European Consensus on the Diagnosis and Management of Iron Deficiency and Anaemia in Inflammatory Bowel Diseases
Anaemia is the most common systemic complication and extraintestinal manifestation of inflammatory bowel disease [IBD].1–3 In the majority of cases, IBD-associated anaemia is a unique example of the combination of chronic iron deficiency and anaemia of chronic disease [ACD].4,5 Other more rare causes of anaemia in IBD include vitamin B12 and folate deficiency, toxic effects of medications, and others. The impact of anaemia on the quality of life of IBD patients is substantial. It affects various aspects of quality of life such as physical, emotional, and cognitive functions, the ability to work, hospitalization, and healthcare costs.6 Anaemia in IBD is not just a laboratory marker; it is a complication of IBD that needs appropriate diagnostic and therapeutic approaches.3 Despite the broad use of anti-inflammatory therapy, anaemia may recur fast after successful therapy. As anaemia is a serious medical condition that may become life threatening [if blood transfusions are not available or compatible], preventive measures should be considered. Prevention of anaemia and maintenance of iron and vitamin stores are therefore warranted. The goal of this consensus initiated by the European Crohn’s and Colitis Organisation [ECCO] was to establish European consensus guidelines for the diagnosis, treatment and prevention of iron deficiency and iron deficiency anaemia [IDA], but also for non-iron deficiency anaemia and associated conditions. The consensus is based in parts on a previous evidence-based consensus publication on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases.7 The strategy to reach the consensus involved several steps and follows the standard operating procedures for consensus guidelines of ECCO. An open call for chairs and participants for this consensus was made [see acknowledgements and www.ecco-ibd]. Participants were selected by the Guidelines Committee of ECCO [GuiCom] on the basis of their publication record and a personal statement. Four working groups [WGs] were formed: WG 1 on Diagnosis of anaemia, WG 2 on Treatment of iron deficiency anaemia, WG 3 on Prevention of iron deficiency anaemia, and WG 4 on Management of non-iron deficiency anaemia. Participants were asked to answer relevant questions on current practise and areas of controversy related to the diagnosis and management of anaemia in IBD based on their experience as well as evidence from the literature [Delphi procedure].8 In parallel, the WG members performed a systematic literature search of their topic with the appropriate key words using Medline/PubMed/ISI/Scopus and the Cochrane database, as well as their own files. The evidence level [EL] was graded according to the Oxford Centre for Evidence-Based Medicine.9 Provisional guideline statements [with supporting text] were then written by the WG chairs, based upon answers to the questionnaire, and were circulated among the WG members, prompting discussions and exchange of literature evidence. The proposed statements and the supporting text were submitted to an online platform for online discussion and two online voting procedures, among all consensus participants for the first voting procedure and also for all national representatives of ECCO for the second voting procedure. The WGs finally met in Frankfurt on June 28, 2013 for a face-to-face discussion and to vote and consent on the statements. Technically this was done by projecting the statements and revising them on screen until a consensus was reached. Consensus was defined as agreement by more than 80% of participants, termed a Consensus Statement and numbered for convenience in the document. The final manuscript was written by the WG chairs in conjunction with the WG members and was revised for consistency by CG and AD. An update of this current consensus guideline is planned in about 4 years. The currently used WHO definition of anaemia [Table 1] applies also to patients with IBD. All patients with IBD should be assessed for the presence of anaemia. The major forms of anaemia in IBD are iron deficiency anaemia, anaemia of chronic disease and anaemia of mixed origin [EL 5] Minimum hemoglobin and hematocrit levels used to define anaemia in people living at sea level. 10 Minimum hemoglobin and hematocrit levels used to define anaemia in people living at sea level. 