Management of Anemia in Patients with Inflammatory Bowel Disease (IBD)

Purpose of Review

Anemia is the most common complication as well as an extra intestinal manifestation of inflammatory bowel disease (IBD). It is associated with a significant impact on patient’s quality of life (QoL); as well it represents a common cause of frequent hospitalization, delay of hospital inpatient discharge and overall increased healthcare burden. In spite of all these, anemia is still often underdiagnosed and undertreated. Our aim in this review is to provide a pathway for physicians to help them achieve early diagnosis as well as timely and appropriate treatment of anemia which in turn would hopefully reduce the prevalence and subsequent complications of this condition among IBD patients.

Recent Findings

The etiology of anemia among IBD patients is most commonly due to iron deficiency anemia (IDA) followed by anemia of chronic disease. Despite this, more than a third of anemic ulcerative colitis (UC) patients are not tested for IDA and among those tested and diagnosed with IDA, a quarter are not treated with iron replacement therapy. A new algorithm has been validated to predict who will develop moderate to severe anemia at the time of UC diagnosis. While oral iron is effective for the treatment of mild iron deficiency-related anemia, the absorption of iron is influenced by chronic inflammatory states as a consequence of the presence of elevated levels of hepcidin. Also, it is important to recognize that ferritin is elevated in chronic inflammatory states and among patients with active IBD, ferritin levels less than 100 are considered to be diagnostic of iron deficiency. Newer formulations of intra-venous (IV) iron have a good safety profile and can be used for replenishment of iron stores and prevention of iron deficiency in the future.

Summary

Routine screening for anemia is important among patients with IBD. The cornerstone for the accurate management of anemia in IBD patients lies in accurately diagnosing the type of anemia. All IBD patients with IDA should be considered appropriate for therapy with iron supplementation whereas IV administration of iron is recommended in patients with clinically active IBD, or for patients who are previously intolerant to oral iron, with hemoglobin levels below 10 g/dL, and in patients who need erythropoiesis-stimulating agents (ESAs). As the recurrence of anemia is common after resolution, the monitoring for recurrent anemia is equally important during the course of therapy.

     

Emerging causes of iron deficiency anemia refractory to oral iron supplementation

While oral iron supplementation is commonly used throughout many clinical setting,treatment with intravenous(IV) iron has historically been reserved for specific settings,such as chronic kidney disease,gynecologic issues,and anemia associated with cancer and its treatments.However,the use of IV iron has begun to gain popularity in the treatment of iron deficiency anemia(IDA) associated with two conditions that are being seen more frequently than in years past:patients who are status post gastric bypass procedure and those with inflammatory bowel disease(IBD).The Roux-en-Y procedure involves connecting a gastric pouch to the jejunum,creating a blind loop consisting of distal stomach,duodenum,and proximal jejunum that connects to the Roux limb to form a common tract.IDA occurs in 6%-50% of patients who have undergone a gastric bypass,the etiology being multifactorial.The proximal gastric pouch,the primary site of gastric acid secretion,is bypassed,resulting in a decreased ability to metabolize molecular iron.Once metabolized,most iron is absorbed in the duodenum,which is entirely bypassed.After undergoing bypass procedures,most patients significantly limit their intake of red meat,another factor contributing to post-bypass IDA.Chronic anemia occurs in approximately 1/3 of patients who suffer from IBD,and almost half of all IBD patients are iron deficient.IBD leads to IDA through multiple mechanisms,including chronic intestinal blood loss,decreased absorption capabilities of the duodenum secondary to inflammation,and an inability of many IBD patients to tolerate the side effects of oral ferrous sulfate.In this study,we reviewed the charts of all patients who received IV iron at Sylvester Comprehensive Cancer Center/University of Miami Hospital Clinic from January 2007 to May 2012.The most common indications for IV iron were for issues related to cancer and its treatment(21.9%),IBD(20.1%),and gastric bypass(15.0%).Of the 262 patients who received IV iron,230 received iron sucrose and 36 received iron dextran.While doses of 100,200,300,and 400 mg of iron sucrose were given,100 and 200 mg were by far the most common dosages used,122 and 120 times,respectively.The number of dosages of iron sucrose given ranged from 1 to 46,with a mean of 5.5 and a median of 4 doses.The average dose of iron dextran given was 870.5 mg,with 1000 mg being the most common dosage used.Most patients(22 of 36) who received iron dextran only received one dose.While patients with traditional indications for IV iron,such as gynecologic issues and kidney disease,still were represented in this study,we expect to see a continued increase in physicians using IV iron for emerging gastrointestinal indications,especially considering the increased safety of new low-molecular formulations.     

