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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Definition
  5. Methods
  6. Prevalence
  7. Aetiology
  8. Laboratory tests
  9. Therapy
  10. Discussion
  11. Acknowledgements
  12. References

Background  Anaemia is a serious complication of Crohn's disease that triggers hospitalization and, if not interfered with, may lead to death.

Aims  To systematically summarize and compare the literature on anaemia in Crohn's disease.

Methods  For this systematic review the literature was searched for English-language articles using anaemia, Crohn* and IBD as key words. 144 articles were identified and sorted according to the following topics: prevalence, aetiology, diagnostic tests and therapy.

Results  The reported prevalence of anaemia varied between 6.2% and 73.7%, with higher reported frequencies in older studies and in in-patients. Iron deficiency is the most common underlying condition. Vitamin B12 deficiency is related to the extent of ileal resection but has rarely impact on anaemia. Diagnostic criteria are not established and treatment guidelines are missing. Oral iron supplementation seems effective for short periods but intolerance leads to discontinuation in up to 21%. Eleven of 11 studies show that oral iron enhances intestinal inflammation and colon carcinogenesis in animal models of colitis. Intravenous iron supplementation with iron sucrose has been tested in over 250 Crohn's disease patients, is safe, effective and does not carry such hazards.

Conclusions  As disease activity is determining the degree of anaemia in Crohn's disease, implementation of more effective therapy for Crohn's disease will lower its incidence. However, further studies regarding the safety and effectiveness of iron supplementation are needed.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Definition
  5. Methods
  6. Prevalence
  7. Aetiology
  8. Laboratory tests
  9. Therapy
  10. Discussion
  11. Acknowledgements
  12. References

Crohn's disease (CD) is a chronic inflammatory disease involving small and/or large bowel. The aetiology of CD is attributed to a genetic predisposition and to environmental factors (which are mostly – with the exception of cigarette smoking – unknown).1 Several susceptibility regions have been linked to inflammatory bowel disease (IBD), some genes (such as Nod2) were identified but the functional relationship between disease-associated mutations and the development of chronic bowel inflammation is still obscure.2 One striking feature of CD is its phenotypic heterogeneity. This is obvious with regard to the variety of mucosal lesions (from normal to deep penetrating ulcers), the intestinal pattern of disease location, and the mixture of symptoms. Attempts to classify common disease patterns reach back to the 1970s and are still ongoing.3–5

Patients do not only suffer from symptoms arising from the inflamed bowel, such as bowel cramps, abdominal pain or diarrhoea, but may also be affected by certain extraintestinal manifestations at joints, skin or eyes. Systemic disease symptoms include malnutrition and certainly anaemia. Anaemia is commonly complicating CD. It affects quality of life,6, 7 cognitive function, the ability to work and is a comorbid condition that is associated with other diseases (e.g. transfusion-associated hepatitis C) or even death.8 Many underlying conditions lead to anaemia but the most often ones are iron deficiency anaemia (IDA), anaemia of chronic disease (ACD) and a combination of both.9 Diagnosis is sometimes difficult, i.e. when vitamin B12 deficiency and iron deficiency occur at the same time and the erythrocytes are neither macrocytic nor hypochrome. Careful laboratory evaluation and the surveillance of treatment efficacy are a prerequisite to successful therapy. Taken together anaemia is a common complication in CD that is easily diagnosed by regular blood counts and is crucial for the patient's physical and emotional well-being.

Definition

  1. Top of page
  2. Summary
  3. Introduction
  4. Definition
  5. Methods
  6. Prevalence
  7. Aetiology
  8. Laboratory tests
  9. Therapy
  10. Discussion
  11. Acknowledgements
  12. References

The World Health Organization defines anaemia as haemoglobin concentration <12 g/dL for non-pregnant women and <13 g/dL for men. These values vary between countries, regions and laboratories. A haemoglobin level below 10 g/dL is commonly considered as severe anaemia.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Definition
  5. Methods
  6. Prevalence
  7. Aetiology
  8. Laboratory tests
  9. Therapy
  10. Discussion
  11. Acknowledgements
  12. References

A review of the medical literature was conducted to identify original studies, case reports and reviews concerning anaemia and CD. In February 2006, PubMed was searched for English-language articles. The terms used for the online bibliographic search included: anaemia, Crohn* and IBD. A total of 403 articles (69 reviews) were identified, 305 of which (51 reviews) were in English language. Non-relating articles were discarded, while additional articles (on ‘iron, vitamin B12, cobalamine, folic acid, or erythropoietin’) were identified through a manual search. One-hundred and forty-four articles were finally selected and sorted according the following topics: prevalence, aetiology, diagnostic tests and therapy.

