losartan-potassium and Inflammatory-Bowel-Diseases

Anemia, a common complication associated with inflammatory bowel disease (IBD), is frequently overlooked in the management of IBD patients. Unfortunately, it represents one of the major causes of both decreased quality of life and increased hospital admissions among this population. Anemia in IBD is pathogenically complex, with several factors contributing to its development. While iron deficiency is the most common cause, vitamin B12 and folic acid deficiencies, along with the effects of pro-inflammatory cytokines, hemolysis, drug therapies, and myelosuppression, have also been identified as the underlying etiology in a number of patients. Each of these etiological factors thus needs to be identified and corrected in order to effectively manage anemia in IBD. Because the diagnosis of anemia in IBD often presents a challenge, combinations of several hematimetric and biochemical parameters should be used. Recent studies underscore the importance of determining the ferritin index and hepcidin levels in order to distinguish between iron deficiency anemia, anemia due to chronic disease, or mixed anemia in IBD patients. With regard to treatment, the newly introduced intravenous iron formulations have several advantages over orally-administered iron compounds in treating iron deficiency in IBD. In special situations, erythropoietin supplementation and biological therapies should be considered. In conclusion, the management of anemia is a complex aspect of treating IBD patients, one that significantly influences the prognosis of the disease. As a consequence, its correction should be considered a specific, first-line therapeutic goal in the management of these patients.

Topics: Anemia; Anemia, Iron-Deficiency; Cytokines; Dietary Supplements; Erythropoietin; Ferritins; Folic Acid Deficiency; Hemolysis; Hepcidins; Humans; Inflammatory Bowel Diseases; Iron; Prognosis; Quality of Life; Vitamin B 12 Deficiency

Anemia is common in inflammatory bowel disease (IBD), with a prevalence ranging from 8.8% to 73.7%. This wide range reflects the definitions used and the populations studied. Although many patients are reported to be asymptomatic, systematic studies have shown anemia to have a significant impact on quality of life. Consequently treatment should be instituted early. The commonest cause of anemia in IBD is iron deficiency, predominantly related to gastrointestinal blood loss. Anemia of chronic disease often occurs concomitantly, due to cytokine-mediated impaired erythropoiesis and dysregulated iron metabolism. Oral iron is a simple and effective method for treating iron deficiency, but requires long courses of treatment. It is also theoretically implicated with worsening intestinal inflammation, via the production of toxic reactive oxygen species. Intravenous iron avoids these concerns, especially with the development of ferric carboxymaltose, which allow up to 1000mg to be given rapidly. In patients failing to respond to intravenous iron, the anemia of chronic disease is most likely to be causative. In this setting evidence suggests that additional erythropoietin therapy can be effective. Blood transfusions should be avoided as part of routine management and reserved for patients with substantial acute gastro-intestinal bleeding, where there is a risk of hemodynamic compromise. This article discusses the underlying physiology of anemia in IBD, and presents the current evidence supporting treatment options available.

Topics: Anemia, Iron-Deficiency; Animals; Erythropoietin; Humans; Inflammatory Bowel Diseases; Iron

Anaemia is the most frequent extraenteric complication of inflammatory bowel disease (IBD, Crohn's disease and ulcerative colitis). A disabling complication of IBD, anaemia worsens the patient's general condition and quality of life, and increases hospitalization rates. The main types of anemia in IBD are iron deficiency anemia and anemia of chronic disease. The combination of the serum transferrin receptor with ferritin concentrations and inflammatory markers allows a reliable assessment of the iron status. Iron deficiency is usually treated with oral iron supplements. However, it is less effective in IBD and may lead to an increased inflammatory activity through the generation of reactive oxygen species. A systematic review of anemia in IBD, its pathogenetic features, epidemiology, diagnosis and therapy based on the evidence from recent studies will be the focus of this article.

Topics: Administration, Oral; Anemia, Iron-Deficiency; Epoetin Alfa; Erythropoietin; Ferritins; Humans; Inflammatory Bowel Diseases; Injections, Intravenous; Iron Compounds; Recombinant Proteins; Time Factors; Transferrin

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.

Topics: Anemia; Anemia, Iron-Deficiency; Dietary Supplements; Erythropoietin; Humans; Inflammatory Bowel Diseases; Iron; Iron Deficiencies; Prevalence; Quality of Life; Treatment Outcome

Anemia is the most common complication of inflammatory bowel disease (IBD). Control and inadequate treatment leads to a worse quality of life and increased morbidity and hospitalization. Blood loss, and to a lesser extent, malabsorption of iron are the main causes of iron deficiency in IBD. There is also a variable component of anemia related to chronic inflammation. The anemia of chronic renal failure has been treated for many years with recombinant human erythropoietin (rHuEPO), which significantly improves quality of life and survival. Subsequently, rHuEPO has been used progressively in other conditions that occur with anemia of chronic processes such as cancer, rheumatoid arthritis or IBD, and anemia associated with the treatment of hepatitis C virus. Erythropoietic agents complete the range of available therapeutic options for treatment of anemia associated with IBD, which begins by treating the basis of the inflammatory disease, along with intravenous iron therapy as first choice. In cases of resistance to treatment with iron, combined therapy with erythropoietic agents aims to achieve near-normal levels of hemoglobin/hematocrit (11-12 g/dL). New formulations of intravenous iron (iron carboxymaltose) and the new generation of erythropoietic agents (darbepoetin and continuous erythropoietin receptor activator) will allow better dosing with the same efficacy and safety.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hematinics; Hepatitis C; Humans; Inflammatory Bowel Diseases; Ribavirin

