Basic and clinical aspects of osteoporosis in inflammatory bowel disease

Low bone mineral density and the increased risk of fracture in gastrointestinal diseases have a multifactorial pathogenesis. Inflammatory bowel disease （IBD） has been associated with an increased risk of osteoporosis and osteopenia and epidemiologic studies have reported an increased prevalence of low bone mass in patients with IBD. Certainly, genetics play an important role, along with other factors such as systemic inflammation, malnutrition, hypogonadism, glucocorticoid therapy in IBD and other lifestyle factors. At a molecular level the proinflammatory cytokines that contribute to the intestinal immune response in IBD are known to enhance bone resorption. There are genes influencing osteoblast function and it is likely that LRP5 may be involved in the skeletal development. Also the identification of vitamin D receptors （VDRs） and some of its polymorphisms have led to consider the possible relationships between them and some autoimmune diseases and may be involved in the pathogenesis through the exertion of its immunomodulatory effects during inflammation. Trying to explain the physiopathology we have found that there is increasing evidence for the integration between systemic inflammation and bone loss likely mediated via receptor for activated nuclear factor kappa-B （RANK）, RANK-ligand, and osteoprotegerin, proteins that can affect both osteoclastogenesis and T-cell activation. Although glucocorticoids can reduce mucosal and systemic inflammation, they have intrinsic qualities that negatively impact on bone mass. It is still controversial if all IBD patients should be screened, especially in patients with preexisting risk factors for bone disease. Available methods to measure BMD include single energy x-ray absorptiometry, DXA, quantitative computed tomography （QCT）, radiographic absorptiometry, and ultrasound.DXA is the establish method to determine BMD, and routinely is measured in the hip and the lumbar spine. There are several treatments options that have proven their effectiveness, whil     

Vascular development in inflammatory bowel disease

There are 4 major concepts in vascular development: vasculogenesis (formation of blood vessels from angioblasts), angiogenesis (formation of vascular sprouts from preexisting vessels), arteriogenesis (thickening and development of vessels) and lymphangiogenesis (formation of lymphatic vessels). In the last decade, these concepts, especially angiogenesis and lymphangiogenesis, have acquired major importance due to their role in tumoral growth and metastatic dissemination. Moreover, the activity of various diseases that involve chronic inflammation, such as asthma, psoriasis and rheumatoid arthritis, has been associated with vascular development. Several growth factors and cytokines are involved in this process and consequently investigation into these elements, both in peripheral blood and their expression in affected tissues, could elucidate the role of vascular development in diseases whose pathogenesis involves chronic inflammation, such as inflammatory bowel disease. The presence of distinct molecules involved in vascular development processes, such as vascular endothelial growth factor (VEGF), basic fibroblastic growth factor and placental growth factor, among others, has been studied in both ulcerative colitis and Crohn's disease, although not extensively. It has been suggested that the phenomena of vasculogenesis, angiogenesis and lymphangiogenesis play a critical, although not exclusive, role in the inflammation that characterizes inflammatory bowel disease. In general, the results obtained to date suggest that new vascular formation is involved in the pathogenesis of these diseases.     

Pulmonary involvement in inflammatory bowel disease

AIM:To determine the relationship of pulmonary abnormalities and bowel disease activity in inflammatory bowel disease(IBD).METHODS:Thirty ulcerative colitis(UC)and nine Crohn’s disease patients,and 20 control subjects were enrolled in this prospective study.Detailed clinical information was obtained.Extent and activity of the bowel disease were established endoscopically.Each patient underwent pulmonary function tests and high-resolution computed tomography(HRCT).Blood samples for measurement of C-reactive protein(CRP),erythrocyte sedimentation rate(ESR),angiotensin converting enzyme and total IgE were delivered by the patients.RESULTS:Ten(25.6%)patients had respiratory symptoms.A pulmonary function abnormality was present in 22 of 39 patients.Among all patients,the most prevalent abnormalities in lung functions were a decrease in forced expiratory volume in 1 s(FEV1),FEV1/forced vital capacity(FVC),forced expiratory flow(FEF)25%-75%,transfer coefficient for carbon monoxide(DLCO),DLCO/alveolar volume.Increased respiratory symptoms score was associated with high endoscopic activity index in UC patients.Endoscopic and clinical activities in UC patients were correlated with FEV1,FEV1/FVC,and FEF 25%-75%.Smoking status,duration of disease and medication were not correlated with pulmonary physiological test results,HRCT abnormalities,clinical/endoscopic disease activity,CRP,ESR or total IgE level or body mass index.CONCLUSION:It is important that respiratory manifestations are recognized and treated early in IBD.Otherwise,they can lead to destructive and irreversible changes in the airway wall.     

