colitis models. In spite of the high overall number of models, none of them is the 'perfect' model and therefore numerous aspects need to be considered when choosing one model for a particular study. Importantly, most clinical aspects (e.g. extraintestinal manifestations or fistula) have recently been described in one or the other model allowing further studies with relevance for almost all aspects of IBD. So far, IBD animal models have taught us important lessons, e.g. the requirement of T-helper cells in most models, the need of a particular genetic background, and the role of the flora in the initiation of IBD. It is expected that our understanding of IBD will further increase in a number of additional areas using animal models, e.g. exploring the role of the innate immune system in IBD.

Animals↗

Effect of nimesulide on acetic acid- and leukotriene-induced inflammatory bowel disease in rats.

Inflammatory bowel disease (IBD) is a relapsing inflammation of intestine, which is mediated by release of inflammatory mediators. Both cyclo-oxygenase product prostaglandin (PGE2) and lipo-oxygenase product leukotriene (LTB4), may contribute to the pathogenesis of the inflammatory response. Nimesulide, a preferential COX-2 inhibitor was evaluated for its efficacy against experimental colitis in two different models (acetic acid- and LTB4-induced IBD) in rats. Inflammatory response was induced by intrarectal single administration of acetic acid or LTB4. Nimesulide (9 and 18 mg/kg, p.o.) significantly prevented development of inflammatory changes, decreased myeloperoxidase (MPO) activity, and also restored the altered contractility response of the isolated colon segment to KCl. The results suggested the involvement of both cyclo-oxygenase (COX) and lipo-oxygenase-mediated proinflammatory agents in colonic inflammatory process associated with IBD. Further, this study suggests that such therapeutic interventions may be of value in the treatment of IBD.

Acetic Acid↗

[Epidemiological study on the incidence of inflammatory bowel disease in 4 Spanish areas. Spanish Group on the Epidemiological Study of Inflammatory Bowel Disease].

BACKGROUND: The incidence of inflammatory bowel disease (IBD) shows marked geographical variations. The aim of this study was to determine and compare the incidence of IBD in four Spanish areas: Sabadell (Northeast), Vigo (Northwest), Mallorca island and Motril (South). PATIENTS AND METHODS: Prospective survey based on inception cohorts over a two-years period (1 October 1991 to September 1993). Subjects were the patients resident in these areas and diagnosed of IBD according to a standard protocol for case ascertainment and definition. RESULTS: Altogether 328 cases were identified, of whom 191 were diagnosed as ulcerative colitis (UC), 135 as Crohn's disease (CD) and 2 as indeterminate colitis. The overall adjusted incidence rate per 100,000 persons between ages 15-64 years of UC and CD were respectively 9.8 and 5.2 in Sabadell, 7.7 and 5.0 in Vigo, 7.8 and 5.8 in Mallorca and 4.3 and 6.5 in Motril. The Incidence rate ratio showed no significant differences for either conditions among these areas. The global adjusted incidence rate of UC in Spanish areas (8.0; IC 95%: 6.3-9.7) was significantly lower to that of Northern European countries while that of CD (5.5; IC 95%: 4.1-6.9) was between that of Northern and Southern Europe with no significant differences. CONCLUSIONS: The incidence of IBD did not show differences among the Spanish areas, and rates are between 2 and 6 times higher than those previously reported. The incidence of UC is significantly lower than that observed in the North of Europe, while for CD the incidence is between that of Northern and Southern Europe.

Adolescent↗

Inflammatory bowel disease up to 1932.

Inflammatory bowel diseases have been a major interest of generations of Mount Sinai Hospital gastroenterologists. Although clinical descriptions of diarrhea with or without blood go back thousands of years, clear distinctions between enteritis and ulcerative colitis were possible only in the 19th century. At that time, many case reports were published of, in retrospect, classical regional enteritis. The term "ulcerative colitis" dates from 1888; the introduction of the electric sigmoidoscope soon after made it possible to make proper diagnosis of ulcerative colitis and distinguish it from infective dysentery, membranous mucous or catarrhal colitis, and nervous diarrhea. Doctors at The Mount Sinai Hospital adopted this diagnostic approach in the 1870s and 1880s, and were particularly interested in patients with tuberculosis-like ileocecal disease without tubercle bacilli. Articles were written by Weiner in 1914, Moschcowitz and Wilensky in 1923 and 1927, and Goldfarb and Suissman in 1931. Dr. A.A. Berg, in 1925, encouraged his assistant Leon Ginzburg to conduct a study of the inflammatory granulomatous diseases of the bowel, when Ginzburg and Gordon Oppenheimer were working in Dr. Paul Klemperer's laboratory. Initial reports came in 1927 and 1928, but Ginzburg and Oppenheimer "in conjunction with Dr. Burrill B. Crohn" presented a definitive paper, "Non-specific Granulomata of the Intestine," on May 2, 1932, to the American Gastro-Enterological Association. On May 13, 1932, Dr. Crohn presented a paper on "Terminal Ileitis" to the American Medical Association; this was published later that year with the title "Regional Ileitis: A Pathologic and Chronic Entity," under the authorship of Crohn, Ginzburg and Oppenheimer.