Anemia is a frequent complication in patients with inflammatory bowel disease (IBD), and is associated with decreased quality of life and increased rate of hospitalization. The primary therapeutic targets of IBD-associated anemia are iron deficiency and anemia of chronic disease. An important prognostic parameter of the success or failure of therapy is the outcome of the underlying disease. Iron deficiency should be appropriately managed with iron supplementation. However, the use of oral iron therapy is limited by several problems, the most important being gastrointestinal side effects leading occasionally to disease relapse and poor iron absorption. Intravenous iron preparations are more reliable, with iron sucrose demonstrating the best efficacy and tolerability. Treatment with erythropoietin or darbepoetin has been proven to be effective in patients with anemia, who fail to respond to intravenous iron. Patients with ongoing inflammation have anemia of chronic disease and may require combination therapy comprising of intravenous iron sucrose and erythropoietin. After initiating treatment, careful monitoring of hemoglobin levels and iron parameters is needed in order to avoid recurrence of anemia. In conclusion, anemia in the setting of IBD should be aggressively diagnosed, investigated, and treated. Future studies should define the optimal dose and schedule of intravenous iron supplementation and appropriate erythropoietin therapy in these patients.

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Inflammatory Bowel Diseases; Iron

The prevalence of anemia in patients with inflammatory bowel disease ranges from 8.8% to 73.7% depending on the patient subpopulation. Anemia, one of many extraintestinal complications of ulcerative colitis and Crohn disease, is generally defined as a hemoglobin value <120 g/L or hematocrit <0.4; severe anemia is defined as a hemoglobin level <100 g/L. Many patients have been shown to be intolerant of oral iron replacement therapy or their anemia was refractory to such supplementation. Correction of anemia through the administration of intravenous iron saccharate and/or supplemental erythropoietin has been shown to improve patient hematologic indices and quality of life. Future studies are needed to determine the type of patients at highest risk of developing severe anemia as well as the treatment interventions with the most beneficial effect.

Topics: Adolescent; Adult; Anemia; Child; Comorbidity; Erythropoietin; Female; Health Status; Hematocrit; Hemoglobins; Humans; Inflammatory Bowel Diseases; Iron Compounds; Male; Outcome Assessment, Health Care; Patient Satisfaction; Prevalence; Quality of Life; Risk Assessment; Risk Factors; Severity of Illness Index

Iron deficiency anaemia is one of the most common disorders in the world. Also, one third of inflammatory bowel disease (IBD) patients suffer from recurrent anaemia. Anaemia has significant impact on the quality of life of affected patients. Chronic fatigue, a frequent IBD symptom itself, is commonly caused by anaemia and may debilitate patients as much as abdominal pain or diarrhoea. Common therapeutic targets are the mechanisms behind anaemia of chronic disease and iron deficiency. It is our experience that virtually all patients with IBD associated anaemia can be successfully treated with a combination of iron sucrose and erythropoietin, which then may positively affect the misled immune response in IBD.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Fatigue; Folic Acid; Humans; Inflammatory Bowel Diseases; Iron; Quality of Life; Recombinant Proteins; Vitamin B 12 Deficiency

Recombinant human erythropoietin (rHuEPO) and intravenous (i.v.) iron administration may be useful tools to save blood in surgery. In the perioperative period, rHuEPO should be used in slightly anemic patients for whom an autologous predonation program is not recommended (or feasible). In such cases, i.v. iron is only given if there is a functional or real iron deficiency state. In the post-operative period, i.v. iron is administered in association with rHuEPO in an attempt to rapidly correct severe post-operative anemia. The same regimen is used for patients undergoing surgery for inflammatory bowel disease and rheumatoid arthritis. Finally, other particular categories of patients, such as those with reduced body weight (< 50 kg), candidates for surgery with increased blood needs (> 5 units), or those with a too-short period of time before surgery, also benefit from the administration of these two drugs.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anemia; Arthritis, Rheumatoid; Blood Loss, Surgical; Blood Transfusion, Autologous; Erythropoietin; Hemoglobins; Humans; Inflammatory Bowel Diseases; Infusions, Intravenous; Iron; Iron Deficiencies; Postoperative Care; Postoperative Complications; Preoperative Care; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Surgical Procedures, Operative; Time Factors

Topics: Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Female; Humans; Inflammatory Bowel Diseases; Iron; Male; Recombinant Proteins