Prevalence

  1. Top of page
  2. Summary
  3. Introduction
  4. Definition
  5. Methods
  6. Prevalence
  7. Aetiology
  8. Laboratory tests
  9. Therapy
  10. Discussion
  11. Acknowledgements
  12. References

A total of 19 articles contained data about the prevalence of anaemia in CD or IBD.10–28 The reported prevalence of anaemia in these patients varies between 6%12 and 74%21 (Table 1). This discrepancy may be partially caused by differences in the criteria used and in the patient population (in-patient vs. out-patient). Anaemia seems to be a trigger for hospitalization, which is reflected, in the higher prevalence of anaemia in hospitalized patients. However, incidence of anaemia is decreasing during the last years. Possible reasons may involve improvements in the treatment of the underlying diseases or in iron supplementation.10 Most studies were performed at referral centres and may thereby overestimate the actual prevalence. Population-based case–control studies are needed.

Table 1.   Prevalence of anaemia in CD
StudyCountry   nPhenotypeHospitalizationDefinition of anaemiaPrevalence (%)Publication
  1. * Children and adolescents.

  2. Hb, haemoglobin; Hct, haematocrit; IBD, inflammatory bowel disease; CD, Crohn's disease; nd, not defined; M, males; F, females.

Vijverman et al.10Belgium 80 (1993)IBDNoM: Hb  < 13 g/dL; F: Hb  < 11.6 g/dL342006
 90 (2003)IBDNoM: Hb  < 13 g/dL; F: Hb  < 11.6 g/dL17
Ershler et al.11USA7200IBDNond132005
Ebinger et al.12Germany 390CDNond62004
Lakatos et al.13Hungary 254CDNond602003
Oldenburg et al.14The Netherlands  ndCDNond292001
Revel-Vilke et al.15Israel 63IBD*NoM: Hb  < 12.5 g/dL; F: Hb  < 12 g/dL412000
Schreiber et al.16Germany 334CDNoHb < 10 g/dL261996
Gasche et al.17Austria 49CDNoHb < 12 g/dL341994
Horina et al.18Austria 85IBDNoHb ≤ 12 g/dL331993
Harries et al.19England 55CDNoM: Hb  < 13.5 g/dL441984
F: Hb  < 11.5 g/dL
Bambach and Hill20Australia 36IBD with extensive small intestine resectionNond171982
Werlin and Grand21USA 19Severe colitis*Yeshct < 0.30741977
Reilly et al.22USA  9Small bowel CDYesnd331976
 14Large bowel ± small bowel CD71
Greenstein et al.23USA 160CD or ileocolitisYesnd711975
Burbige et al.24USA 58CD*NoHb < 11 g/dL521975
Beeken25USA 63Regional enteritisYeshct < 0.40701975
Beeken26USA 11CD*NoHct < 0.36731973
Dyer et al.27England 63Active CDYesM: Hb  < 13.5 g/dL641972
     F: Hb  < 11.5 g/dL
Hoffbrand et al.28England 64CD24 (64)nd441968

Aetiology

  1. Top of page
  2. Summary
  3. Introduction
  4. Definition
  5. Methods
  6. Prevalence
  7. Aetiology
  8. Laboratory tests
  9. Therapy
  10. Discussion
  11. Acknowledgements
  12. References

Four review articles on anaemia and IBD were identified,9, 29, 30, 31 and one on haematological complications in IBD in general.32 The most important causal conditions are iron deficiency and ACD. Besides, the aetiology of anaemia in IBD may involve various impairments of erythropoiesis and haemolysis, but these seem to be rare events. All original articles concerning the aetiology of anaemia in CD were organized according to the following topics.

Iron deficiency

Original articles were found on the prevalence of iron deficiency,13, 15, 17, 33 on iron intake34, 35 and on iron absorption33, 36 (summarized in Table 2). One review was identified on iron and IBD.14 According to these reports, iron deficiency seems to be a common condition in CD. Its prevalence varies between 36% and 90% depending on the cohort and even more on the definition of iron deficiency. This points to the high variability in recognition of iron deficiency in clinical practice. The most appropriate definition of iron deficiency is the proliferative response of the bone marrow to intravenous iron supplementation, an approach that has not been studied so far in IBD. Epidemiological data from larger cohort analyses are missing, but would be of great interest to the IBD community. In normal subjects, the daily iron loss averages 1–2 mg and the same amount is absorbed from food sources. Upon iron deficiency, these figures may increase. A prospective case–control study assessing the dietary iron intake revealed low amounts of bioavailable iron in CD.34 Inadequate iron intake was already reported 20 years earlier.35 In contrast to this unanimous evidence for dietary iron avoidance in CD, data on iron absorption are conflicting. Bartels et al. tested iron absorption (by a radioactive test) rigorously in a cohort of CD patients and controls and found no general (but some individual) absorption deficit.36 In a paediatric cohort, however, abnormal absorption was suspected in 90%.33 As iron is absorbed in the duodenum and upper jejunum, only patients with upper gastrointestinal (GI) disease (L4 at the Vienna Classification4) should be at risk of iron malabsorption. Appropriate studies (using sensitive and specific tests) linking iron absorption and disease location and disease activity are missing.