Etiology and pathogenesis of inflammatory bowel disease

Despite of scientific efforts during the last decades, etiology and pathogenesis of the two major inflammatory bowel diseases, namely Crohn's disease and ulcerative colitis, remain rather unclear. According to the results of multiple studies it is accepted that the development of either disease is the result of an exaggerated or insufficiently suppressed immune response to a hitherto undefined luminal antigen, probably derived from the microbial flora. This inflammatory process leads to the well-known mucosal damage and therefore a further disturbance of the epithelial barrier function, resulting in an increased influx of bacteria into the intestinal wall, even further accelerating the inflammatory process. However, these immunological disturbances that have been investigated extensively during the past years have to be considered on the genetic background of the individual patient and the environmental factors the patient is exposed to. In this review we will attempt to summarize the current knowledge about risk factors for inflammatory bowel diseases, genetic and environmental factors of IBD and focus on the immunological alterations of innate and acquired immune system underlying Crohn's disease and ulcerative colitis.     

Adipose tissue and inflammatory bowel disease pathogenesis

Creeping fat has long been recognized as an indicator of Crohn's disease (CD) activity. Although most patients with CD have normal or low body mass index (BMI), the ratio of intraabdominal fat to total abdominal fat is far greater than that of controls. The obesity epidemic has instructed us on the inflammatory nature of hypertrophic adipose tissue and similarities between mesenteric depots in obese and CD patients can be drawn. However, several important physiological differences exist between these two depots as well. While the molecular basis of the crosstalk between mesenteric adipose and the inflamed intestine in CD is largely unknown, novel evidence implicates neuropeptides along with adipocyte-derived paracrine mediators (adipokines) as potential targets for future investigations and highlight adipose tissue physiology as a potential important determinant in the course of IBD.     

营养与炎症性肠病发病

营养不良在炎症性肠病(IBD)患者中非常普遍,营养治疗也已成为IBD基础治疗的措施,但因关于营养不良究竟是IBD发病原因亦或结果一直存在争议,此文就其进展综述如下。     

Immunosuppressant therapy of inflammatory bowel disease. Pharmacologic and clinical aspects

The history of immunosuppressant drug use, both azathioprine (Aza) and 6-mercaptopurine (6-MP), in inflammatory bowel disease (IBD) over the past 20 years is briefly reviewed. The two drugs appear identical in their pharmacologic and biologic effects. Azathioprine is converted to 6-MP while in the body. Conflicting reports on the effectiveness of Aza have been published. The major National Cooperative Crohn's Disease Study (NCCDS) has found no advantage in Aza over placebo. In contrast, 6-MP was found to be effective in a large randomized trial. The shortcomings of the NCCDS reports are discussed with possible explanations for their negative findings. Our own studies, dating from 1968, are reviewed with 38 patients having been treated for up to 18 years, always in combination with small doses of steroids. Our results with Aza are similar to those of Present and Korelitz with 6-MP; about 70% of previously intractable patients improved substantially. Both Aza and 6-MP bring about healing and closure of most fistulas. Side effects can be serious but are usually manageable and, to some extent, preventable by appropriate dosage schedules. Since Aza has been approved for another benign, presumably autoimmune disease--rheumatoid arthritis--and because of its extensive use in other autoimmune diseases, we prefer to use Aza in selected patients with Crohn's disease who have failed to respond to more conventional modes of therapy. The use of immunosuppressants in ulcerative colitis is less clearly indicated.     

Cardiovascular involvement in inflammatory bowel disease: dangerous liaisons

Increasing evidence of a link between inflammatory bowel disease(IBD) and adverse cardiovascular events has emerged during the last decade.In 2014,an important number of meta-analyses and cohort studies clarified the subtle dangerous liaisons between gut inflammation and cardiovascular pathology.The evidence suggests that patients with IBD have a significantly increased risk of myocardial infarction,stroke,and cardiovascular mortality,especially during periods of IBD activity.Some populations(e.g.,women,young patients) may have an even greater risk.Current effective treatment of IBD is aimed at disease remission and seems to reduce cardiovascular risk in these patients.A beneficial effect was demonstrated for salicylates,but not for steroids or azathioprine.tumor necrosis factor-α antagonists,which are highly effective in the reduction of inflammation and in the restoration of the digestive mucosa,lead to conflicting cardiovascular effects,as they seem to reduce the risk for ischemic heart disease but increase the rate of cerebrovascular events.Future supplemental treatment strategies that may reduce the atherothrombotic risk during periods of IBD activity should be explored.     

炎症性肠病的遗传与免疫

炎症性肠病(IBD)是肠道慢性非特异性炎性疾病,包括溃疡性结肠炎(UC)和克罗恩病(CD),是常见的消化系统疾患之一.亚洲国家IBD患病率低于欧美国家,但近20年来国内发病率有明显上升趋势.     

Vascular complications associated with inflammatory bowel disease

Thromboembolic episode is a well known extraintestinal manifestation of inflammatory bowel disease, but it is a clinical rare complication. Histological and hematological studies suggest that a hypercoagulable state is involved in the pathogenesis of inflammatory bowel disease. However, the exact mechanism of hypercoagulability is still unknown. During the acute recurrences there is an increase of factor VIII, fibrinogen, platelet, factor V and decrease of antithrombin III. Hematologic disorders seem markedly correlated with the activity of the disease. We report on two patients with Inflammatory bowel disease and hypercoagulable state. We review the literature and discuss about the pathogenic mechanisms of such complication.     