Both anaemia of iron deficiency and anaemia of chronic disease are frequently encountered in inflammatory bowel disease. Anaemia of iron deficiency is mostly due to inadequate intake or loss of iron. Anaemia of chronic disease probably results from decreased erythropoiesis, secondary to increased levels of proinflammatory cytokines, reactive oxygen metabolites and nitric oxide. Assessment of the iron status in a condition associated with inflammation, such as inflammatory bowel disease, is difficult. The combination of serum transferrin receptor with ferritin concentrations, however, allows a reliable assessment of the iron deficit. The best treatment for anaemia of chronic disease is the cure of the underlying disease. Erythropoietin reportedly may increase haemoglobin levels in some of these patients. The anaemia of iron deficiency is usually treated with oral iron supplements. Iron supplementation may lead to an increased inflammatory activity through the generation of reactive oxygen species. To date, data from studies in animal models of inflammatory bowel disease support the theoretical disadvantage of iron supplementation in this respect. The results, however, cannot easily be extrapolated to the human situation, because the amount of supplemented iron in these experiments was much higher than the dose used in patients with iron deficiency.

Topics: Administration, Oral; Anemia, Iron-Deficiency; Dietary Supplements; Erythropoietin; Ferritins; Humans; Inflammatory Bowel Diseases; Iron; Receptors, Transferrin

The anaemia of chronic disease is the second most common anaemia in the world and is an underproduction anaemia with relatively low erythropoietin (EPO) values for the degree of the anaemia. This anaemia occurs with inflammation, infection, or malignancy and a principle question has been whether it would respond to recombinant human EPO (r-HuEPO). Several studies are now available to answer this question. In one study 12 of 16 patients with rheumatoid arthritis receiving r-HuEPO increased their haematocrits 6 percentage points or more and 11 of 12 reached normal haematocrits. Investigations of the effect of r-HuEPO on the anaemia of AIDS showed that patients with EPO levels of 500 U/L or less had an increase in the mean haematocrit of 4.6 percentage points with a decrease in red cell transfusions from 5.3 to 3.2 units per patient. Quality of life indices significantly improved in responders. When 413 patients with anaemia due to a wide variety of malignancies were randomized to r-HuEPO treatment, 58% of those receiving chemotherapy increased their haematocrits by at least 6 points over 12 weeks. Quality of life parameters of responders also significantly improved. Anaemia in three patients with inflammatory bowel disease also responded in 8-14 weeks to r-HuEPO and two of the three reached normal haemoglobin levels. It is clear that r-HuEPO can correct the anaemia of chronic disease and can improve the quality of life of responders.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Arthritis, Rheumatoid; Erythropoietin; Humans; Inflammatory Bowel Diseases; Neoplasms; Recombinant Proteins

If one reviews the literature with zeal, it is increasingly apparent that few organs escape recruitment when IBD is chronic or progressive. Insights into mucosal pathophysiology have helped with understanding the more frequent extraintestinal manifestations, but the mechanisms attendant to the development of less common events (e.g. acute pancreatitis, concurrent gluten sensitive enteropathy, or active pulmonary disease) remain either poorly studied or obscure. It is particularly interesting, however, to read reports of abnormal pulmonary function, generally of the obstructive type, correlated to measurements of abnormal intestinal permeability in patients with either active pulmonary sarcoid or pulmonary involvement in Crohn's disease. It has been further speculated that similarities in the mucosal immune system of the lung and intestine are responsible for evidence of bronchial hyperreactivity in patients with active IBD. Finally, it is important to recognize that extensions of the inflammatory process are not restricted to the development of organ-based events but may be responsible for some of the most frequent systemic abnormalities detected in IBD patients. It is now also well confirmed that the cytokine environment in IBD can support activated coagulation and, in some clinical situations, overt vascular thrombosis. The cerebrovascular complications of IBD are well recognized and range from peripheral venous thrombosis to central stroke syndromes and pseudotumor cerebri. Reports of focal white matter lesions in the brains of patients with IBD or an increased incidence of polyneuropathy may be other clinical examples of regional microvascular clotting. Microvascular injury appears to be more ubiquitously present, with reports ranging from a speculated primary causative role (e.g., granulomatous vasculitis in the mesenteric circulation) to the utility of nailbed vasospasm, in Crohn's disease, as a clinical marker for disease activity. It is also reported that IL-6 suppression of erythropoietin production is a major feature of the chronic anemia seen in active IBD. Moreover, the capacity of peripheral monocytes from active IBD patients to secrete TNF and IL-8 is reported predictive for the degree of therapeutic response from recombinant erythropoietin. These collected observations constitute another excellent example of the symmetry between basic science and clinical utility. It is from the context of applied basic science that many future therapies wi

Topics: Anemia; Animals; Brain Diseases; Bronchial Hyperreactivity; Cerebrovascular Disorders; Crohn Disease; Cytokines; Disease Models, Animal; Erythropoietin; Humans; Inflammatory Bowel Diseases; Interleukin-6; Lung Diseases; Lung Diseases, Obstructive; Sarcoidosis; Thrombosis