Table 2.   Prevalence of iron deficiency, impaired iron intake and impaired iron absorption in CD
StudynPhenotypeParameterIron deficiencyPublication
  1. MCV, mean corpuscular volume; MCHC, mean corpuscular haemoglobin concentration; TfS, transferrin saturation; Hb, haemoglobin; IBD, inflammatory bowel disease; CD, Crohn's disease.

  2. * All with anaemia.

  3. † Mainly due to low Fe density in food.

Lakatos et al.13254CDNot defined36%*2003
Revel-Vilke et al.15 26*IBDMCV < 66 fl + ferritin  < 6 (female)/23 (male) μg/L42%*2000
Gasche et al.17 49CDFerritin < 60 μg/L76%1994
TfS < 20%90% 
DeVizia et al.33 11CD with malnutritionTfS < 12%, ferritin < 12 μg/L72%1992
    Iron intake 
Lomer et al.3491CD in remission7-day food diaryLow†2003
Hodges et al.3547CDDescriptive study25% impaired (females)1984
    Iron absorption 
De Vizia et al.3311CD with malnutritionFe absorption (serum increase after 2 h)90% impaired1992
Bartels et al.3631CD59Fe absorption testNormal1978

Intestinal blood loss through ulcerated mucosal surface is regarded the predominant cause of iron deficiency. We did not identify a single study that used quantitative tests to estimate the loss of intestinal blood. Faecal occult blood test was positive in six of 11 children with CD.33 Again, correlation with disease location, extent and severity of iron deficiency would be informative. The low iron uptake and high iron loss; however, cause a negative iron balance resulting in reduced haemoglobin production and microcytic, hypochromic anaemia. As iron is essential for all cells of the body, symptoms of iron deficiency are not only limited to anaemia-specific signs (such as fatigue and shortness of breath), but also affects nail growth, skin defects, mucosal regeneration (that might impair healing of CD lesions), headache, sleeping disorder, libido, erectile dysfunction and many more. All of this adds to the impairment in quality of life that makes the diagnosis and treatment of iron deficiency so important in CD.

Anaemia of chronic disease

As the diagnostic criteria for ACD are vague, no reliable data are available on the prevalence of ACD in CD. One difficulty is based on the exclusion of concomitant iron deficiency. Before testing erythropoietin (EPO) therapy for ACD, Horina et al. supplemented their anaemic patients with high amounts of intravenous iron,18 which is considered the most accurate measure to exclude iron deficiency. Of 28 anaemic IBD patients, only three were identified with ACD (11%). In a paediatric cohort, when ferritin and mean cell volume (MCV) was applied to separate IDA from ACD these figures were much higher (26 with anaemia, 11 with ACD; 42%).15 Tsitsika et al. linked ACD to the presence of active disease.37

From these few data, ACD seems to be the second most frequent aetiology of anaemia in CD that typically coexists with IDA. The pathogenesis of ACD has been recently reviewed and involves altered erythropoiesis, iron homeostasis and red cell survival.38 In IBD, the inflamed intestine and the surrounding mesentery is considered as the main source of cytokine production [including tumour necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-10 and interferon (IFN)-γ] that may drive such pathways.39, 40 Only few studies have tried to link elevated cytokine levels to the presence of ACD.16, 17

Vitamin B12 deficiency

Although megalocytic anaemia has been described as a possible feature of CD long time ago,41 only two reports were found on the prevalence of macrocytic anaemia: Lakatos et al. found a prevalence of 4.3% (without distinguishing between folate and cobalamine deficiency)13 compared with 26.6% in a smaller series by Hoffbrand et al.28 Out of these, only one case showed subnormal vitamin B12 levels (1.5%).

We identified 18 original studies on vitamin B12 absorption and vitamin B12 serum levels20, 27, 28, 42–56 (Table 3). Vitamin B12 deficiency seems to be common in patients with ileal CD or resection of the ileum, but its haematopoietic consequence in CD is unclear. An odd case of pernicious anaemia caused by intrinsic factor deficiency in gastroduodenal CD highlights the wide spectrum of clinical findings.57 In general, as most of these studies have been performed decades ago, the quality of these data are limited. The daily requirement for vitamin B12 is 1–3 μg; body stores contain about 5 mg, which explains why clinical manifestation of vitamin B12 deficiency occurs late. Routine vitamin B12 measurements are not necessary, only if patients have macrocytic anaemia or do not respond to iron treatment.

Table 3.   Prevalence of impaired vitamin B12 absorption and vitamin B12 deficiency in CD
StudynPhenotypeImpaired vitamin B12 absorptionPublication
  1. IBD, inflammatory bowel disease; CD, Crohn's disease; nd, not defined.

