Risk of cardiovascular disease in inflammatory bowel disease

Abundant scientific evidence supporting an association between inflammatory bowel disease(IBD) and venous thromboembolic events, caused by an IBD related hypercoagulability, is acknowledged and thromboprophylactic treatment strategies are now implemented in the management of IBD patients. In contrary, the risk of arterial thromboembolic disease, as ischemic heart disease, cerebrovascular events, and mesenteric ischemia in patients with IBD remains uncertain and the magnitude of a potentially increased risk is continuously debated, with ambiguous risk estimates among studies. The evident role of inflammation in the pathogenesis of atherosclerosis forms the basis of a biological plausible link; the chronic systemic inflammation in IBD patients increases the risk of atherosclerosis and thereby the risk of thrombotic events. Further, studies have shown that the burden of traditional risk factors for atherosclerosis, such as obesity, diabetes mellitus, and dyslipidemia is lower in IBD populations, thus further strengthen the role of non-traditional risk factors, as chronic inflammation in the linking of the two disease entities. Likewise, mortality from cardiovascular disease in IBD remains questioned. The aim of the current review is to give an up-date on the existing evidence of the possible association between IBD and cardiovascular disease and to discuss traditional and non-traditional risk factors.     

Who and how to screen for cancer in at-risk inflammatory bowel disease patients

Inflammatory bowel diseases (IBDs) include both Crohn’s disease and ulcerative colitis and both diseases are marked by inflammation within the gastrointestinal tract. Due to long-standing inflammation, IBD patients are at increased risk of colorectal cancer, especially patients with chronic inflammation, pancolitis, co-diagnosis of primary sclerosing cholangitis and a longer duration of disease. Small bowel inflammation places Crohn’s patients at an increased risk of small bowel cancer. A higher risk of skin cancers, lymphomas and cervical abnormalities is also seen in IBD patients; this is likely related to both disease factors and the presence of immunosuppressive medication. This article reviews which patients are at an increased risk of IBD-associated or IBD treatment-associated cancers, when to begin screening and which screening methods are recommended.     

Inflammation and coagulation in inflammatory bowel disease: The clot thickens

Inflammation and coagulation play crucial roles in the pathogenesis of multiple chronic inflammatory disorders. Growing evidence highlights a tight mutual network in which inflammation, coagulation, and fibrinolysis play closely related roles. Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD), are chronic inflammatory conditions, characterized by a hypercoagulable state and prothrombotic conditions, and accompanied by abnormalities in coagulation. From a pathophysiological point of view, cells and molecules classically implicated in the physiological process of coagulation have now been shown to behave abnormally in IBD and possibly to also play an active role in disease pathogenesis and/or disease progression. This paper reviews studies performed on the coagulation profile and risk factors for thrombosis in IBD. In particular, an overview is provided of the epidemiology, clinical features, and etiology of thromboembolic complications in IBD. Furthermore, we review hemostatic abnormalities in IBD, as well as the cell types involved in such processes. Finally, we highlight the coagulation system as a dynamic participant in the multifaceted process of chronic intestinal inflammation. Overall, an overview is provided that the coagulation system represents an important, though previously underestimated, component of IBD pathogenesis, and may be a possible target for therapeutic intervention.     

Chronic inflammation, colorectal cancer and gene polymorphisms

Chronic inflammation is commonly present in gastrointestinal mucosal sites at increased risk for cancer, such as in inflammatory bowel disease (IBD) or chronic gastritis caused by Helicobacter pylori infection. Why some patients have more mucosal inflammation than others, and why certain individuals with chronic inflammation develop cancer, are problems that have not been solved. Unlike the case for the syndromic forms of familial colorectal cancer (CRC), the risks for IBD and other forms of chronic inflammation have not been linked to highly penetrant single gene mutations. Single nucleotide polymorphisms (SNP) are variations in DNA sequence that can be linked to any phenotype (cancer, chronic inflammation, etc.) in genome-wide association studies (GWAS). CRC has been linked to several highly penetrant single gene loci, as well as multiple SNP. The propensity to develop IBD has not been linked to single gene mutations in most instances, but has been linked to SNP in the NOD2 locus (which appear to create hypomorphic alleles for this bacterial response gene), the IL23R locus, the autophagy gene ATG16L1 and a wide range of other loci including the Toll-like receptors, JAK2 and STAT3, and perhaps 70 more. At present, the problem in predicting risk for chronic inflammation is that there are many genetic polymorphisms with relatively modest individual effects. Our challenge is to understand how the SNPs that are linked to variations in the inflammatory response interact with one another (i.e. to understand the 'epistasis' involved), and to integrate this with the variety of individual environmental exposures. This represents an opportunity for informatics science to help personalize our approach to chronic inflammatory diseases of the gut and identify those at greatest risk for cancer.     