Secondary thrombocytosis is a common clinical feature. In patients with cancer, it is a risk factor for venous thromboembolic events. In inflammatory bowel disease (IBD), thrombocytosis is so far considered a marker of active disease and may contribute to the increased thromboembolic risk in this population. Observed effects of iron therapy on normalization of platelet counts led us to hypothesize that iron itself may regulate megakaryopoiesis. Here, we want to test the effect of iron replacement on platelet count and activity in IBD-associated thrombocytosis.. We performed a randomized, single-blinded placebo-controlled trial testing the effect of ferric carboxymaltose (FCM) in patients with IBD with secondary thrombocytosis (platelets > 450 G/L). Changes in platelet counts, hemoglobin, iron parameters, disease activity, megakaryopoietic growth factors, erythropoietin, and platelet activity were assessed. Patients received placebo or up to 1500 mg iron as FCM. Endpoints were evaluated at week 6.. A total of 26 patients were included in the study, 15 patients were available for the per protocol analysis. A drop in platelets >25% (primary endpoint) was observed in 4 of 8 (50%, iron group) and 1 of 7 patients (14%, placebo group, P = 0.143). Mean platelet counts dropped on FCM but not on placebo (536 G/L to 411 G/L versus 580 G/L to 559 G/L; P = 0.002). Disease activity and megakaryopoietic growth factors remained unchanged and hemoglobin and iron parameters increased on FCM. The normalization of platelet counts was associated with a decrease in platelet aggregation and P-selectin expression.. FCM lowers platelet counts and platelet activation in patients with IBD-associated secondary thrombocytosis.

Topics: Adolescent; Adult; Anemia, Iron-Deficiency; Erythropoietin; Female; Ferric Compounds; Hepcidins; Humans; Inflammatory Bowel Diseases; Intercellular Signaling Peptides and Proteins; Male; Maltose; Middle Aged; P-Selectin; Platelet Activation; Platelet Aggregation; Platelet Count; Prognosis; Prospective Studies; Thrombocytosis; Young Adult

Anemia is a common complication of inflammatory bowel disease (IBD) and iron deficiency (ID) is its predominant cause. Therefore, oral and intravenous iron replacements are widely used. This study was performed to evaluate the frequency and timing of anemia and ID recurrence after a successful treatment cycle.. Medical records of patients who had received iron sucrose with or without erythropoietin (EPO) in one of three prospective clinical trials that had been conducted at our center (Ann Intern Med 1997, Digestion 1999, and Am J Gastroenterol 2001) were analyzed for a 5-year follow-up period. The risk for recurrence of anemia (hemoglobin (Hb)<12/13 g per 100 ml) and ID (ferritin <30 microg/l) was evaluated by Kaplan-Meier analysis using the log-rank test.. Eighty-eight patients were available for analysis. Patients had received a mean iron dose of 2,500 mg (range 600-3,600 mg); 33 (37.1%) patients had also received EPO. Anemia recurred in a median of 10 months (95% confidence interval (CI) 8-12) and ID recurred within 19 months (95% CI 11-28). The iron dose had no influence on recurrence of ID or anemia. ID (but not anemia) recurred faster in patients with a post-treatment ferritin level <100 microg/l (median 4 months, 95% CI 1-7) than in patients with ferritin level between 100 and 400 microg/l (median 11 months, 95% CI 6-16) and >400 microg/l (median 49 months, 95% CI 32-66; P<0.001).. IBD-associated ID and anemia recur surprisingly fast, indicating that maintenance treatment may be needed in a portion of the patient population. Recurrence of ID (but not anemia) can be delayed by aiming for high post-treatment ferritin levels.

Topics: Adult; Anemia, Iron-Deficiency; Dose-Response Relationship, Drug; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Follow-Up Studies; Glucaric Acid; Hemoglobins; Humans; Inflammatory Bowel Diseases; Injections, Intravenous; Iron; Male; Prognosis; Prospective Studies; Recurrence; Treatment Outcome

Inflammatory bowel disease (IBD)-associated anemia responds to i.v. iron therapy. However, because of concurrent chronic inflammation, some patients do not respond adequately. Erythropoietin therapy has been shown to be effective in the latter cohort. Our goal was to find parameters that can predict the effectiveness of iron sucrose in IBD-associated anemia.. One hundred three patients with severe IBD-associated anemia (Hb < or = 10.5 g/dl) were treated prospectively for 4 wk with iron sucrose (total iron dose = 1.2 g) in an open label, multicenter trial. Treatment response was defined as an increase in Hb of > or =2.0 g/dl. A logistic regression analysis was performed with treatment response as the dependent variable and the following independent variables: serum erythropoietin, mean corpuscular Hb, transferrin, ferritin, soluble transferrin receptor (sTfR), C-reactive protein, interleukin 6 (IL-6), and disease activity.. Sixty-seven of 103 patients (65%) responded to iron sucrose. From the variables under investigation, erythropoietin, sTfR, transferrin, and IL-6 were significantly associated with treatment response. The R2 values showed that erythropoietin (8.0%), sTfR (11.4%), and transferrin (10.4%), but not IL-6 (1.3%), contribute a relevant amount of information to the model. An estimated 80% probability of treatment response was found at erythropoietin levels of >166 U/L, sTfR levels of >75 nmol/L, or transferrin levels of >3.83 g/L.. Serum erythropoietin, sTfR, and transferrin concentrations have the potential to predict the response to iron sucrose therapy in IBD-associated anemia. These parameters may help to identify individuals who benefit the most from additional erythropoietin treatment.