Behrend et al.42 82CD, <10 cm resection38%1995
CD, 10–60 cm resection53%
CD, >60 cm resection100%
Bayat et al.43  7CD86%1994
Kennedy et al.44 51IBD with ileostomy, resection > 17 cmLow absorption1982
Papazian et al.45 14CD with ileal resectionNegative correlation between length of lesion/resection and absorption1981
Filipsson et al.46 70CD, <30 cm resection21%1978
CD, 30–60 cm resection48%
CD, >60 cm resection60%
Jagenburg et al.47 34Ileostomy15%1975
Valman and Roberts48 10Paediatric CD, >45 cm resection70%1974
Dyer et al.27 ndCD, not operated60%1973
   Vitamin B12 deficiency 
Vasilopoulos et al.49125CDNormal2001
CD with terminal ileum resectionDecreased levels
Koutroubakis et al.50 55CDNormal2000
Chowers et al.51105CDNormal2000
CD, diseased terminal ileumDecreased levels
Lambert et al.52 21CDNormal1996
Kuroki et al.53 24CDNormal1993
Fernandez-Banares et al.54  8CD, small bowel or ileocaecalDecreased levels1989
 15IBD, extensive colitisNormal
Shaw et al.55 ndCD, diseased or resected ileumLow levels1989
IBD, colitisNormal 
Nilsson et al.56213CD, ileostomy27% subnormal/borderline1984
Kennedy et al.44 51IleostomyNormal1982
Bambach and Hill20 31CD, small intestinal resectionFrequent1982
Hoffbrand et al.28 54CD6% subnormal levels1968

Folic acid deficiency

Two studies described the prevalence of macrocytic anaemia (4.3%13 and 26.6%,28 respectively). All patient with macrocytosis had subnormal folate levels.28 Eleven original articles report on folic acid absorption or concentrations20, 28, 35, 44, 49–51, 53, 54, 58, 59 (Table 4). In general, folate deficiency seems to be more common than vitamin B12 deficiency, specifically in patients on sulfasalazine. However, a correlation between intake of sulfasalazine and folate levels was not found in the studies of Elsborg and Larsen59 and Bechi et al.60 This dispute may originate in the simple fact that most of the data are observational and uncontrolled. Nowadays, as sulfasalazine has been commonly replaced by mesalazine, this debate lacks clinical relevance. Routine measurements of folic acid levels are not required. Nevertheless patients with low levels of folate acid or vitamin B12 should receive appropriate replacement therapy, because it has been shown, that low levels of these vitamins correlate with high levels of homocysteine which is a risk factor for thromboembolism.49–51 Vice versa, hyperhomocysteinaemia may be indicative for folate acid or vitamin B12 deficiency.

Table 4.   Prevalence of impaired folic acid absorption and deficiency in CD
Study nPhenotypeFolic acid absorptionPublication
  1. IBD, inflammatory bowel disease; CD, Crohn's disease.

Steger et al.58100CD16% impaired1994
Kuroki et al.53 24CDDecreased1993
   Folate deficiency 
Vasilopoulos et al.49125CDNo deficiency (8% received supplementations)2001
Koutroubakis et al.5055CDNo deficiency2000
Chowers et al.51105CDNo deficiency2000
Fernandez-Banares et al.5423IBDDecreased levels1989
Hodges et al.3524CD, female26%1984
23CD, male21%
Kennedy et al.4451IBD (12 CD)2%1982
Bambach and Hill2031CD with major small intestinal resectionFrequent1982
Elsborg and Larsen59216IBD (serum level)59% low serum levels1979
IBD (erythrocyte level)26% low erythrocyte levels
Hoffbrand et al.2864CD81% subnormal (vs. 42% controls)1968

Drug-induced anaemia

The comparative tolerability of various treatments in IBD was reviewed previously.61 Several anti-inflammatory drugs that are used for treatment of IBD, such as sulfasalazine, mesalazine and purine analogues may interfere with erythropoiesis.

Mesalazine and sulfasalazine Sulfasalazine effects erythropoiesis by several mechanisms including folate absorption, haemolysis and aplasia.62 While haemolysis may be prevalent in 11–43% of patients with only little effects on haemoglobin concentrations,63, 64 pancytopenia is a rare complication that may also occur on mesalazine.65, 66

Azathioprine and mercaptopurine As purine analogues are widely used for treatment of CD and may interfere with erythropoiesis, they may contribute to the occurrence of anaemia in a large number of patients. However, as long as they do not cause pancytopaenia, the degree of bone marrow inhibition is moderate and the clinical presentation of anaemia is rare. The toxicity related to treatment with purine antagonists was the topic of various recent reviews.67–69 This is specifically true for the role of thiopurine methyltransferase (TPMT) activity.70–72 Connell et al. reviewed in 739 IBD patients that received azathioprine.73 Significant bone marrow toxicity was identified in 5%, a figure that was a little higher than what was published for mercaptopurine (6-mercaptopurine, MP; 2%).74 The risk of developing aplasia or leukopaenia is high in individuals with low TPMT activity. This is genetically determined and genotyping has been suggested as a means for identifying patients at risk.75, 76 In clinical practice, however, concerns have been raised about the value of this test.77 As treatment recommendations changed over the past decades, the relative importance of drug-induced anaemia shifted from sulfasalazine to 6-MP and azathioprine. In fact, the increase in MCV is commonly used as marker of drug efficacy.78, 79 The coexistence of iron deficiency may obstruct this feature and vice versa. This MCV increase is typically not associated with significant anaemia and rarely needs dose adaptation.