Subclinical gut inflammation in spondyloarthropathy patients is associated with upregulation of the E-cadherin/catenin complex

OBJECTIVE: Previously an upregulation of E-cadherin and its associated molecules alpha-catenin, beta-catenin and plakoglobin has been demonstrated in clinically overt inflammatory bowel disease (IBD). The aim of this study was to investigate the expression of the E-cadherin/catenin complex in subclinically inflamed bowel mucosa from spondyloarthropathy (SpA) patients. METHODS: Ileal and colonic biopsy specimens from 19 SpA patients with subclinical inflammatory gut lesions and from seven controls were stained with monoclonal antibodies against E-cadherin, beta-catenin and plakoglobin and a polyclonal antibody against alpha-catenin. E-cadherin mRNA was detected using a riboprobe. Inflammation was histologically classified into acute, chronic active and chronic quiescent forms. RESULTS: In acute and chronic active bowel inflammation of SpA patients, upregulation of the E-cadherin/catenin glycoprotein complex could be observed. Chronic lesions in a quiescent state did not show such an upregulation. Furthermore, chronic inflammation was associated with an increase in E-cadherin mRNA. CONCLUSIONS: As some of the SpA patients with subclinical gut inflammation develop IBD, upregulation of the E-cadherin/catenin complex in inflamed bowel mucosa from SpA patients may point to early cellular changes in the development of IBD. However, at present it cannot be excluded that increased E-cadherin/catenin complex expression is a bystander phenomenon of active inflammation.     

Long-term evolution of gut inflammation in patients with spondyloarthropathy

BACKGROUND & AIMS: Intestinal inflammation has been observed in patients with spondyloarthropathy (SpA). This prospective study reports the evolution of the intestinal inflammation observed in patients with SpA. METHODS: One hundred twenty-three patients with SpA who had undergone initial endoscopy were clinically reassessed. Intestinal evolution was evaluated by ileocolonoscopy and the histological study of biopsy specimens in 49 patients. RESULTS: Articular remission rates were independent of initial gut inflammation and associated with endoscopic and histological remission. Persistent gut inflammation was observed in active joint disease. Gut inflammation rarely disappeared, despite the persistence of articular complaints. Initial chronic gut inflammation implied a high risk of evolution to ankylosing spondylitis. Evolution to inflammatory bowel disease (IBD) was observed in 7% of patients. Mainly patients with initial chronic inflammation and mild complaints of diarrhea were at risk. Sulfasalazine was more frequently needed in the treatment of patients with gut inflammation with a beneficial effect on articular and intestinal evolution but did not prevent evolution to IBD. CONCLUSIONS: This study supports the etiopathogenetic role of the gut in SpA. Presence of chronic gut inflammation and mild complaints of diarrhea implies a high risk of evolution to ankylosing spondylitis and IBD. Sulfasalazine has a beneficial effect on articular activity by controlling gut inflammation, but it cannot prevent evolution to overt IBD. (Gastroenterology 1996 Jun;110(6):1696-703)     

Iron deficiency anemia in inflammatory bowel disease

Anemia is a common extraintestinal manifestation of inflammatory bowel disease(IBD) and is frequently overlooked as a complication. Patients with IBD are commonly found to have iron deficiency anemia(IDA) secondary to chronic blood loss, and impaired iron absorption due to tissue inflammation. Patients with iron deficiency may not always manifest with signs and symptoms; so, hemoglobin levels in patients with IBD must be regularly monitored for earlier detection of anemia. IDA in IBD is associated with poor quality of life, necessitating prompt diagnosis and appropriate treatment. IDA is often associated with inflammation in patients with IBD. Thus, commonly used labora-tory parameters are inadequate to diagnose IDA, and newer iron indices, such as reticulocyte hemoglobin content or percentage of hypochromic red cells or zinc protoporphyrin, are required to differentiate IDA from anemia of chronic disease. Oral iron preparations are available and are used in patients with mild disease activity. These preparations are inexpensive and con-venient, but can produce gastrointestinal side effects, such as abdominal pain and diarrhea, that limit their use and patient compliance. These preparations are partly absorbed due to inflammation. Non-absorbed iron can be toxic and worsen IBD disease activity. Although cost-effective intravenous iron formulations are widely available and have improved safety profiles, physicians are reluctant to use them. We present a review of the pathophysiologic mechanisms of IDA in IBD, improved diagnostic and therapeutic strategies, efficacy, and safety of iron replacement in IBD.     