10 Normal hemoglobin varies with age and gender. Also other factors influence hemoglobin levels such as pregnancy, high altitudes, smoking, and ethnicity.11,12 The lower limits of normal hemoglobin concentration are even lower in African Americans [11.5g/dL for women, 12.9g/dL for men] and in the elderly. Interpretation of hemoglobin and hematocrit levels needs to consider such modulating factors. The definitions of anaemia in IBD is indifferent to other conditions and it is reasonable that WHO cut-offs apply.10 IBD patients should be regularly assessed for the presence of anaemia because of its high prevalence, its impact on quality of life, and comorbidity.13 About two-thirds of such patients have anaemia at diagnosis. During follow-up the prevalence and causes of anaemia may change.14 In children anaemia is even more common [about 70%] than in adults [about 30–40%].15 For laboratory screening, complete blood count, serum ferritin, and C-reactive protein [CRP] should be used. For patients in remission or mild disease, measurements should be performed every 6 to 12 months. In outpatients with active disease such measurements should be performed at least every 3 months [EL 5]. Patients at risk for vitamin B12 or folic acid deficiency [eg small bowel disease or resection] need proper surveillance. Serum levels of vitamin B12 and folic acid should be measured at least annually, or if macrocytosis is present in the absence of thiopurine use [EL 4] The risk of developing anaemia relates to disease activity, because both blood loss and ACD are triggered by intestinal inflammation. Complete [or full] blood count, CRP, and serum ferritin are minimum requirements to detect anaemia, an inflammatory flare, or iron deficiency at an early stage. Diagnostic measurement of complete blood counts and CRP has been part of previous recommendations in IBD.7,16 The recommended timelines are based on expert opinion and reflect common clinical practice, but do not apply to hospitalized patients. In patients with extensive small bowel resection, extensive ileal Crohn’s disease, ileal-anal pouch, evidence of vitamin B12 or folic acid deficiency should be assessed more frequently than once a year.17 Anaemia workup should be initiated if the hemoglobin is below normal. The minimum workup includes red blood cell indices such as red cell distribution width [RDW] and mean corpuscular volume [MCV], reticulocyte count, differential blood cell count, serum ferritin, transferrin saturation [TfS], and CRP concentration. More extensive workup includes serum concentrations of vitamin B12, folic acid, haptoglobin, the percentage of hypochromic red cells, reticulocyte hemoglobin, lactate dehydrogenase, soluble transferrin receptor, creatinine, and urea [EL 4]. Advice from a hematologist is appropriate if the cause of anaemia remains unclear after more extensive workup [EL 5] The purpose of these recommendations is to set an appropriate threshold to trigger action, and to advise on necessary tests. The initial workup of anaemia should follow a simple algorithm widely used in hematology [Figure 1]. Starting from the evaluation of MCV, the most common causes of anaemia in IBD may be recognized: microcytosis indicates iron-restricted anaemia [true or functional iron deficiency], macrocytosis may indicate B12 or folate deficiency, and normocytosis anaemia of chronic disease [ACD]. Thus, the MCV and mean corpuscular hemoglobin [MCH] are useful variables and available within the complete blood count. In ACD, they may be normal or low.18 Macrocytosis is indicative of vitamin deficiency, but also arises from thiopurine treatment [azathioprine or 6-mercaptopurine], other medications, alcohol abuse, hypothyroidism, or reticulocytosis. Anaemia classification based on MCV and reticulocytes. Anaemia can be effectively classified by using a combination of MCV and reticulocytes. Micro-, normo- and macrocytic anaemias cover all forms of anaemia, and the reticulocyte count tells whether the bone marrow can respond by increasing erythropoiesis, which gives early and important information on the direction of the investigation. All deficiency states are excluded by increased reticulocytes. Retic, reticulocyte count; N, normal; Tsat, transferrin saturation; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; DAT, direct antibody test; Hb, hemoglobin; IDA, iron deficiency anaemia; FID, functional iron deficiency; MDS, myelodysplastic syndrome; N, normal; S-ferritin, serum ferritin; Tsat, transferrin saturation; *anaemia secondary to malignancy, infection, kidney disease etc. In the next step, reticulocyte count is considered. Low or ‘normal’ reticulocytes indicate inability to respond properly to anaemia, either because of deficiencies that result in inappropriate erythropoiesis or primary bone marrow disease. Increased reticulocytes indicate increased red cell formation and therefore exclude deficiencies. Instead, hemolysis should be sought after by estimation of serum concentrations of haptoglobin, lactate dehydrogenase, and bilirubin. The minimum workup should include complete blood count with MCV, reticulocytes, serum ferritin, transferrin saturation, and CRP. In accordance with the algorithm in Figure 1, more extensive workup may include vitamin B12, folic acid, haptoglobin, a differential white blood cell count, and