Topics: Anemia, Iron-Deficiency; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Inflammatory Bowel Diseases; Interleukin-6; Logistic Models; Male; Prospective Studies; Receptors, Transferrin; ROC Curve; Sensitivity and Specificity; Transferrin; Treatment Outcome

Topics: Anemia, Iron-Deficiency; Double-Blind Method; Erythropoietin; Humans; Inflammatory Bowel Diseases; Iron; Prospective Studies; Recombinant Proteins

Topics: Adolescent; Anemia; Anemia, Iron-Deficiency; Biomarkers; C-Reactive Protein; Celiac Disease; Child; Erythropoietin; Female; Ferritins; Folic Acid; Hemoglobins; Hepcidins; Humans; Infections; Inflammatory Bowel Diseases; Iron; Male; Receptors, Transferrin; Transferrin; Vitamin B 12

Inflammatory Bowel Disease (IBD) is recognized as a group of chronic inflammatory disorders, localized in the gastrointestinal tract, which does not have a cure known. Indeed, the pharmacological approaches, commonly used, demonstrate significant toxicity, which highlights the need of investigating new possible treatments. Erythropoietin (EPO) is clinically used in anemic patients, with chronic renal insufficiency, due to its erythropoietic effect. However, it has also been described other non-erythropoietic effects, such as an anti-inflammatory role. There is already preclinical evidence about its anti-inflammatory effect in the IBD context, namely in an acute model of colitis in mice. Therefore, it is relevant to ascertain its anti-inflammatory effect in a chronic model, but mainly its hematopoietic side effect, during chronic treatment.. This experiment aims to evaluate the efficacy and safety of EPO treatment in a chronic 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis model in rodents.. The induction of chronic colitis consistedofn five weekly intrarectal administrations of 1% TNBS, and then mice were treated daily with 500 IU/Kg or 1000 IU/Kg of EPO, through intraperitoneal injections, for 14 days.. EPO demonstrated a significant anti-inflammatory effect, translated by a significant reduction of the concentration oftumorr necrosis factor-α, fecal calprotectin, and fecal hemoglobin. Moreover, it has also been demonstrated to be safe, considering the cardiovascular system, in terms of extraintestinal manifestations, namely at renal and hepatic functions.. EPO demonstrated to be a promising pharmacological approach to be considered in the management of IBD, being an interesting target for drug repositioning.

Topics: Animals; Anti-Inflammatory Agents; Chronic Disease; Colitis; Erythropoietin; Graft vs Host Disease; Inflammatory Bowel Diseases; Mice; Trinitrobenzenesulfonic Acid

Topics: Adalimumab; Adolescent; Adult; Anemia; C-Reactive Protein; Chronic Disease; Colitis, Ulcerative; Crohn Disease; Erythropoietin; Female; Ferritins; Hemoglobins; Hepcidins; Humans; Inflammatory Bowel Diseases; Infliximab; Interleukin-6; Iron; Male; Middle Aged; Peptide Hormones; Tumor Necrosis Factor-alpha; Young Adult

The prevalence of inflammatory bowel disease (IBD) is increasing. Since patients usually need long-term treatment and suffer from reduced quality of life, there is a need to develop new therapeutic strategy. The aim of this study was to investigate the therapeutic potential of erythropoietin (EPO) for the treatment of IBD.. Murine colitis was induced by 3.0% Dextran Sulfate Sodium (DSS). Recombinant human EPO (rhEPO) was given to evaluate the anti-inflammatory and regenerative effects on intestinal inflammation. The effect of rhEPO on human colon epithelial cells was also evaluated. Immunohistochemical analysis of EPO receptor was performed in human IBD tissues.. While about 62% of control mice with severe colitis induced by 5-day DSS died, 85% of mice treated with rhEPO survived. Histological analysis confirmed that EPO treatment reduced the colonic inflammation. Furthermore, EPO treatment significantly downregulated the local expressions of IFN-γ, TNF-α and E-selectin in the colon, suggesting that the effect was associated with inhibiting local immune activation. In a 4-day DSS-induced colitis model, rhEPO significantly improved the recovery of body weight loss compared to controls. Furthermore, proliferating cell nuclear antigen expression was significantly upregulated in the colon tissue from mice treated with rhEPO compared to controls. In addition, rhEPO increased the growth of cultured human colon epithelial cells in a dose-dependent manner. Furthermore, EPO-receptor expression was confirmed in human IBD colon tissues.. Three major functions of EPO, hematopoiesis, anti-inflammation and regeneration, may produce significant effects on intestinal inflammation, therefore suggesting that rhEPO might be useful for IBD.