Treatment of iron deficiency anemia associated with gastrointestinal tract diseases

The gastrointestinal (GI) tract is a common site of bleeding that may lead to iron deficiency anemia (IDA). Treatment of IDA depends on severity and acuity of patients’ signs and symptoms. While red blood cell transfusions may be required in hemodynamically unstable patients, transfusions should be avoided in chronically anemic patients due to their potential side effects and cost. Iron studies need to be performed after episodes of GI bleeding and stores need to be replenished before anemia develops. Oral ...     

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.     

Management of Iron-Deficiency Anemia in Inflammatory Bowel Disease: A Systematic Review

Anemia is the most frequent complication of inflammatory bowel disease (IBD), but anemia, mostly due to iron deficiency, has long been neglected in these patients.The aim was to briefly present the pathophysiology, followed by a balanced overview of the different forms of iron replacement available, and subsequently, to perform a systematic review of studies performed in the last decade on the treatment of iron-deficiency anemia in IBD.Given that intravenous therapies have been introduced in the last decade, a systematic review performed in PubMed, EMBASE, the Cochrane Library, and the websites of WHO, FDA, and EMA covered prospective trials investigating the management of iron-deficiency anemia in IBD published since 2004.A total of 632 articles were reviewed, and 13 articles (2906 patients) with unique content were included. In general, oral supplementation in iron-deficiency anemia should be administered with a target to restore/replenish the iron stores and the hemoglobin level in a suitable way. However, in patients with IBD flares and inadequate responses to or side effects with oral preparations, intravenous iron supplementation is the therapy of choice. Neither oral nor intravenous therapy seems to exacerbate the clinical course of IBD, and intravenous iron therapy can be administered even in active disease stages and concomitantly with biologics.In conclusion, because many physicians are in doubt as to how to manage anemia and iron deficiency in IBD, there is a clear need for the implementation of evidence-based recommendations on this matter. Based on the data presented, oral iron therapy should be preferred for patients with quiescent disease stages and trivial iron deficiency anemia unless such patients are intolerant or have an inadequate response, whereas intravenous iron supplementation may be of advantage in patients with aggravated anemia or flares of IBD because inflammation hampers intestinal absorption of iron.     

Common misconceptions in the diagnosis and management of anemia in inflammatory bowel disease

Anemia is the most common systemic complication of inflammatory bowel disease (IBD); so common that it is almost invariably not investigated and rarely treated. Several misconceptions are the reason for these clinical errors, and our goal will be to review them. The most common misconceptions are: anemia is uncommon in IBD; iron deficiency is also uncommon; just by treating the intestinal disease, anemia will be corrected; iron deficiency is the only cause for anemia in IBD; ferritin is an accurate parameter for the diagnosis of iron deficiency in IBD; the impact of anemia on the quality of life of IBD patients is limited; iron supplementation is rarely needed in IBD; high-dose oral iron solves the problem of iron malabsorption in IBD; intravenous (IV) iron is dangerous and of no proven benefit in IBD; IV iron is useful only for severe anemia; and erythropoietin has no role in the treatment of IBD anemia. These misconceptions are not evidence-based. On the contrary, there is enough evidence to support the following statements: (a) anemia is very common in IBD, (b) anemia should be investigated with care because many factors can be responsible, (c) treatment of anemia results in clear improvement in the objective parameters of well-being, especially in the quality of life, (d) IV iron is safe and effective in the treatment of iron deficiency anemia in IBD patients, and (e) erythropoietin is useful in a subset of patients with refractory anemia. Anemia diagnosis and treatment must not be neglected in IBD patients, and several misconceptions should be promptly abandoned.     