bone marrow smear.19 A comprehensive list of anaemias classified with MCV and reticulocytes is given in Table 2. In some situations microcytosis and macrocytosis co-exist, so that the two abnormalities may neutralize each other and result in a normal MCV. A wide of the red can in this as is an of iron of anaemia by MCV and reticulocytes from of anaemia by MCV and reticulocytes from and white blood cell counts are also available within the complete blood count and to anaemia from A soluble of the transferrin in the and its concentration is to the of transferrin It is in in situations the bone marrow needs more both in and in iron deficiency [true or An soluble transferrin is a of erythropoiesis, in the of iron deficiency in the presence of [with normal or even serum The percentage of hypochromic red cells, the hemoglobin concentration of reticulocytes, and the red blood cell are also useful for the diagnosis of iron-restricted blood cell is a which the volume of and the volume of reticulocytes. disease is not associated with an in in and may not be by clinical may be to disease in patients with a or CRP. Diagnostic for iron deficiency on the level of inflammation. In patients or evidence of active disease, serum ferritin is an appropriate [EL In the presence of a serum ferritin to may be with iron deficiency [EL 4] In the iron deficiency anaemia and ACD is both conditions In the management of IBD patients with anaemia, the of the appropriate treatment is based on this deficiency may be by blood loss from the of the with iron or iron the In the absence of or clinical evidence of iron deficiency is if the serum ferritin is In the presence of serum ferritin levels can be high iron In such cases, is an appropriate to after iron therapy, serum ferritin levels well with iron iron ferritin and levels deficiency anaemia may cause an of or The concentration of in the serum is an of the iron available for erythropoiesis ferritin, chronic has on a that the and ferritin are to iron deficiency anaemia and ACD with a high diagnostic The measurement of percentage of hypochromic red and reticulocyte hemoglobin two measurements useful in the diagnosis of functional iron deficiency, can be in In the presence of or clinical evidence of the diagnostic for ACD are a serum ferritin and the serum ferritin level is and a combination of iron deficiency and ACD is [EL The ACD includes all anaemia associated with and by chronic disease. the of on to anaemia as well as the direct of in the bone More has also that has a on iron In patients with active various the of in the which iron from the of transferrin saturation and iron to the a of functional iron deficiency for erythropoiesis and also and The in also iron from the The may to ACD with functional iron deficiency and are common for with and others. iron deficiency is defined as a with normal or iron a of iron from the a transferrin saturation in and iron in the bone which ACD with is if the serum ferritin is and the is below An in hypochromic red a of reticulocyte hemoglobin indicate FID, but as these measurements are not available in the diagnosis of is made from the combination of and normal or In the serum ferritin may be useful to exclude iron deficiency [if the is MCV may be or normal in is not MCV is but this may also be the with ACD gives reticulocyte not all IBD patients with anaemia of In an may be all the involved in anaemia, but is or not anaemia of chronic disease may with or The definitions are useful in this Anaemia of chronic disease anaemia chronic disease and by inflammatory ACD with functional iron ACD can be by and normal or [or increased levels of hypochromic red in ACD anaemia of chronic inflammatory disease of anaemia this definition is widely used for anaemia the is to a of iron in the bone either by iron deficiency or is recommended in all IBD patients iron deficiency anaemia is present [EL 1] of life with of anaemia, and this is of clinical The to iron in patients anaemia is more and on the and is evidence of in iron deficiency anaemia in other conditions such as chronic and such evidence is not available in the of The goal of iron is to hemoglobin levels and iron stores [EL 1] The lower the hemoglobin, the is the to of An in hemoglobin of at least within 4 of treatment is an of iron should be as first treatment in patients with active with previous to with hemoglobin below and in patients need [EL 1] The treatment of iron deficiency anaemia with iron has relevant in IBD patients. iron is more a and is than Thus, iron are in the of IBD-associated anaemia and were recommended also in previous iron is and well both in the of and maintenance of iron stores in patients with iron are currently available for treatment of by and can be and iron in IBD patients are available from iron and iron of to iron have been is to treatment For iron are to The can be within are