Topics: Animals; Cell Proliferation; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Erythropoietin; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; Regeneration

States of chronic inflammation such as inflammatory bowel disease are often associated with dysregulated iron metabolism and the consequent development of an anemia that is caused by maldistribution of iron. Abnormally elevated expression of the hormone hepcidin, the central regulator of systemic iron homeostasis, has been implicated in these abnormalities. However, the mechanisms that regulate hepcidin expression in conditions such as inflammatory bowel disease are not completely understood. To clarify this issue, we studied hepcidin expression in mouse models of colitis. We found that dextran sulfate sodium-induced colitis inhibited hepcidin expression in wild-type mice but upregulated it in IL-10-deficient animals. We identified two mechanisms contributing to this difference. Firstly, erythropoietic activity, as indicated by serum erythropoietin concentrations and splenic erythropoiesis, was higher in the wild-type mice, and pharmacologic inhibition of erythropoiesis prevented colitis-associated hepcidin downregulation in these animals. Secondly, the IL-10 knockout mice had higher expression of multiple inflammatory genes in the liver, including several controlled by STAT3, a key regulator of hepcidin. The results of cohousing and fecal transplantation experiments indicated that the microbiota was involved in modulating the expression of hepcidin and other STAT3-dependent hepatic genes in the context of intestinal inflammation. Our observations thus demonstrate the importance of erythropoietic activity and the microbiota in influencing hepcidin expression during colitis and provide insight into the dysregulated iron homeostasis seen in inflammatory diseases.

Topics: Animals; Bacteroides fragilis; Colitis; Dextran Sulfate; Disease Models, Animal; Erythropoiesis; Erythropoietin; Female; Hepcidins; Homeostasis; Inflammation Mediators; Inflammatory Bowel Diseases; Interleukin-10; Intestinal Mucosa; Iron; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiota; STAT3 Transcription Factor; Streptococcaceae

Topics: Animals; Erythropoiesis; Erythropoietin; Female; Hepcidins; Inflammation Mediators; Inflammatory Bowel Diseases; Intestinal Mucosa; Iron; Male; Microbiota

Topics: Animals; Erythropoiesis; Erythropoietin; Female; Hepcidins; Inflammation Mediators; Inflammatory Bowel Diseases; Intestinal Mucosa; Iron; Male; Microbiota

To describe our 15-year experience on the patients' response and safety to the use of EPO in IBD patients with refractory anemia.. Single center retrospective chart analysis of all IBD patients receiving EPO for the period 1994-2009. Patients with resistant anemia not responding to I.V. iron therapy were enrolled. Concommitant medication, medical and laboratory data on short and long-term patients' responses and safety were recorded.. In total 820 IBD files were reviewed and among 78 patients treated with I.V. iron we identified 26 patients who received EPO in concordance to our inclusion criteria. Azathioprine or methotrexate was administered in 17 patients and 7 patients received concomitant Infliximab. After EPO, 22/26 patients (84.6%) responded and peripheral blood parameters were significantly improved and blood transfusions were significantly decreased (p<0.001). Erythropoietin dose was increased in three non-responders while two patients required emergency transfusions. No adverse events were recorded.. In anemic IBD patients who are refractory to I.V. iron monotherapy, administration of EPO significantly improved peripheral blood parameters with safety. Prospective controlled trials are needed to confirm positive patients' response to EPO and identify those patients who are more likely to benefit.

Topics: Adult; Aged; Anemia, Refractory; Erythropoietin; Female; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Treatment Outcome

Secondary thrombocytosis is a clinical feature of unknown significance. In inflammatory bowel disease (IBD), thrombocytosis is considered a marker of active disease; however, iron deficiency itself may trigger platelet generation. In this study we tested the effect of iron therapy on platelet counts in patients with IBD-associated anemia.. Platelet counts were analyzed before and after iron therapy from four prospective clinical trials. Further, changes in hemoglobin, transferrin saturation, ferritin, C-reactive protein, and leukocyte counts, before and after iron therapy were compared. In a subgroup the effect of erythropoietin treatment was tested. The results were confirmed in a large independent cohort (FERGIcor).. A total of 308 patient records were available for the initial analysis. A dose-depended drop in platelet counts (mean 425 G/L to 320 G/L; p<0.001) was found regardless of the type of iron preparation (iron sulphate, iron sucrose, or ferric carboxymaltose). Concomitant erythropoietin therapy as well as parameters of inflammation (leukocyte counts, C-reactive protein) had no effect on the change in platelet counts. This effect of iron therapy on platelets was confirmed in the FERGIcor study cohort (n=448, mean platelet counts before iron therapy: 383 G/L, after: 310 G/L, p<0.001).. Iron therapy normalizes elevated platelet counts in patients with IBD-associated anemia. Thus, iron deficiency is an important pathogenetic mechanism of secondary thrombocytosis in IBD.

