Diagnosing anemia in inflammatory bowel disease: Beyond the established markers

The main types of anemia in inflammatory bowel disease (IBD) are iron deficiency anemia (IDA) and anemia of inflammatory etiology, or anemia of chronic disease (ACD). In the management of IBD patients with anemia it is essential for the physician to diagnose the type of anemia in order to decide in an evidence-based manner for the appropriate treatment. However, the assessment of iron status in IBD in many cases is rather difficult due to coexistent inflammation. For this assessment several indices and markers have been suggested. Ferritin, seems to play a central role in the definition and diagnosis of anemia in IBD and transferrin, transferrin saturation (Tsat), and soluble transferrin receptors are also valuable markers. All these biochemical markers have several limitations because they are not consistently reliable indices, since they are influenced by factors other than changes in iron balance. In this review, in addition to them, we discuss the newer alternative markers for iron status that may be useful when serum ferritin and Tsat are not sufficient. The iron metabolism regulators, hepcidin and prohepcidin, are still under investigation in IBD. Erythrocytes parameters like the red cell distribution width (RDW) and the percentage of hypochromic red cells as well as reticulocyte parameters such as hemoglobin concentration of reticulocytes, red blood cell size factor and reticulocyte distribution width could be useful markers for the evaluation of anemia in IBD.     

Anemia and digestive diseases： An update for the clinician

Too often anemia is considered a rare or unimportant manifestation in inflammatory bowel disease （IBD）. However, over the last 10 years a number of studies have been conducted and the most relevant conclusions obtained are： （1） anemia is quite common in IBD; （2） although in many cases anemia parallels the clinical activity of the disease, many patients in remission have anemia, and iron, vitamin B12 and/or folic acid deficiency; （3） anemia, and also iron deficiency without anemia, have important consequences in the clinical status and quality of life of the patient; （4） oral iron can lead to gastrointestinal intolerance and failure of treatment; （5） intravenous iron is an effective and safe way to treat iron deficiency; （6） erythropoietin is needed in a significant number of cases to achieve normal hemoglobin levels. Thus, the clinician caring for IBD patients should have a comprehensive knowledge of anemia, and apply recently published guidelines in clinical practice.     

A new iron free treatment with oral fish cartilage polysaccharide for iron deficiency chronic anemia in inflammatory bowel diseases： A pilot study

AIM:To investigate the effect of a new oral preparation,highly concentrated in fish cartilage,in a group of inflammatory bowel diseases(IBD)patients with chronic iron deficient anemia.METHODS:In an open label pilot study,we supple-mented a group of 25 patients(11 with Crohn's disease and 14 with ulcerative colitis)in stable clinical conditions and chronic anemia with a food supplement which does not contain iron but contains a standardized fraction of fish cartilage glycosaminoglycans and a mixture of antioxidants(Captafer Medestea,Turin,Italy).Patients received 500 mg,twice a day during meals,for at least 4 mo.Patients were suggested to maintain their alimentary habit.At time 0 and after 2 and 4 mo,emocrome,sideremia and ferritin were examined.Paired data were analyzed with Student's t test.RESULTS:Three patients relapsed during the study(2 in the 3rd mo,1 in the 4th mo),two patients were lost to follow up and two patients dropped out(1 for orticaria,1 for gastric burning).Of the remaining 18 patients,levels of serum iron started to rapidly increase within the 2nd mo of treatment,P < 0.05),whereas serum ferritin and hemoglobin needed a longer period to significantly improve their serum levels(mo 4)P < 0.05.The product was safe,easy to administer and well tolerated by patients.CONCLUSION:These data suggest a potential new treatment for IBD patients with iron deficiency chronic anemia and warrant further larger controlled studies.     

Extraintestinal manifestations in inflammatory bowel disease

Inflammatory bowel diseases (IBD) can be really considered to be systemic diseases since they are often associated with extraintestinal manifestations, complications, and other autoimmune disorders. Indeed, physicians who care for patients with ulcerative colitis and Crohn's disease, the two major forms of IBD, face a new clinical challenge every day, worsened by the very frequent rate of extraintestinal complications. The goal of this review is to provide an overview and an update on the extraintestinal complications occurring in IBD. Indeed, this paper highlights how virtually almost every organ system can be involved, principally eyes, skin, joints, kidneys, liver and biliary tracts, and vasculature (or vascular system) are the most common sites of systemic IBD and their involvement is dependent on different mechanisms.     