also available for which is for use in chronic kidney disease and is currently in a of other conditions associated with iron deficiency, IBD and The currently available iron are not and has been direct Thus, a direct of the currently available with to and other not as and other in various are not A is for iron as they a risk for serious The risk of iron in patients are as in is a transferrin saturation and serum ferritin should be used as limits for iron is as are to and are associated with The estimation of iron need is based on hemoglobin and and this is more for the treatment of in IBD patients than based on the [EL the iron in in hemoglobin in the is to used in clinical practice, and iron The a and simple [Table with the in patients with The simple and as well as a with the iron In this clinical the simple has been used for of In clinical practice, it is also used for of other iron of this include patients with hemoglobin below need an the estimation of iron needs in iron deficiency anaemia is not A minimum of should be for estimation of iron for estimation of iron iron is in patients with IBD and may be used in patients with mild anaemia, disease is and have not been to iron anaemia has been defined by the WHO as hemoglobin in and in indicate that iron may be as as iron in a has a in ferritin and hemoglobin in of the effects from iron are of iron from the is and iron is to the intestinal has been in in of IBD indicate that iron may disease and intestinal In a in African iron and increased on iron were done with on as indicate with a even in IBD patients with a of to more than iron is recommended in patients with IBD [EL The of iron from is in can to iron stores are and iron is In and women, iron treatment is in in IBD is as are associated with more effects and lower Patients with IBD should be for iron deficiency every 3 months for at least a after and 6 and 12 months [EL 4] iron anaemia by within 10 patients with IBD should be for iron deficiency every 3 months using a combination of hemoglobin, ferritin, transferrin saturation, and CRP. anaemia may be indicative of intestinal disease even if is clinical remission and inflammatory are normal [EL 5] A intestinal disease and on and the of blood loss and of anaemia on the other important for prevention of anaemia is the treatment of the this is in clinical the to anaemia on the ability to bowel A of iron deficiency in patients should the of a on inflammatory The goal of preventive treatment is to hemoglobin and serum ferritin levels within the normal [EL deficiency can cause and quality of life even anaemia is not In it is common in clinical to iron deficiency as the of disease in IBD patients. The to iron in patients with but anaemia may on the clinical and the The for are based on the that iron is for all of the of iron deficiency may anaemia. and cognitive loss of or may be present anaemia and may upon iron Also and can be IBD-associated iron deficiency and anaemia recur frequently and even after treatment with of iron deficiency is lower in patients with ferritin levels [EL Anaemia to recur frequently and fast after iron The of relates to the of iron stores by serum serum ferritin levels of of iron deficiency within the than levels below this it was that iron at ferritin levels of to successful treatment of iron deficiency anaemia with with iron should be initiated as as serum ferritin below or hemoglobin below 12 or to As iron deficiency anaemia frequently and iron maintenance may anaemia The whether can anaemia in patients been for IBD-associated was a patients Serum ferritin was assessed every 2 months and patients of ferritin levels below of patients lower in with patients the of the to until the of the a from is and of IBD were in the and were and the was not to detect a treatment on quality of life, a in of was in of The that of anaemia in patients with IBD. In to the and the such a to anaemia management the healthcare are more than as high for with IBD patients The of non-iron deficiency anaemia by MCV and reticulocytes is recommended [EL 5] The WHO for the hemoglobin are widely and should be used also for factors pregnancy, high and age be considered. Anaemia in IBD may have causes iron The causes of in IBD are indifferent to other conditions and can be classified according to MCV and reticulocytes [Table The initial of anaemia should follow the algorithm in Figure The classification of anaemia is in Table 2. It is not that more than cause of anaemia in a may the initial diagnosis of The risk of developing anaemia relates to disease activity, because both blood loss and anaemia of chronic disease are triggered by intestinal inflammation. For differential diagnosis it should be that the causes of in IBD can be or [Table 4]. of non-iron deficiency anaemia in from of non-iron deficiency anaemia in from Anaemia of chronic disease is the most anaemia in