Topics: Anemia, Iron-Deficiency; Blood Platelets; C-Reactive Protein; Cohort Studies; Erythropoietin; Ferritins; Hemoglobins; Humans; Inflammatory Bowel Diseases; Iron; Iron Compounds; Iron Deficiencies; Leukocyte Count; Platelet Count; Prospective Studies; Thrombocytosis; Transferrin

The combination of intravenous iron and recombinant human erythropoietin has been proved to be effective in the treatment of refractory anaemia in patients with inflammatory bowel disease (IBD). Darbepoetin-alpha (DPO) has a three-fold longer terminal half-life than erythropoietin. The purpose of this pilot study was to determine whether darbepoetin-alpha is also effective for the treatment of refractory anaemia in IBD.. Twenty IBD patients (nine ulcerative colitis and 11 Crohn's disease) and refractory anaemia received intravenous iron sucrose (total iron dose 1.3+/-0.5 g, range 0.7-1.9) and darbepoetin-alfa at the single, weekly dose of 0.9 microg/kg subcutaneously for 4 weeks. Serum erythropoietin, ferritin, transferrin, soluble transferrin receptor, C-reactive protein and interleukin-6 were measured at baseline and after treatment.. Haematopoietic response (increase of haemoglobin > or = 2.0 g/dl) was observed in 15 out of the 20 patients (75%). The mean haemoglobin concentrations increased from 9.48+/-0.82 g/dl at baseline to 12.71+/-1.12 g/dl after treatment (P<0.0001). Mean corpuscular volume and serum ferritin levels were also significantly increased whereas mean C-reactive protein levels and endogenous erythropoietin levels significantly decreased after treatment.. In IBD patients with refractory anaemia the administration of darbepoetin in combination with intravenous iron sucrose can raise haemoglobin levels.

Topics: Anemia, Refractory; C-Reactive Protein; Darbepoetin alfa; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Hematinics; Hemoglobins; Humans; Inflammatory Bowel Diseases; Injections, Intravenous; Interleukin-6; Male; Pilot Projects; Receptors, Transferrin; Transferrin; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Erythropoietin; Female; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Osteoarthropathy, Secondary Hypertrophic

Iron deficiency anemia (IDA) and anemia of chronic disease (CDA) are often encountered in patients with inflammatory bowel disease (IBD). Inadequate intake or loss of iron is a clear cause of IDA, but mechanisms of CDA induction are multifactorial and involve erythropoiesis disturbance due to circulating inflammation mediators. The authors investigated erythropoietin (Epo) levels in children and adolescents with IBD and correlated them to disease activity, with the aim of gaining an improved understanding of the role of Epo in CDA. Thirty-three patients with IBD were examined (18 boys, 15 girls) ages 4 to 15 years (median 11 years). Two study groups related to the disease activity were formed: group A, those with active disease (n = 21), and group B, those in remission (n = 12). Epo levels were measured using a two-site chemiluminescence immunoassay. Predictive Epo values in response to the degree of anemia were calculated by the equation: logEpo = (3.48 - 0.20) x Hb. According to the results, CDA anemia was present only in patients with active disease. These patients also had a significantly higher possibility of altered Epo levels than expected compared with patients with inactive disease (16/21 vs. 4/12, P < 0.05). It was also interesting that most of the patients with anomalous Epo concentrations presented with an elevated Epo value compared with that expected from the calculation (14/20). It seems that disturbed Epo concentrations are correlated with disease activity in children and adolescents with IBD. It is possible that failure of the bone marrow to respond to increased Epo levels leads to further incremental response. These in turn lead to the high Epo concentrations detected in most of the authors' patients. Impaired Epo production is another mechanism of CDA development and is the one mainly expressed in patients with low Epo values.

Topics: Adolescent; Child; Disease Progression; Erythropoietin; Female; Humans; Inflammatory Bowel Diseases; Prognosis

Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of the expression of intercellular adhesion molecule-1 (ICAM-1) in the colon. Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells, and its expression is enhanced by hypoxia. Here we investigate the effects EPO has on the development of experimental colitis. To address this question, we used an experimental model of colitis induced by dinitrobenzene sulfonic acid (DNBS). When compared with DNBS-treated mice, EPO (1000 IU/kg day s.c.)-treated mice subjected to DNBS-induced colitis experienced significantly lower rates in the extent and severity of the histological signs of colon injury. DNBS-treated mice experienced diarrhea and weight loss. At 4 days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology as well as an increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) showed an intense staining in the inflamed colon. On the contrary, the treatment of DNBS-treated mice with EPO significantly reduced the degree of diarrhea and weight loss caused by administration of DNBS. EPO also caused a substantial reduction of the degree of colon injury, the rise in myeloperoxidase activity (mucosa), and the increase in staining (immunohistochemistry) for nitrotyrosine as well as the up-regulation of ICAM-1 caused by DNBS in the colon. Thus, treatment of rat with EPO reduces the degree of colitis caused by DNBS. We propose that EPO may be useful in the treatment of inflammatory bowel disease.