Interleukin-10 Interesting observations on the role of IL-10 in development of ACD have been derived from clinical trials that tested this cytokine for treatment of IBD.80–82 IL-10 caused a temporary decline in haemoglobin levels that was associated with hyperferritinaemia and increased soluble transferrin receptor (sTfR) levels indicating iron restriction to the erythroid progenitor cells. IL-10 is not available for treatment of IBD.

Others Mattis et al. reported a case of ceftriaxone-induced haemolytic anaemia in a child with CD.83

Haemolytic anaemia

Most reports on haemolytic anaemia in IBD are actually reporting on findings in patients with ulcerative colitis (UC). In CD, only five case reports were found.84–88 Interestingly, these are cases of UC-like Crohn's colitis that were associated with pANCA positivity or primary sclerosing cholangitis. One patient was reported with haemolytic anaemia upon treatment with infliximab.89 This type of anaemia seems to be extremely rare in CD.

Myelodysplastic syndromes

According to the French-American-British classification,90 the myelodysplastic syndromes include refractory anaemia (type 1), refractory anaemia with ringed sideroblasts (type 2), chronic myelomonocytic leukaemia (type 3), refractory anaemia with excess blasts (type 4) and refractory anaemia with excess blasts in transformation (type 5). Myelodysplastic syndromes are rare and characteristically develop in patients older than 60 years of age. Eighteen patients in seven case reports on myelodysplastic syndrome have been identified by systematic literature search.91–97 As in any population, the possibility of myelodysplastic syndrome should be considered in patients over 60 years.

Inborn haemoglobin disorders

Glucose-6-phosphate dehydrogenase deficiency has been reported in single patients with IBD.98–102 It is still unclear whether this disorder is genetically linked to IBD susceptibility genes or not.

Laboratory tests

  1. Top of page
  2. Summary
  3. Introduction
  4. Definition
  5. Methods
  6. Prevalence
  7. Aetiology
  8. Laboratory tests
  9. Therapy
  10. Discussion
  11. Acknowledgements
  12. References

Diagnosing iron deficiency in the setting of IBD may be difficult and no single laboratory test has been established. There is little doubt that serum ferritin levels below 20 μg/L are indicative of iron deficiency. However, in the presence of inflammation ferritin levels may increase in spite of iron deficiency. In fact, bone marrow studies in rheumatoid arthritis patients showed a 86% sensitivity to predict iron deficiency for ferritin levels below 60 μg/L.103 Similar figures were described for IBD104 indicating that in one of six patients iron deficiency is missed even when the ferritin cut-off level is set to 60 μg/L. Measurement of the sTfR which increases upon iron deficiency (and enhanced erythropoiesis) or the sTfR/log ferritin ration may further help solving this dilemma.105

Laboratory findings in ACD can be summarized as following: reduced transferrin saturation, reduced or normal transferrin, normal or increased ferritin and normal sTfR. In contrast, patients with iron deficiency have low transferrin saturation, increased transferrin, reduced ferritin and increased sTfR.38 In CD, iron deficiency overlapping with ACD is difficult to judge but considered likely when ferritin levels are below 100 μg/L and the transferrin saturation is below 16%.38 In these cases the sTfR/log ferritin ratio can be applied. A ratio above 2 is suggestive of iron deficiency. The MCV and mean corpuscular haemoglobin concentration (MCHC) are sensitive indicators of iron deficiency, but are also affected by immunosuppressive therapy or vitamin B12/folic acid deficiency (see above).

The EPO levels increase with the degree of anaemia.17 In some patients, however, EPO concentrations are not elevated despite significant anaemia.37 This information maybe helpful when considering EPO therapy.106

Therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Definition
  5. Methods
  6. Prevalence
  7. Aetiology
  8. Laboratory tests
  9. Therapy
  10. Discussion
  11. Acknowledgements
  12. References

The variety of available iron compounds and the different routes of administration (oral and intravenous) have been a topic of several clinical trials (Table 5). In most studies testing oral iron, 100–200 mg of ferrous salts (fumarate or sulphate) were administered. As only small amounts of iron are absorbed (10–30 mg) the majority of ingested iron passes along within the bowel content. At sites of ulcers, the iron-rich luminal matter may increase the formation of hydroxyl radicals (by catalysing the Fenton reaction: Fe2+ + H2O2 [RIGHTWARDS ARROW] Fe3+ + OH + OH). The hydroxyl radical is the primary oxidizing species; it can be used to oxidize and break apart organic molecules and thereby may enhance tissue damage and disease activity of the underlying IBD. As this hypothesis is difficult to test in patients, it has been subject of several studies using animal model of IBD (Table 6). Our search identified 11 publications that tested the effect of iron on intestinal disease activity, oxidative stress or the degree of mucosal inflammation in rodent models of IBD.107–117 Although the experimental setting, the iron dose and the readout are quite diverse, these studies unanimously support the hypothesis of iron-induced hydroxyl radical generation in the inflamed tissue leading to worsening of intestinal inflammation and increased colon carcinogenesis.