hospitalized patients and in from that are associated with chronic of such as chronic inflammatory or ACD is by a normal or MCV and or normal reticulocyte clinical are also causes of related to IBD to to and to B12 or folic acid deficiencies. Treatment of may include of IBD folic treatment of other causes of such as or use of in cases, such as or kidney secondary or bone marrow Patients with anaemia of chronic disease with an to iron and IBD may be for treatment [EL 1] with a hemoglobin level not [EL 5] The presence of anaemia of chronic disease is a of active disease. of IBD treatment should In two the of on hemoglobin and in patients with or it was that treatment hemoglobin levels with even after for disease In IBD patients to has been to by increasing serum and has been the to anaemia in some IBD As anaemia of chronic disease from erythropoiesis secondary to increased levels of as may bone marrow It is that the of than its effects on the bone marrow the The to iron can be by reticulocyte counts after iron Patients with a diagnosis of anaemia of chronic disease, anaemia or to and may be for indicate that a majority of patients with IBD respond to treatment with an in hemoglobin and of quality of treatment is to hemoglobin of in or is in therefore the measures iron should functional iron deficiency and ferritin levels should be Low transferrin and levels are associated with to iron and may be used for of of B12 and folate should be to anaemia [EL 5] and folate may in after ileal and deficiency to and serum levels should be measured in patients with high MCV. In cases, measurement of or can be Increased indicates deficiency of either B12 or folate with a than serum B12 is for B12 deficiency and has a Serum levels of vitamin B12 and folic acid should be measured at least annually, or if macrocytosis is Patients at risk for vitamin B12 or folic acid deficiency [eg small bowel disease or resection] need surveillance. The recommended timelines are based on expert and reflect common clinical practice, but do not apply to patients with extensive small bowel resection, extensive ileal Crohn’s disease, or ileal-anal used may erythropoiesis, both such as the of folate and as in the of or from folate deficiency, or acid have been related to a of hemolysis or In the treatment of anaemia, red blood cell may be hemoglobin concentration is below or if or risk factors are present [EL 4]. transfusions should be by iron [EL 4] In the transfusions of red blood were common in the treatment of anaemia in IBD. requirements with the of iron and transfusions to such as anaemia with anaemia, of all other The trigger to is and The to blood transfusions is not based on the hemoglobin but and blood transfusions and whether they are to in patients or in remains transfusions are widely used as an for of or anaemia. transfusions do not the and have Other iron with or should be of and after transfusions as these are a which not normal Management of in IBD should exclude other such as and effects of Patients with of anaemia of chronic disease should be also for the of an may be by and may be based on clinical and laboratory tests. In intestinal or extraintestinal with anaemia may the of macrocytosis and may cause mild In of of chronic disease, treatment of IBD should be in combination with treatment In active inflammatory may iron erythropoiesis, and to the anaemia of chronic disease. this of anaemia, the most important is to complete disease is not associated with an in and may not be by clinical may be also to disease in patients with a cause anaemia. other causes of anaemia are the should be or of should be and are for inflammatory bowel disease but they are associated with a of The of from to and bone marrow is of the most serious In has been associated with anaemia, and red cell have an of in in bone marrow The thiopurine and the majority of with In a with Crohn’s disease patients developing or treatment of be by these most In measurement is not and is by and blood can be by the presence of rare In an increased may result from of or ECCO has a of of The of is based on a used by the Committee of The is not at the ECCO and the of but also is open to on the ECCO a comprehensive of of of The ECCO Consensus Guidelines are based on an Consensus treatment are a for the and should not be based on the of the ECCO Consensus The European Crohn’s and Colitis Organisation of its members consensus may not be for information in in the ECCO Consensus of working groups for the ECCO Anaemia Consensus chairs are Diagnosis of A Treatment of iron deficiency Prevention of iron deficiency Management of non-iron deficiency The national representatives and in the online voting are to from the ECCO for to and the are to all an in and to the ECCO Consensus procedures on are also to as in this guideline in to this guideline an and to the of this guideline in clinical