Pulse cyclophosphamide therapy for inflammatory bowel disease

AIM: To assess the efficacy of intravenous cyclophosphamide pulse therapy for refractory inflammatory bowel disease (IBD). METHODS: We included in our cohort eight patients with (moderate/severe) steroid refractory IBD (4 with ulcerative colitis and 4 with Crohn's disease). They all received 6 cycles of intravenous cyclophosphamide (800 mg) per month. RESULTS: Patients entered into remission after the second/third cyclophosphamide pulse. Disease activity decreased. There were no side effects and toxicity. All the patients went into long lasting remission. All Crohn's disease patients and 3 of 4 ulcerative colitis patients achieved complete remission. One patient with ulcerative colitis showed an impressive clinical response but did not enter into remission. For the maintenance, patients with Crohn's disease were treated with methotrexate (15 mg/wk) and patients with ulcerative colitis were treated with azathioprine (2.5 mg/kg body weight/d). CONCLUSION: Remission was maintained in all patients for 6 mo on the average. The drug was well tolerated. These findings suggest that aggressive immunosuppressive therapy may be useful in some refractory patients and further controlled study should be considered in order to fully evaluate this type of treatment as a potential therapy for IBD.     

Pulse cyclophosphamide therapy for inflammatory bowel disease

AIM: To assess the efficacy of intravenous cyclophosphamide pulse therapy for refractory inflammatory bowel disease (IBD).METHODS: We included in our cohort eight patients with (moderate/severe) steroid refractory IBD (4 with ulcerative colitis and 4 with Crohn's disease). They all received 6 cycles of intravenous cyclophosphamide (800mg) per month.RESULTS: Patients entered into remission after the second/third cyclophosphamide pulse. Disease activity decreased. There were no side effects and toxicity. All the patients went into long lasting remission. All Crohn's disease patients and 3 of 4 ulcerative colitis patients achieved complete remission. One patient with ulcerative colitis showed an impressive clinical response but did not enter into remission. For the maintenance, patients with Crohn's disease were treated with methotrexate (15 mg/wk) and patients with ulcerative colitis were treated with azathioprine (2.5 mg/kg body weight/d).CONCLUSION: Remission was maintained in all patients for 6 mo on the average. The drug was well tolerated. These findings suggest that aggressive immunosuppressive therapy may be useful in some refractory patients and further controlled study should be considered in order to fully evaluate this type of treatment as a potential therapy for IBD.     

Pharmacogenetics in inflammatory bowel disease

Pharmacogenetics is the study of the association between variability in drug response and (or) drug toxicity and polymorphisms in genes. The goal of this field of science is to adapt drugs to a patient's specific genetic background and therefore make them more efficacious and safe. In this article we describe the variants in genes that influence either the efficacy or toxicity of common drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) including sulfasalazine and mesalazine, azathioprine (AZA) and 6-mercaptopurine (6-MP), methotrexate (MIX), glucocorticosteroids (CSs) and infliximab. Furthermore, difficulties with pharmacogenetic studies in general and more specifically in IBD are described. Although pharmacogenetics is a promising field that already contributed to a better understanding of some of the underlying mechanisms of action of drugs used in IBD, the only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment. In the future it is necessary to organize studies in well characterized patient cohorts who have been uniformly treated and systematically evaluated in order to quantitate drug response more objectively. An effort should be made to collect genomic DNA from all patients enrolled in clinical drug trials after appropriate informed consent for pharmacogenetic studies.     

Pediatric inflammatory bowel disease

Inflammatory bowel disease is an important cause of gastrointestinal pathology in children and adolescents. The incidence of pediatric inflammatory bowel disease is increasing; therefore, it is important for the clinician to be aware of the presentation of this disease in the pediatric population. Laboratory tests, radiology studies, and endoscopic procedures are helpful in diagnosing inflammatory bowel disease and differentiating between Crohn's disease and ulcerative colitis. Once diagnosed, the goal of medical management is to induce remission of disease while minimizing the side effects of the medication. Specific attention needs to be paid to achieving normal growth in this susceptible population. Surgical management is usually indicated for failure of medical management, complication, or malignancy. Algorithms for diagnostic evaluation and treatment of pediatric inflammatory bowel disease are presented. The specific psychosocial issues facing these patients are also discussed in this review as are the future goals of research in the complex problem of pediatric inflammatory bowel disease.     