Table 5.   Iron therapy in CD
StudyDesign nPhenotypeDoseCompoundDuration (weeks)ResponseHb change (g/dL)Adverse eventsPublication
  1. AE, adverse event; IBD, inflammatory bowel disease; CD, Crohn's disease; EPO, erythropoietin; dct, discontinued.

  2. * Difference between groups only for the occurrence of abdominal pain (only in the oral group).

  3. † 1 g/dL increase.

  4. Response is defined as increase of haemoglobin of ≥ 2 g/dL.

Oral iron
De Silva et al.118Open-label19CD3 × 200 mg/dayFerrous sulphate4Not specified10.0–11.721% dct2005
Schroeder et al.119Randomized, open-label, multicentre46 (24 oral)IBD100/200 mg/dayFerrous sulphate653%9.6–11.721 AE*, 21% dct, Harvey-Bradshaw index increased2005
Erichsen et al.120Crossover, safety19IBD120 mg/dayFerrous fumarate2Not specified11.6–11.811% dct2005
Erichsen et al.121Randomized, open-label, safety41IBD100 mg 2×/day (n = 21) orFerrous sulphate2Not specified13.1–13.314% dct2005
200 mg iron 1×/day (n = 20)Ferric polymaltose2Not specified12.5–12.55% dct
Erichsen et al.122Open-label, safety10CD120 mg/dayFerrous fumarate1Not specified10.6–10.680% AE, 0% dct2003
De Silva et al.123Retrospective53IBDVariousVariousVariousNot specifiedNot specified25% AE, 8% dct2003
Harvey et al.124Open-label23IBD (n = 15)2 × 30 mg/dayFerric trimaltol1274%10.6–12.621% dct1998
Schreiber et al.16Randomized double-blind (EPO)34 (17)IBD100 mg/day + placeboIron-glycin-sulphate1224%†8.7–7.8Not specified1996
Intravenous iron
Schroeder et al.119Randomized, open-label, multicentre46 (22 intravenous)IBD1418 mg totalIron sucrose655%9.8–12.320 AE*, 5% dct, Harvey-Bradshaw index unchanged2005
Erichsen et al.120Crossover, safety19IBD200 mg 3×Iron sucrose2Not specified10.6–11.30% dct2005
Schroeder et al.127Open, safety31CD (13)7 mg/kg BW single infusion (maximum 500 mg)Iron sucroseSingle infusion0%10.2–10.832% AE (6.5% definitely related to medication)2004
Bodemar et al.128Retrospective59IBD1400 mg totalIron sucroseVarious91%9.7–12.81 AE, 0% dct2004
Mamula et al.129Retrospective70 (119 infusions)IBD, childrenTotal dose ironIron dextranSingle infusionNot specifiedMean increase 2.911 allergic reactions2002
Gasche et al.106Multicentre, open-label103IBD1200 mg (6 × 200 mg)Iron sucrose465%8.8–11.34 AE, 0% dct2001
Gasche et al.126Randomized double-blind (EPO)40 (20)CD200–400 mg/weekIron sucrose880%8.5–11.810 AE, 0% dct1997
Gasche et al.17Open 2CD200 mg/weekIron sucrose550%9.5–11.50%1994
Bartels et al.36Open 8IBD1 g total dose infusionIron dextranSingle infusionFerritin increaseNot reportedNot reported1978
Table 6.   Iron therapy in various animal models of colitis
StudyModelApplication and iron doseDisease activityOxidative stressIntestinal inflammationColorectal tumourPublication
  1. DSS colitis, dextran sulphate sodium-induced colitis in rats; TNBS colitis, trinitrobenzene sulfonic acid induced-colitis in rats; BW, body weight; i.p., intraperitoneal iron; ±, no difference to controls.

  2. * iNOS and COX-2 expression.

  3. † Proinflammatory cytokines produced by colonic tissue.

  4. Empty fields: test not done.

Carrrier et al.107DSS colitis3000 mg/kg diet++++  2006
Same + vitamin E++  
Erichsen et al.108DSS colitis0.6 mg/kg BW oral  + 2005
Seril et al.109DSS colitis6 mg/kg BW i.p.±±*±2005
12 mg/kg BW i.p.±±*±
90 mg/kg diet++*++
IL-2−/− mice12 mg/kg BW i.p. 
90 mg/kg diet+ ++
Reifen et al.110Iodoacetamide colitis300 mg/kg diet  ++ 2004
Uritski et al.111TNBS colitis7 mg/kg diet ±+ 2004
35 mg/kg diet ±+ 
3000 mg/kg diet +++ 
Seril et al.112DSS colitis100 mg/kg diet++++2002
250 mg/kg diet+++ 
5000 mg/kg diet +++ 
Carrier et al.113DSS colitis3000 mg/kg diet+++++ 2002
Same + vitamin E+++ 
Carrier et al.114DSS colitis3000 mg/kg diet+++ 2001
30 000 mg/kg diet+++ 
Aghdassi et al.115DSS colitis1000 mg/kg BW i.p. ++ 2001
Reifen et al.116Iodoacetamide rat modelDose not defined+   2000
Oldenburg et al.117IL-10−/− mice500 mg/kg diet  +† 2000
1 mm enema  +† 