Arterial structure and function in inflammatory bowel disease

Inflammatory bowel disease(IBD) is the result of a combination of environmental,genetic and immunologic factors that trigger an uncontrolled immune response within the intestine,which results in inflammation among genetically predisposed individuals. Several studies have reported that the prevalence of classic cardiovascular risk factors is lower among subjects with IBD than in the general population,including obesity,dyslipidaemia,diabetes and hypertension. Therefore,given the risk profile of IBD subjects,the expected cardiovascular morbidity and mortality should be lower in these patients than in the general population. However,this is not the case because the standardized mortality ratio is not reduced and the risk of coronary heart disease is increased in patients with IBD. It is reasonable to hypothesize that other factors not considered in the classical stratification of cardiovascular risk may be involved in these subjects. Therefore,IBD may be a useful model with which to evaluate the effects of chronic low-grade inflammation in the development of cardiovascular diseases. Arterial stiffness is both a marker of subclinical target organ damage and a cardiovascular risk factor. In diseases characterized by chronic systemic inflammation,there is evidence that the inflammation affects arterial properties and induces both endothelial dysfunction and arterial stiffening. It has been reported that decreasing inflammation viaanti tumor necrosis factor alpha therapy decreases arterial stiffness and restores endothelial function in patients with chronic inflammatory disorders. Consistent with these results,several recent studies have been conducted to determine whether arterial properties are altered among patients with IBD. In this review,we discuss the evidence pertaining to arterial structure and function and present the available data regarding arterial stiffness and endothelial function in patients with IBD.     

Gut-lung crosstalk in pulmonary involvement with inflammatory bowel diseases

Pulmonary abnormalities,dysfunction or hyper-reactivity occurs in association with inflammatory bowel disease(IBD) more frequently than previously recognized.Emerging evidence suggests that subtle inflammation exists in the airways among IBD patients even in the absence of any bronchopulmonary symptoms,and with normal pulmonary functions. The pulmonary impairment is more pronounced in IBD patients with active disease than in those in remission. A growing number of case reports show that the IBD patients develop rapidly progressive respiratory symptoms after colectomy,with failure to isolate bacterial pathogens on repeated sputum culture,and often request oral corticosteroid therapy. All the above evidence indicates that the inflammatory changes in both the intestine and lung during IBD. Clinical or subclinical pulmonary inflammation accompanies the main inflammation of the bowel.Although there are clinical and epidemiological reports of chronic inflammation of the pulmonary and intestinal mucosa in IBD,the detailed mechanisms of pulmonaryintestinal crosstalk remain unknown. The lung has no anatomical connection with the main inflammatory site of the bowel. Why does the inflammatory process shift from the gastrointestinal tract to the airways? The clinical and subclinical pulmonary abnormalities,dysfunction,or hyper-reactivity among IBD patients need further evaluation. Here,we give an overview of the concordance between chronic inflammatory reactions in the airways and the gastrointestinal tract. A better understanding of the possible mechanism of the crosstalk among the distant organs will be beneficial in identifying therapeutic strategies for mucosal inflammatory diseases such as IBD and allergy.     

ICAM-1在炎症性肠病发病中的作用

炎症性肠病(IBD)是一类以肠道炎症为主要表现的慢性复发性肠道自身免疫病,近年其发病率在我国已明显升高。由于IBD的病因和发病机制尚未完全阐明,导致其治疗疗效不尽如人意。目前认为肠道持续慢性炎症是IBD难以治愈的关键,而造成肠道慢性炎症的核心机制之一是由细胞间黏附分子-1(ICAM-1)介导的肠道血循环中淋巴细胞与血管内皮细胞的黏附和渗出。本文就ICAM-1在IBD发病中的作用作一综述。     