炎症性肠病并发缺铁性贫血的诊治

贫血是炎症性肠病(IBD)患者常见的肠外并发症之一,会导致生活质量下降,也可增加患者的住院频率。据报道IBD并发贫血的发病率为6%～74%[1]。尽管在IBD患者中导致贫血是多因素的,但缺铁性贫血(IDA)是最常见的[2]。本文就近年来有关IBD合并缺铁性贫血的诊断及治疗研究作一概述。     

Treatment of iron deficiency anemia in pediatric inflammatory bowel disease

Opinion statement Anemia is a frequent extraintestinal manifestation of inflammatory bowel disease (IBD) that is commonly overlooked, despite its significant impact on quality of life. Characteristic symptoms include chronic fatigue, headache, and subtle impairment of cognitive function, although some less common symptoms include dyspnea, dizziness, pica, angular stomatitis, shortened attention span, and esophageal webs. Several types of anemia are associated with IBD, but iron deficiency anemia (IDA) accounts for the majority of cases and others include anemia of chronic disease, anemia associated with vitamin deficiency (vitamin B₁₂ and folate), autoimmune anemia, and anemia caused by medication used to treat IBD. The diagnosis of IDA relies on laboratory blood tests. Therefore, these tests should be obtained on a regular basis because characteristic symptoms may be absent or not readily recognized by patients and their clinicians. Complete blood count may suffice; however, iron studies and serum vitamin levels may be necessary to differentiate between specific types of anemia. During the diagnostic process, it is important to consider coexistence of different types of anemia, especially if no response to therapy is noted. The therapy for anemia is directed towards treatment of the underlying inflammatory process and supplemental therapy, depending on the type of deficiency. Iron deficiency anemia is treated with iron preparations, first orally, and if unresponsive or if associated with untoward adverse events leading to decrease in adherence with the therapeutic regimen, with intravenous preparations. Intramuscular therapy has been abandoned due to high rate of complications. Intravenous therapy may be administered as a multiple-dose regimen (intravenous iron sucrose and gluconate) or as a single intravenous dose (iron dextran), which is associated with a higher risk of allergic infusion reactions and requires obligatory test dose administration. Treatment with erythropoietin is reserved for a select subgroup of patients with anemia of chronic disease. With appropriate treatment, the majority of patients with IBD will have significant improvement or resolution of anemia, which can lead to a better quality of life. However, a high index of suspicion should be maintained in order to identify the precise cause of anemia and to prescribe the appropriate therapy.     

Stimulating erythropoiesis in inflammatory bowel disease associated anemia

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.     

Intravenous iron sucrose versus oral iron supplementation for the treatment of iron deficiency anemia in patients with inflammatory bowel disease--a randomized, controlled, open-label, multicenter study

OBJECTIVES: Anemia is a frequent complication in patients with inflammatory bowel disease (IBD). The optimal route for iron supplementation to replenish iron stores has not been determined so far. We therefore evaluated the efficacy and safety of intravenous iron sucrose as compared with oral iron sulfate for the treatment of iron deficiency anemia (IDA) in patients with IBD. METHODS: A randomized, prospective, open-label, multicenter study was performed in 46 patients with anemia and transferrin saturation 相似文献   

Iron replacement therapy in inflammatory bowel disease patients with iron deficiency anemia: A systematic review and meta-analysis