Reticulocyte hemoglobin content (MCHr) in the assessment of iron deficient erythropoiesis in inflammatory bowel disease

BackgroundIn conditions associated with inflammation, biochemical parameters alone could be inadequate for assessing iron status. We investigated the potential utility of mean reticulocyte hemoglobin content (MCHr) in the assessment of the erythropoiesis status in inflammatory bowel disease (IBD).MethodsWe recruited 124 anemic outpatients with IBD. Serum iron, transferrin and ferritin were tested. Complete blood counts were performed on a CELL-DYN Sapphire analyzer (Abbott Diagnostics).Differences among groups were assessed using analysis of variance, considering P < 0.05 to be significant.Receiver operating characteristic analysis was used to assess the diagnostic performance of MCHr for detecting iron deficient erythropoiesis.The reference used as an indicator of insufficient iron availability was transferrin saturation <20%.ResultsOverall, 47.6% of the patients had iron deficiency anemia (IDA) and 31.5% anemia of chronic disease (ACD), while the others (20.9%) had mixed anemia.Patients with ACD or mixed anemia showed functional iron deficiency: normal or high ferritin and low MCHr. The area under curve was 0.858 (95% CI 0.742–0.942), considering a cut off 30.3 pg, the sensitivity was 82.2%, specificity 83.3%.ConclusionsMCHr provides information on iron availability in IBD patients. It is a reliable test to assess iron supply for erythropoiesis.     

Genetic factors associated with the development of inflammatory bowel disease

Crohn＇s disease （CD） and ulcerative colitis （UC） are complex polygenic disorders, characterized by several genes together with environmental factors contributing to the development of inflammatory bowel disease （IBD）. Recent advances in research on genetic susceptibility have allowed the identification of diverse genes at different levels： （1） Innate immunity; （2） Antigen presentation molecules; （3） Epithelial integrity; （4） Drug transporter; （5） Cell adhesion. The application of genetic testing into clinical practice is close and all genetic markers may have several clinical implications： prediction of disease phenotype, molecular classification, prevention of complications, and prognosis.     

High incidence of inflammatory bowel disease in The Netherlands

PURPOSE: To gain recent epidemiologic information about inflammatory bowel disease in The Netherlands, a prospective study over four years (1991–1995) was performed. METHODS: The incidence of inflammatory bowel disease and its subgroups was examined using standardized reports of newly diagnosed patients. A separate study compared the Inflammatory Bowel Disease Registration and computerized diagnostic files of a subgroup of general practitioners with the aim of estimating completeness of case ascertainment. RESULTS: The following mean incidence rates (per 100,000 inhabitants and year) were found: 6.9 (95 percent confidence interval, 5.9–7.9) for Crohn's disease, 10 (95 percent confidence interval, 8.7–11.2) for ulcerative colitis (23 percent of these with ulcerative proctitis), and 1.1 (95 percent confidence interval, 0.7–1.5) for indeterminate colitis. In the age category 20 to 29 years, the incidence rate of Crohn's disease with small-bowel involvement was higher in females than in males. In extended ulcerative colitis, a male preponderance was observed in the older age groups. Estimated case ascertainment was 78 percent. CONCLUSIONS: Compared with recent studies in neighboring countries, the observed age and gender standardized incidence rates are high in the south of The Netherlands. Completeness of case ascertainment might have contributed to this observation; however, case ascertainment was low in ulcerative proctitis. In the study area, differences in age and gender standardized incidence rates and in disease localizations could be compatible with an influence of environmental risk factors.Supported by The Development Fund, University Hospital Maastricht, Byk BV, Zwanenburg, and Pharmacia BV, Woerden, The Netherlands. The European Collaborative Study of Inflammatory Bowel Disease has been assisted by a grant of the European Communities Brussels (DG XII-F-6).     

Immunopathogenesis of inflammatory bowel disease

Crohn＇s disease and ulcerative colitis are chronic relapsing immune mediated disorders that results from an aberrant response to gut luminal antigen in genetically susceptible host. The adaptive immune response that is then triggered was widely considered to be a T-helper-1 mediated condition in Crohn＇s disease and T-helpero2 mediated condition in ulcerative colitis. Recent studies in animal models, genome wide association, and basic science has provided important insights in in the immunopathogenesis of inflammatory bowel disease, one of which was the characterization of the interleukin-23/Th-17 axis.     

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.     

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.     