From eight studies that tested oral iron in IBD (Table 5),16, 118–124 intolerance was a common finding leading to discontinuation in up to 21%. Two studies using ferric iron reported fewer side effects despite good effectiveness.121, 124 Some case–control studies saw similar intolerance to non-IBD patients123 in others the frequency and spectrum of side effects (increase in diarrhoea vs. constipation) was considerably different.122 A 15-year-old girl developed typical symptoms of UC after treatment of anaemia with ferrous sulphate.125 Recently, some worsening of proctosigmoiditis was demonstrated by rigid sigmoidoscoy.118 Due to the location of intestinal inflammation in CD, similar tests have not been performed yet (as an ileocolonoscopy would be needed). One study aimed to compare tolerability of ferrous fumarate applying a crossover design.120 CDAI increased in the oral group (due to worsening of general well-being and abdominal pain) but was unchanged in the intravenous group.

Intravenous iron therapy for IBD-associated anaemia has been suggested in the 1970s,36 but clinical trials have not been performed until the early 1990s.126 We identified a total of nine trials, all of which tested iron sucrose except for two that analysed iron dextran (Table 5).17, 36, 106, 119, 120, 126–129 The first prospective, controlled trial tested iron sucrose as adjunct to EPO therapy.126 A consecutive, multicentre trial followed a stepwise approach (first iron sucrose, then combination with EPO).106 Iron sucrose was effective in 50–91% depending on the criteria used. Two comparative trials (oral vs. intravenous iron) have been published recently.119, 120 The only available randomized-controlled trial measuring efficacy (maximum increase in haemoglobin within 6 weeks) showed a comparable response in both groups (55% on iron sucrose vs. 53% on ferrous sulphate).119 Secondary end points, such as an increase in ferritin as marker of iron reserve were only met in the intravenous treatment group. The other study as mentioned above120 was not designed to measure efficacy, but demonstrated better tolerability of intravenous iron therapy. At this point, larger and well-designed studies are needed to evaluate the efficacy and safety of various routes and compounds of iron supplementation.

Six original reports16–18, 126, 130, 131 (Table 7), one letter132 and one review133 testing EPO in CD have been identified. There is grade A evidence (from two randomized-controlled trials) for the efficacy of EPO in IBD-associated anaemia. In all trials, however, EPO therapy was accompanied by iron supplementation again pointing to the importance of iron therapy. From a set of laboratory parameters high serum EPO levels, high sTfR levels or high transferrin levels were predictive of a response to iron therapy alone.106 EPO therapy should be considered for patients with low levels or unresponsiveness to iron sucrose. No reports were identified on the use of vitamin B12 or folate therapy of CD-associated anaemia.

Table 7.   EPO therapy in patients with CD
StudyDesign nPhenotypeDoseCompoundDuration (weeks)ResponseHb change (g/dL)Adverse eventsPublication
  1. * 1 g/dL increases.

  2. IBD, inflammatory bowel disease; CD, Crohn's disease; EPO, erythropoietin.

  3. Response is defined as increase of haemoglobin of ≥ 2 g/dL.

Koutroubakis et al.130Refractory anaemia20IBD0.9 μg/kg BW once/week, 1300 mg iron totalDarbepoetin-α iron sucrose 4759.5–12.70%2006
Dohil et al.131CD 3CD150 U/kg BW 3×/weekEpoetin-α1210010.9–13.81 AE1998
Gasche et al.126Randomized double-blind (EPO)40 (20)CD150 U/kg BW 3×/week, 200–400 mg iron/weekEpoetin-α iron sucrose 8958.7–13.65 AE1997
Schreiber et al.16Randomized double-blind (EPO)34 (17)IBD150 U/kg BW 2×/week, 100 mg iron/dayEpoetin-α iron- glycin-sulphate1282*8.8–10.5Not specified1996
Gasche et al.17Open 2CD150 U/kg BW 3×/week, 200 mg iron /weekEpoetin-α iron sucrose 51009.1–14.10%1994
Horina et al.18Open 3IBD200–300 U/kg BW 3×/week, 100 mg iron/dayEpoetin-β oral iron 8–141008.6–12.8Not specified1993