Vascular endothelial growth factor in inflammatory bowel disease

BACKGROUND AND AIMS: Angiogenesis is an important component of tissue regeneration. As Inflammatory bowel disease (IBD) involves inflammation, ulceration, and regeneration of the intestinal mucosa, angiogenesis may be an integral part of IBD pathology. This study investigated the role of vascular endothelial growth factor in IBD. PATIENTS AND METHODS: The VEGF plasma (pVEGF) and serum (sVEGF) levels were assessed in patients with ulcerative colitis (UC; n=50) or Crohn's disease (CD; n=44) and in healthy controls (n=23). The immunohistochemical expression of VEGF was also assessed in surgical material from 11 patients with active IBD. RESULTS. Overall the sVEGF levels ranged from 30-899 pg/ml (median 200 pg/ml) and were significantly higher than the pVEGF levels (range 20-80 pg/ml, median 30 pg/ml). pVEGF levels were significantly lower in patients with active and quiescent CD than in healthy controls. Despite the lower pVEGF levels noted also for patients with UC, the difference was not significant. sVEGF levels were also reduced in patients with IBD, but the difference was not significant. No association of pEGF/sVEGF with beta-thromboglobulin and platelet factor 4 levels (markers of platelet activation) was noted. On immunohistochemistry VEGF was not expressed in the inflammatory component (lymphocytes and macrophages), the fibroblasts, or the muscular layer of the intestinal wall. The intestinal epithelium was negative in CD, while a cytoplasmic reactivity was noted in UC and normal controls. CONCLUSION. As VEGF is a vascular and epithelial cell survival factor, the defective VEGF response ability, confirmed here for patients with CD, may be a key element in the pathology of the disease. The pathology of UC, however, seems not to be VEGF dependent.     

Advances in the pathogenesis of inflammatory bowel disease

Most people do not develop inflammatory bowel disease (IBD) in spite of the density of the commensal flora. In the past few years, several areas of gut mucosal immunology have emerged that will permit advances in the management of IBD at the bedside. The commensal flora is only beginning to be fully appreciated as another metabolic organ in the body. Innate immunity as it relates to the gut has complemented our understanding of the adaptive immune response. The most important susceptibility gene described for Crohn’s disease, the NOD2 gene, participates in the innate immune response to pathogens. Patients carrying NOD2 mutations have an increased adaptive immune response to commensal organisms as measured by higher titers of antimicrobial antibodies, such as anti-CBir and anti-Saccharomyces cerevisiae antibodies. Toll-like receptors expressed by antigen-presenting cells (APCs) in the gut and intestinal epithelial cells also play a role in recognition of intestinal flora. Within the APC category, dendritic cells link the innate and adaptive immune systems and shape the nature of the adaptive immune response to commensal bacteria. With respect to adaptive immunity, a new signaling pathway involving a distinct helper CD4 T-cell subset producing interleukin-17 may become a target for the treatment of chronic inflammatory diseases. This review focuses on developments likely to culminate in advances in patient care.     

炎症性肠病发病机制的微生物因素

炎症性肠病(IBD)的病因和发病机制尚不明确,肠道微生物与IBD发病关系密切,IBD患者肠道菌群存在失调,有证据表明,正常人群的肠黏膜免疫系统对肠道正常菌群存在耐受,而某些具有IBD遗传易感性人群的肠黏膜免疫系统对其肠道菌群失去耐受,肠道茵群参与了 IBD的发病．肠道细菌及其产物能刺激肠黏膜免疫系统,诱发这些具有IBD遗传易感性人群肠黏膜免疫系统功能紊乱,产生异常的免疫反应．不过,探究肠道细菌与IBD发病之间的关系,尚需要进一步的临床和实验研究．     

Bacteria in the pathogenesis of inflammatory bowel disease

PURPOSE OF REVIEW: Inflammatory bowel disease is thought to result from an abnormal response to the gut microbiota. This review discusses advances in knowledge of the changes in gut microbiota and host response in inflammatory bowel disease. RECENT FINDINGS: Approximately 15% of Crohn's disease cases in western populations result from mutations in NOD2/CARD15. This disease leads to defective intestinal defensin production and defective monocyte interleukin-8 response to bacterial peptidoglycan. A similar defective interleukin-8 response and consequent delayed neutrophil recruitment have also been shown in patients with Crohn's disease who do not have the NOD2 mutation. A consequence seems to be the accumulation in tissue of macrophages containing various bacteria, perhaps particularly Escherichia coli. In keeping with this patients with Crohn's disease have circulating antibodies against bacterial flagellar proteins of enterobacteria and clostridia. In ulcerative colitis, there is less evidence for invasion by or immune response to bacteria but changes in gut microbiota include a relative deficiency of bifidobacteria. There is considerable interest in probiotic or prebiotic therapies although so far little evidence for their efficacy. SUMMARY: Molecular techniques are giving us better insight into the gut microbiota in inflammatory bowel disease that should translate into improved therapies.