Topics: Animals; Benzenesulfonates; Colitis; Erythropoietin; Immunohistochemistry; Inflammatory Bowel Diseases; Intercellular Adhesion Molecule-1; Interleukin-1; Intestinal Mucosa; Male; Mice; Neutrophil Infiltration; Peroxidase; Poly Adenosine Diphosphate Ribose; Recombinant Proteins; Tumor Necrosis Factor-alpha; Tyrosine

We investigated whether the mean platelet volume would be a useful marker in the evaluation of inflammatory bowel disease activity.. Complete blood count, C-reactive protein, erythrocyte sedimentation rate, serum thrombopoietin and erythropoietin, plasma beta-thromboglobulin, and platelet factor 4 were measured in 93 patients with ulcerative colitis, 66 patients with Crohn's disease, and 38 healthy blood donors. Disease activity was assessed by the Clinical Colitis Activity Index in patients with ulcerative colitis and by the Crohn's Disease Activity Index in patients with Crohn's disease.. Mean platelet count was increased in patients with active compared to inactive ulcerative colitis (p < 0.05), and in patients with active compared to inactive Crohn's disease (p = 0.0002) or healthy controls (p < 0.0001). On the other hand, mean platelet volume was significantly decreased in patients with active compared to inactive ulcerative colitis (p = 0.02) or healthy controls (p < 0.0001), and in patients with active compared to inactive Crohn's disease (p = 0.0005) or healthy controls (p < 0.0001). Mean platelet volume was inversely correlated with the white blood cell count (r = -0.17, p = 0.02), C-reactive protein (r = -0.46, p = 0.009) and erythrocyte sedimentation rate (r = -0.28, p = 0.008). No significant correlations were found between mean platelet volume and serum thrombopoietin or erythropoietin levels; however, a strong negative correlation between mean platelet volume and beta-thromboglobulin (r = -0.34, p < 0.0001) and platelet factor 4 (r = -0.30, p = 0.0002) was observed.. Mean platelet volume is significantly reduced in active inflammatory bowel disease and is negatively correlated with the known inflammatory bowel disease activity markers and the platelet activation products. We propose that mean platelet volume provides a useful marker of activity in inflammatory bowel disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta-Thromboglobulin; Erythropoietin; Female; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Platelet Count; Platelet Factor 4; Thrombopoietin

Topics: Anemia; Anemia, Iron-Deficiency; Chronic Disease; Cytokines; Erythropoietin; Humans; Inflammatory Bowel Diseases; Intestinal Absorption; Quality of Life; Vitamin B 12 Deficiency

During the past decade relevant progress has been made in the understanding and treatment of IBD-associated anemia. Effective replacement of iron deficits has become safe by using novel intravenous iron preparations such as iron sucrose. The ability of erythropoietin to interfere with key mechanisms of myelosuppression in anemia of chronic diseases also benefits patients with IBD-associated anemia. Concerns about cost effectiveness have been raised and weighed against the potential improvement in quality of life. Gastroenterologists who are caring for IBD patients should be concerned with low hemoglobin levels, since the quality of life in these patients can be as low as in anemic patients with advanced cancer. Also provided is a structured approach to cost-effective therapy.

Topics: Anemia; Cost-Benefit Analysis; Erythropoietin; Hemoglobins; Humans; Inflammatory Bowel Diseases; Iron; Quality of Life

In 39 patients with non-specific intestinal inflammations the authors examined the erythropoietin level. They found a significantly higher level of serum erythropoietin in patients during relapse, when the organism responds to more severe anaemia by increased erythropoietin production. The idea that the reactivity of the bone marrow or effectiveness of erythropoietin is influenced by mediators of the inflammation is supported by the fact that the group comprised patients with high erythropoietin values of 102, 106.6, 109 and 445 ImU/l but their anaemia did not improve markedly. The theory on an inadequate erythropoietin secretion is supported by the fact that four patients in relapse with relatively severe anaemia had low erythropoietin levels and six patients had despite a significant drop of haemoglobin normal erythropoietin levels. Contrary to other diseases, in non-specific intestinal inflammations the erythropoietin secretion depends not only on the severity of the inflammation but probably on many other factors, incl. immunological ones.

Topics: Adolescent; Adult; Aged; Erythropoietin; Female; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Recurrence

Topics: Anemia; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Inflammatory Bowel Diseases; Iron; Recombinant Proteins

Topics: Administration, Oral; Anemia; Anemia, Iron-Deficiency; Colitis, Ulcerative; Crohn Disease; Erythropoietin; Ferrous Compounds; Humans; Inflammatory Bowel Diseases; Injections, Subcutaneous; Recombinant Proteins