It is needless to mention that anaemia in CD can be managed with blood transfusions.134 Perioperative autologous blood donations have been successfully tested as well.135 In patients with frequent and therapy-resistant haemorrhage, surgical intervention or resection can be considered.136–138 Anti-TNF therapy (e.g. infliximab or ethanercept), as it may interfere with specific mechanisms of ACD, has shown beneficial effects in single cases (when combined with intravenous iron).139 This effect, however, may be caused by intestinal healing of ulcerated mucosal surface rather than the anti-TNF effects on the bone marrow.140 Within clinical trials such effects have not been observed.141

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Definition
  5. Methods
  6. Prevalence
  7. Aetiology
  8. Laboratory tests
  9. Therapy
  10. Discussion
  11. Acknowledgements
  12. References

The variation in prevalence data as summarized in Table 1 of this systematic review indicates that anaemia is more prevalent in in-patients than in out-patients. If anaemia is a trigger for hospitalization, it should be recognized early, diagnosed fast and treated effectively preferably in the ambulant setting. For in-patients, anaemia may prevent doctors from discharging patients. Again, early and effective measures to counteract this condition may reduce the time of hospitalization and prevent the use of blood transfusions. Not only economic reasons should lead to early diagnosis and treatment, but also lower quality of life should sensitize doctor's perception of the magnitude of this problem. Although reliable (population-based) data are not available, the prevalence of anaemia seems to decrease with time. The same was also observed in a recent original analysis.10 As anaemia is related to disease activity, it is likely that the introduction of effective treatment options at the end of the 20th century has changed the natural course.

From the data extracted from Tables 2–4, the most fundamental cause of anaemia in CD is iron deficiency. Although this has been identified as the overwhelming causative factor, little is known on iron absorption in CD. The available studies33, 36 used different absorption tests and came to contradictory results. No data are available for upper GI CD (the L4 phenotype of the Vienna Classification).4 Although most of the laboratory tests have been used for over 30 years, the diagnostic criteria of iron deficiency are still vague. In a recent review on ACD,38 the presence of iron deficiency was considered when ferritin levels drop below 100 μg/L and the transferrin saturation is below 16%.38 The clinical dilemma of diagnosing iron deficiency in CD becomes even bigger as azathioprine and MP are now commonly used for CD therapy. Both drugs increase the MCV and thereby obstruct one of the most sensitive measures of iron deficiency. On the other hand, the MCV increase is considered a good marker for azathioprine drug monitoring.78, 79 In the presence of iron deficiency this marker cannot be used as well.

As iron deficiency is the most prevalent cause of anaemia, iron supplementation is the most relevant therapeutic intervention. In general, oral iron preparations are inexpensive, partially (temporarily) efficient, but are commonly associated with GI side effects (abdominal pain, increase in diarrhoea) that limit their use and compliance. The overwhelming evidence from iron treatment in animal IBD models (as summarized in Table 6) question the safety of ferrous salts in IBD. This is particularly true for the carcinogenic properties of ferrous iron109 as colitis patients per se are already at a higher risk to develop colorectal cancer.142 As ferrous salts are continuously prescribed for these conditions, after marketing safety trials are warranted. Upon these considerations we like to adjust our previous recommendation for using ferrous salts in patients with mild iron deficiency and IBD.9 As long as the safety of ferrous salts is questionable, IBD patients should rely on iron sucrose, currently the only iron compound with sufficient available safety data. This recommendation is mainly based on the dogma: ‘safety first’. As intravenous iron sucrose is more costly (also highly varying from country to country), long-term cost-effectiveness needs to be addressed in future trials. However, apart from IBD (and chronic renal failure) the oral route remains the cornerstone of iron replacement therapy.

Both the clinical trials in IBD and the data from animal models would rather suggest the use of parenteral iron supplementation. The cumulative data on over 250 Crohn's patients who received iron sucrose within clinical trials (Table 5) together with the huge experience in non-IBD patients (over 1 million applications) establish iron sucrose as a safe alternative to iron dextran. As opposed to 9% with iron dextran,129 no allergic reactions were reported with iron sucrose. The only disadvantage of iron sucrose is the need for repeated infusions as a single dose should not exceed 500 mg (or 7 mg/kg body weight).127 The common dose for single infusions seems to be 200 mg iron sucrose in 100 mL sodium chloride.

For the treatment of anaemia, the most important measure is the treatment of the underlying disease. This even holds true for drugs (such as purine analogues) that have adverse effects on erythropoiesis. As effective therapy may cause mucosal healing143, 144 we may expect a lower incidence of anaemia.10 It is unlikely, however, that anaemia will completely disappear in the near future.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Definition
  5. Methods
  6. Prevalence
  7. Aetiology
  8. Laboratory tests
  9. Therapy
  10. Discussion
  11. Acknowledgements
  12. References

This work was supported by the Austrian Science Funds (P17943 and P18270 to CG).

As it is out of the question to absolutely identify all related articles, we like to apologize if we missed important work on this subject and encourage authors to communicate such to us.

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  6. Prevalence
  7. Aetiology
  8. Laboratory tests
  9. Therapy
  10. Discussion
  11. Acknowledgements
  12. References
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