Europe↗

Platelets and anticoagulant capacity in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are susceptible to thromboembolic complications. Several mechanisms can be responsible, including abnormal regulation of coagulation activity, disturbances of fibrinolysis, inflammatory reactions and thrombocytosis. The aim of this study was to assess hemostatic alterations in these parameters during exacerbation of disease. We studied disease activity in 99 IBD patients receiving anti-inflammatory therapy, in relation to: procoagulant markers, i.e. prothrombin fragment F1 + 2 (F1 + 2), D-dimer and platelet count, anticoagulant markers, i.e. protein C, protein S and antithrombin, and a mediator of inflammation (IL-6). Coagulation activity and platelet count were increased during active disease in IBD patients compared with those in a state of remission. The IL-6 concentrations were positively correlated with disease activity and thrombocytosis in patients with ulcerative colitis, but no association with the anticoagulant capacity could be demonstrated except for a decrease in protein C during high disease activity.

Adolescent↗

Expression of 5-lipoxygenase mRNA is unchanged in the colon of patients with active inflammatory bowel disease.

BACKGROUND: In inflammatory bowel disease (IBD) the disease activity correlates with colonic concentrations of leukotrienes (LTs). The enzyme 5-lipoxygenase (5-LO) is responsible for the enzymatic production of LTs. It has previously been demonstrated in experimental models of inflammation, that 5-LO is activated through intracellular translocation of the pre-formed enzyme, and increased constitutive activation of 5-LO has been demonstrated in idiopathic pulmonary fibrosis. The objective of the present study was to investigate whether de novo synthesis of 5-LO is increased in patients with quiescent IBD, or is induced during acute exacerbations of IBD. METHODS: Sixty-one individuals were included in the study. Twenty-eight had ulcerative colitis (UC), 21 had Crohn's disease (CD), and 12 were healthy controls. A standard rigid rectoscopy was performed in all individuals. The degree of inflammation was assessed using a semi-quantitative scale. A mucosal biopsy was taken from the most inflamed area as judged macroscopically. mRNA for 5-LO was detected using a RT-PCR technique, and the assay applied was evaluated by control experiments. RESULTS: The expression of mRNA for 5-LO in colonic biopsies was similar in IBD patients with quiescent disease and healthy controls. When grouped according to endoscopically assessed disease activity the fraction of patients demonstrating 5-LO mRNA in colonic biopsies showed no significant change (p > 0,6; chi2 -test for trend). CONCLUSIONS: This study demonstrates no significant relationship between endoscopically assessed disease activity and relative presence of mRNA for 5-LO in colonic biopsies. Thus, there is no evidence of increased expression of 5-LO mRNA in either quiescent or active stages of IBD.

Adult↗

Does Helicobacter pylori play a role in inflammatory bowel disease?

The cause of inflammatory bowel disease is still unknown although several bacterial and viral agents have been implicated in their aetiologies. Helicobacter pylori infection, the main cause of gastroduodenal diseases, could, theoretically, be involved in the pathogenesis of inflammatory bowel disease. In fact, it induces permeability alterations and immunological derangements in the stomach similar to those detected in the colon of inflammatory bowel disease patients. However, epidemiological data do not support this hypothesis and recent evidence even points to a low prevalence of Helicobacter pylori in inflammatory bowel disease. These data are discussed in the light of possible confounding factors.

Adult↗

Neoplastic and other complications of inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) have long been known to be at increased risk of development of colorectal cancer; however, there are many nuances to cancer prevention strategies in IBD that remain unresolved. During the past year, two publications reported on the resection of otherwise typical adenoma-like masses by means of polypectomy, after which these patients were followed with continued endoscopic surveillance, rather than pursuing colectomy. Another concern in IBD is whether there is an increase in the number of other cancers, in particular lymphomas. One issue regarding lymphoma risk is whether immunomodulatory drug use predisposes to this cancer. One study of a large group of 6-mercaptopurine users did not suggest an increased risk for patients with IBD using this drug. There are a variety of nonintestinal problems that patients with IBD may confront. Osteopenia has received considerable attention in the past decade. This year, data have been published that quantify for the first time the risk of fractures in patients with IBD based on population, and these data were compared with a matched control group from the same population. Data on the further exploration of the issue of osteopenia in pediatric IBD have also been reported, as have some of the only studies of therapy for osteopenia in IBD. These and data on other extraintestinal manifestations of IBD have all emerged in the past year.

Alendronate↗

Information booklets for patients with inflammatory bowel disease.

Patients with inflammatory bowel disease wish to know more about their disease. Booklets must deal with such problems as prognosis and cancer risk. Although this information may depress up to 13% of patients who accept such booklets, between 30% and 39% become less anxious. Patients are highly motivated and can deal with quite difficult text, although illustrations can be helpful. Up to 34% of patients offered such booklets refused them. Nevertheless such booklets reach many people who are not members of self-help groups, and can be used by the doctor in counselling sessions with his or her patient, and in many cases produce reassurance and even lead to fewer consultations.

Humans↗

Cancer in inflammatory bowel disease.

Patients with inflammatory bowel disease, including both ulcerative colitis (UC) and Crohn's disease, are at increased risk for the development of gastrointestinal carcinoma, particularly colorectal adenocarcinoma. The current options to reduce this cancer risk include prophylactic colectomy, periodic endoscopic screening with colectomy performed in those patients found to have dysplastic colonic mucosa, or expectant management with no routine surveillance regimen. Despite the lack of data demonstrating effectiveness of surveillance colonoscopy, this approach has become the standard of care in most communities in the United States. Although it has fallen out of fashion in recent years, prophylactic colectomy remains a good option for reducing cancer risk for select patients with UC.

Colorectal Neoplasms↗