Antineutrophil cytoplasmic antibodies in inflammatory bowel disease

PURPOSE: Perinuclear antineutrophil cytoplasmic antibodies have been found consistently in patients with ulcerative colitis; however, their pathogenetic and clinical role is still uncertain. In this study we tested the prevalence of perinuclear antineutrophil cytoplasmic antibodies in a large population of patients with ulcerative colitis and Crohn's disease, with particular attention to the possible correlation with clinical features. METHODS: Perinuclear antineutrophil cytoplasmic antibody reactivity was investigated with indirect immunofluorescence in 279 patients with ulcerative colitis, 110 patients with Crohn's disease, and 252 unrelated healthy subjects. RESULTS: Perinuclear antineutrophil cytoplasmic antibodies were found in 84 of 279 patients with ulcerative colitis (30 percent), 10 of 110 patients with Crohn's disease (9 percent), and 2 of 252 healthy subjects (<1 percent;P<0.001), respectively. Perinuclear antineutrophil cytoplasmic antibodies were significantly more frequent in patients with ulcerative colitis with higher relapse rate (43vs. 27 percent;P<0.002), and patients with Crohn's disease with colitis (27vs. 2.5 percent;P<0.0003). Perinuclear antineutrophil cytoplasmic antibodies were also significantly less frequent in patients with ulcerative colitis in remission (18vs. 34 percent;P<0.0025). CONCLUSIONS: In this study we confirm the relative specific of perinuclear antineutrophil cytoplasmic antibodies, either for ulcerative colitis or for Crohn's disease involving the colon. Perinuclear antineutrophil cytoplasmic antibodies were more frequently found in patients with ulcerative colitis with a more aggressive clinical behavior; however, their presence had a limited value in identifying homogeneous subgroups of patients in our population.Presented in part at the Digestive Disease Week Meeting, San Francisco, California, May 19 to 22, 1996.     

糖皮质激素治疗炎症性肠病的随访研究

目的 回顾性分析糖皮质激素治疗炎症性肠病(IBD)1个月的疗效及1年后的转归.方法 1998年1月至2006年9年确诊为克罗恩病(CD)患者55例,溃疡性结肠炎(UC)患者154例,评估口服糖皮质激素治疗1个月和1年后的疗效.Logistic回归分析决定预后的影响因子.结果 共有21例(38.2%)CD患者和20例(13.0 %)UC患者口服糖皮质激素(2例UC患者失访).经1个月治疗后,21例CD患者中完全缓解15例(71.4%),部分缓解3例(14.3%),无效3例(14.3%);18例UC患者中,完全缓解15例(83.3%),部分缓解3例(16.7%).随访1年时,21例CD患者中,维持完全或部分缓解11例(52.4%),激素依赖6例(28.6%),被迫接受外科手术者4例(19.0%),18例UC患者中,维持完全或部分缓解11例(61.1%),激素依赖3例(16.7%),手术4例(22.2%).Logistic回归分析显示,发病时血清白蛋白水平与1年后的疗效有关(OR=1.320,95%CI:1. 032～1.690,P=0.027).结论 IBD患者对首次激素治疗有效,近期疗效良好.但无法长期维持缓解状态,亦无法降低手术风险.其预后与血清白蛋白水平相关.     

Micro-RNAs as regulators and possible diagnostic bio-markers in inflammatory bowel disease

Not fully defined pathophysiologic mechanisms of inflammatory bowel disease (IBD) involve an array of genetic, epigenetic, infectious, physiological and immunological factors. Nowadays, an inadequate activation of the innate immune system to a luminal factor occurring in genetically predisposed subjects is the most widely accepted today. Micro-autoimmune diseases, a group of small, single-stranded, non-coding RNA molecules act as potent negative gene regulators. Beyond cancer and various autoimmune diseases, their impact on IBD has recently been the focus of research. Differential expression of various micro-RNAs has been documented in active and inactive ulcerative colitis, while micro-RNA profile appears to differ between ileal and colonic Crohn's disease. Except for tissue samples, attempts have been made to estimate similar differences at patients' blood samples. Apart from offering new directions in related research, these molecules arise as useful diagnostic tools and potential therapeutic targets. This review focuses on micro-RNA alterations in IBD and their potential implication on immunologic deregulation.     

Surgery for inflammatory bowel disease

Despite the new and ever expanding array of medications for the treatment of inflammatory bowel disease （IBD）, there are still clear indications for operative management of IBD and its complications. We present an overview of indications, procedures, considerations, and controversies in the surgical therapy of IBD.     

Venous thromboembolism with inflammatory bowel disease

Venous thrombosis and thromboembolism appear to be increased in patients with inflammatory bowel disease. Although several acquired and genetic risk factors are known, about half that develop a thromboembolic event have no identifiable risk factor. Control of the inflammatory process is thought to be the key factor in risk reduction for thrombotic events. Prophylactic use of anticoagulants is not universally recommended, but possible use should be reviewed in an individual patient after evaluation of the risks, such as hemorrhage, compared to potential benefits. Particular consideration should be given if there has been a prior thrombotic event, if hospitalization will require surgery, or if an underlying coagulation disorder is present.