Inflammatory bowel disease and celiac disease:Overlaps and differences

Recent findings demonstrate the common genetic basis for many immune-mediated diseases,and consequently,the partially shared pathogenesis.We collected these findings and reviewed the extension of these overlaps to other disease characteristics.Two autoimmune diseases were selected that also share the specific target organ,the bowel.The etiology and immunopathogenesis of both conditions characterized by chronic intestinal inflammation,inflammatory bowel disease(IBD)and celiac disease(CeD),are not completely understood.Both are complex diseases with genetics and environment contributing to dysregulation of innate and adaptive immune responses,leading to chronic inflammation and disease.CeD constitutes a particular disease because the main environmental and genetic triggers are largely known.IBD comprises two main clinical forms,Crohn’s disease and ulcerative colitis,which most likely involve a complex interplay between some components of the commensal microbiota and other environmental factors in their origin.These multifactorial diseases encompass a broad spectrum of clinical phenotypes and ages of onset,although the clinical presentation often differs depending on childhood or adult onset,with greater heterogeneity commonly observed in adults.     

Exploring & exploiting our ‘other self’ – Does the microbiota hold the key to the future therapy in Crohn's?

Inflammatory bowel diseases (IBD) with its two major forms Crohn's disease (CD) and ulcerative colitis (UC) are chronic relapsing disorders leading to inflammation of the gastrointestinal tract. Although the precise aetiology of IBD remains unclear, several factors are believed to contribute to disease pathogenesis. Among these, the role of the intestinal microbiota has become more and more appreciated. Evidence from experimental and clinical studies strongly suggests that chronic intestinal inflammation results from a dysregulated immune response towards components of the microbiota in genetically susceptible hosts. The growing perception of the microbiota as a major driver of disease pathogenesis raises the question, if the intestinal microbiota can be used as a therapeutic target in CD. Based on what we know about host microbiota interactions in health and disease, the objective of this review is to address the question if the microbiota holds the key to the future therapy in CD.     

Role of cytokines in inflammatory bowel disease

Inflammatory bowel disease （IBD）, which includes Crohn’s disease （CD） and ulcerative colitis （UC）, rep- resents a group of chronic disorders characterized by inflammation of the gastrointestinal tract, typically with a relapsing and remitting clinical course. Mucosal mac- rophages play an important role in the mucosal im- mune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major con- tributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development, recurrence and exacerbation of the inflammatory process in IBD. Therefore, several cyto- kine therapies have been developed and tested for the treatment of IBD patients.     

Vascular involvement in inflammatory bowel disease: pathogenesis and clinical aspects

Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD), are chronic inflammatory conditions, characterized by a microvascular and also macrovascular involvement. Chronically inflamed intestinal microvessels of IBD patients have demonstrated significant alterations in their physiology and function compared with vessels from healthy and uninvolved IBD intestine. Recently, some studies have revealed that the poor mucosal healing, refractory inflammatory ulcerations and damage in the IBD intestine could depend on microvascular dysfunction, resulting in diminished vasodilatory capacity and tissue hypoperfusion in the IBD gut. Furthermore, several data show that the activation of intestinal endothelium plays a critical role in the pathogenesis and/or in perpetuating and amplifying the inflammatory process in IBD and, consequently, it is now emerging as a potential use of anticoagulant or coagulation-related drugs in treating IBD. IBD is also associated with an increased risk of macrovascular venous and arterial thrombosis. Thrombotic events occur prevalently as deep vein thrombosis and pulmonary embolism. They happen at an earlier age than in non-IBD patients. Prothrombotic risk factors in IBD patients could be distinguished as acquired, such as active inflammation, immobility, surgery, steroid therapy, and use of central venous catheters, and inherited. Furthermore, it has been found that IBD, per se, is an independent risk factor for thrombosis. The prevention of thromboembolic events in IBD patients includes the elimination of removable risk factors and, if thrombosis occurs, a pharmacological therapy similar to that used for thromboembolic events occurring in the general population.     