Background and aimsIron deficiency anemia (IDA) is a common problem in patients with Inflammatory Bowel Disease (IBD) and has a significant negative impact on quality of life. The aim was to compare the clinical efficacy of intravenous (IV) versus oral (PO) iron replacement in adult IBD with iron deficiency anemia (IDA).MethodsA systematic search for randomized controlled trials comparing the efficacy of IV versus PO iron therapy in the treatment of IDA in adult IBD patients. The primary outcome was the mean change in the hemoglobin at the end of study and secondary outcomes include mean change in ferritin, clinical disease activity index, quality of life score and the adverse reaction rate.ResultsThe search strategy identified 757 articles while only three industry-funded articles met the inclusion criteria for systematic review and meta-analysis. The total sample size was 333 patients with 203 patients receiving IV therapy. IV route was associated with a 6.8 g/L higher mean hemoglobin increment and 110 μg/L higher mean ferritin increment. The IBD activity index and Quality of Life scores were comparable between the two treatment groups. More adverse events were reported in the oral treatment group with the odds for discontinuation being 6.2 (CI 2.2, 17.1).ConclusionsIntravenous iron treatment is better tolerated and more effective than oral iron treatment in improving ferritin. The higher hemoglobin gain with the IV route was small and of uncertain clinical significance. The combined sample size of the included studies was small and further clinical trials are required.     

State of the iron: How to diagnose and efficiently treat iron deficiency anemia in inflammatory bowel disease

Iron deficiency anemia (IDA) frequently occurs in patients suffering from inflammatory bowel disease (IBD) and negatively impacts their quality of life. Nevertheless, the condition appears to be both under-diagnosed and undertreated. Regular biochemical screening of patients with IBD for anemia by the gastroenterology community has to be advocated.Oral iron is a low cost treatment however its effectiveness is limited by low bioavailability and poor tolerability. Intravenous (IV) iron rapidly replenishes iron stores and has demonstrated its safe use in a number of studies in various therapeutic areas. A broad spectrum of new IV iron formulations is now becoming available offering improved tolerability and patient convenience by rapidly restoring the depleted iron status of patients with IBD. The following article aims to review the magnitude of the problem of IDA in IBD, suggest screening standards and highlight existing and future therapies.     

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 in inflammatory bowel disease - the role of recombinant human erythropoietin

Anemia is a common problem in inflammatory bowel disease (IBD). It is related to low Karnofsky scores, loss of weight, impaired physical activity, low tolerance to the underlying disease, and a poor growth rate in children. Multiple factors can contribute to the anemia in IBD, such as iron, folic acid or B(12) deficiency, treatment with immunosuppressive drugs or sulfasalazine, hemolysis, and anemia of chronic disease. Anemia of chronic disease is characterized by impaired iron utilization, lower erythropoietin (EPO) production than needed, and a low response of bone marrow erythroid progenitor cells to EPO. In recent years, recombinant human erythropoietin (rhEPO) has been used in combination with iron for the correction of refractory anemia in IBD patients (adults or children) with good results. There is increasing evidence that rhEPO may correct refractory anemia in IBD (both ulcerative colitis (UC) and Crohn's disease (CD)). In addition, such therapy may give IBD patients the opportunity to predonate blood before surgery and to avoid blood transfusions. One must not forget to exclude or correct other causes of anemia in IBD patients before administering rhEPO. Furthermore, the enhancement of erythropoiesis by EPO makes it mandatory to administer oral or intravenous iron supplementation during therapy to meet the increased demand. rhEPO is safe in IBD patients. Further studies with larger numbers of patients are needed to optimize the therapy with rhEPO in the refractory anemia of IBD.     

Single values of serum transferrin receptor and transferrin receptor ferritin index can be used to detect true and functional iron deficiency in rheumatoid arthritis patients with anemia

OBJECTIVE: To elucidate the use of serum transferrin receptor (sTfR) to distinguish between iron-deficiency anemia (IDA) and anemia of chronic disease (ACD), and to establish an improved scheme to identify functional iron deficiency (FID) in rheumatoid arthritis (RA) patients with anemia. METHODS: We studied 30 anemic RA patients whose iron status was confirmed by bone marrow examination and determination of the sTfR level, serum ferritin level, and sTfR-log ferritin index (TfR-F Index). All patients with diminished or exhausted iron stores (n = 18) received oral iron supplementation. RESULTS: Baseline values of sTfR and the TfR-F Index predicted the response correctly in all patients who received supplementation treatment and were normal in 10 of 11 patients with normal initial iron stores (ACD). CONCLUSION: The results of this study elucidate the roles of sTfR and the TfR-F Index in the differential diagnosis between IDA and ACD and provide direct evidence that these parameters are useful in detecting FID, irrespective of the concurrent iron storage status.     

Anemia and iron deficiency in gastrointestinal and liver conditions

Iron deficiency anemia(IDA) is associated with a number of pathological gastrointestinal conditions other than inflammatory bowel disease, and also with liver disorders. Different factors such as chronic bleeding, malabsorption and inflammation may contribute to IDA. Although patients with symptoms of anemia are frequently referred to gastroenterologists, the approach to diagnosis and selection of treatment as well as follow-up measures is not standardized and suboptimal. Iron deficiency, even without anemia, can substantially impact physical and cognitive function and reduce quality of life. Therefore, regular iron status assessment and awareness of the clinical consequences of impaired iron status are critical. While the range of options for treatment of IDA is increasing due to the availability of effective and well-tolerated parenteral iron preparations, a comprehensive overview of IDA and its therapy in patients with gastrointestinal conditions is currently lacking. Furthermore, definitions and assessment of iron status lack harmonization and there is a paucity of expert guidelines on this topic. This review summarizes current thinking concerning IDA as a common co-morbidity in specific gastrointestinal and liver disorders, and thus encourages a more unified treatment approach to anemia and iron deficiency, while offering gastroenterologists guidance on treatment options for IDA in everyday clinical practice.     

Anemia in inflammatory bowel disease: A neglected issue with relevant effects

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 B12and 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-administerediron 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.     

炎症性肠病合并贫血的研究进展

贫血是炎症性肠病(IBD)患者常见的并发症之一,会导致生活质量下降,也可增加患者的住院频率。据报道IBD并发贫血的发病率为6～74[1]。IBD患者贫血的发病机制尚未完全明了,铁摄入与丢失的负平衡、慢性病所致贫血、VitB12和叶酸缺乏、药物介导、炎症因子、溶血等众多因素均可能参与贫血的发生。过去普遍认为贫血是IBD不可避免的伴随症状,往往重视度不够,但最近的观点强调,贫血是此类患者明确的治疗内容。     

Supplementation with oral vs. intravenous iron for anemia with IBD or gastrointestinal bleeding: is oral iron getting a bad rap?

Although iron supplementation is commonly prescribed, the amount of elemental iron needed to achieve clinical efficacy, and the optimal method of supplementation, are under debate. Use of intravenous (IV) iron replacement is increasingly being advocated. We explore the physiology of iron supplementation, review clinical data suggesting that the typical oral dosing of iron may be excessive, and compare IV and oral methods of iron supplementation with a focus on inflammatory bowel disease (IBD). Both IV and oral iron can effectively raise hemoglobin levels in iron-deficiency anemia. There is no evidence that IV iron can raise hemoglobin at a faster pace. Side effects of oral iron are probably related to the relatively high doses of elemental iron that are typically prescribed. Emerging data suggest that low-dose iron has comparable efficacy, with fewer side effects. In IBD, both oral and IV iron are effective, and there is no convincing evidence that oral iron activates or exacerbates clinical symptoms. The use of a low starting dose of oral iron, such as one ferrous sulfate tablet per day, for treatment of iron deficiency is worth considering.