克罗恩病术后治疗和溃疡性结肠炎手术时机的抉择

炎症性肠病(IBD)包括克罗恩病(CD)和溃疡性结肠炎(UC),是一种肠道慢性非特异性炎症性疾病。尽管治疗IBD的药物层出不穷,但仍有部分患者需行手术治疗。CD的术后治疗和UC手术时机的选择对患者的生活质量的提高以及预后非常重要。本文就CD的术后治疗和UC手术时机的选择作一简单概述。     

Inflammatory bowel disease is not associated with increased intimal media thickening

OBJECTIVES: Several studies have suggested that chronic inflammatory diseases might be associated with an acceleration of the atherosclerotic process. There is little information on the effect of chronic inflammation in patients with inflammatory bowel disease (IBD) on the presence of increased intimal media thickening (IMT), a surrogate marker for atherosclerotic diseases. In this work our aim was to determine whether IBD is a risk factor for increased IMT. METHODS: IMT was measured by ultrasound of the carotid arteries; a computer software program was used to analyze 80-100 independent IMT samples from each carotid artery segment in 61 patients with IBD (45 with Crohn's disease and 16 with ulcerative colitis) and in 61 controls matched for age (+/-2 yr), sex, body mass index (BMI, +/-2 kg/m(2)), and smoking status. RESULTS: Inflammatory markers (erythrocyte sedimentation rate, fibrinogen, high-sensitive C-reactive protein) were significantly (P<0.001) elevated in IBD patients compared with controls. Even though there was a disease duration of 8.7 +/- 8.5 yr, the mean IMT of IBD patients was similar to that of the control group (0.66 +/- 0.09 vs 0.64 +/- 0.07 mm; P>0.05). CONCLUSIONS: Despite chronic inflammation, IBD patients had IMT values similar to those of the controls. Thus, unlike other inflammatory diseases, IBD appears not to be a risk factor for accelerated atherosclerosis.     

Inflammatory bowel disease and cancer: The role of inflammation,immunosuppression, and cancer treatment

In patients with inflammatory bowel disease(IBD), chronic inflammation is a major risk factor for the development of gastrointestinal malignancies. The pathogenesis of colitis-associated cancer is distinct from sporadic colorectal carcinoma and the critical molecular mechanisms underlying this process have yet to be elucidated. Patients with IBD have also been shown to be at increased risk of developing extra-intestinal malignancies. Medical therapies that diminish the mucosal inflammatory response represent the foundation of treatment in IBD, and recent evidence supports their introduction earlier in the disease course. However, therapies that alter the immune system, often used for long durations, may also promote carcinogenesis. As the population of patients with IBD grows older, with longer duration of chronic inflammation and longer exposure to immunosuppression, there is an increasing risk of cancer development. Many of these patients will require cancer treatment, including chemotherapy, radiation, hormonal therapy, and surgery. Many patients will require further treatment for their IBD. This review seeks to explore the characteristics and risks of cancer in patients with IBD, and to evaluate the limited data on patients with IBD and cancer, including management of IBD after a diagnosis of cancer, the effects of cancer treatment on IBD, and the effect of IBD and medications for IBD on cancer outcomes.     

Intestinal mucosal permeability in inflammatory rheumatic diseases. II. Role of disease

Gut permeability as measured by the 51Cr-EDTA resorption test was determined in 56 patients with rheumatoid arthritis (RA), 73 patients with spondyloarthropathies (SpA), 18 patients with inflammatory bowel disease (IBD) and 97 controls (42 patients with no inflammatory rheumatic diseases and 55 healthy controls). Gut permeability was found to be increased in the 3 patient groups, partially due to the intake of antiinflammatory drugs. When only patients not taking these drugs were considered, an increased gut permeability was found in patients with SpA and IBD. In patients with RA gut permeability could not be evaluated as they were all taking antiinflammatory medication. Ileocolonoscopy with biopsies of the gut was performed in 62 of the 73 patients with SpA and disclosed subclinical gut inflammation in 21. No difference in gut permeability was found between patients with or without gut inflammation. However, when the type of gut inflammation was considered, a significant increase of gut permeability was found in patients with chronic gut inflammation compared with patients presenting acute lesions. Our findings again suggest that the chronic gut inflammation seen in SpA is fundamentally different from acute gut inflammation and possibly related to the gut inflammation of IBD.     

炎症性肠病的胃肠动力学改变

炎症性肠病（inflammatory bowel disease,IBD）是一种原因不明的顽固性难治的慢性非特异性肠炎,主要包括溃疡性结肠炎（ulcerative colitis,UC）和克罗恩病（Crohn’s disease,CD）。它的发病在我国呈逐渐上升的趋势,然而其病因和发病机制尚不明确。目前认为它是环境、遗传、病原体和机体免疫等多因素相互作用失衡产生的疾病。IBD的特点之一是慢性肠道炎症伴随有动力方面的改变。近年来,关于IBD与肠道动力之间关系的研究已经受到越来越多的关注,并已成为IBD发病机制研究的一大热点。