Anaemia and iron deficiency in children with inflammatory bowel disease

Journal of Crohn's and Colitis (2012) 6, 687 691 Available online at www.sciencedirect.com Anaemia and iron deficiency in children with inflammatory bowel disease Anthony E. Wiskin a, Ben J. Fleming b, Stephen A. Wootton a, R. Mark Beattie c, a NIHR Biomedical Research Unit (Nutrition, Diet & Lifestyle), Southampton General Hospital, SO16 6YD, UK b School of Medicine, University of Southampton, Southampton General Hospital, SO16 6YD, UK c Paediatric Medical Unit, Southampton General Hospital, SO16 6YD, UK Received 19 September 2011; received in revised form 2 December 2011; accepted 2 December 2011 KEYWORDS Inflammatory bowel disease; Anaemia; Iron deficiency; Paediatrics Abstract Background and aims: Anaemia and iron deficiency are common in children with Inflammatory Bowel Disease (IBD) however it is not known if the prevalence of anaemia and iron deficiency alters following diagnosis. Methods: Laboratory results from diagnosis, and at follow up one and two years later were recorded retrospectively in children with IBD recruited from a tertiary centre. Anaemia was defined using WHO standards and iron deficiency defined using published guidelines. Results: 46 children (16 girls) with Crohn's disease and 34 children (18 girls) with UC were studied. 75% of children with IBD were anaemic at diagnosis, 30% were anaemic at follow up two years later. 90% of children with Crohn's and 95% of children with Ulcerative Colitis (UC) were iron deficient at diagnosis. At follow up two years later 70% of children with Crohn's and 65% of children with UC were iron deficient. Conclusions: Persistent anaemia and iron deficiency are common in childhood IBD, prevalence alters with duration of time from diagnosis. 2011 Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation. 1. Background These data have been accepted for presentation at the British Association of Parenteral and Enteral Nutrition conference in Harogate, UK in November 2011. Corresponding author at: Paediatric Medical Unit, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. Tel.: +44 2380 796888; fax: +44 2380 798688. E-mail address: mark.beattie@suht.swest.nhs.uk (R.M. Beattie). 25% of inflammatory bowel disease (IBD) presents in childhood. Anaemia is common and studies of children with IBD report prevalence between 41% and 75%. 1 5 The aetiology of anaemia is multi-factorial. Investigation often reveals a combination of iron deficiency and the anaemia of chronic disease but anaemia may be induced by other 1873-9946/$ - see front matter 2011 Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation. doi:10.1016/j.crohns.2011.12.001

688 A.E. Wiskin et al. Table 1 WHO definition of anaemia in childhood. Age (years) Haemoglobin (g/l) b5 110 5 11 115 12 14 120 Non-pregnant girls N 15 120 Boys N15 130 nutrient deficiencies, or as a result of drugs used to treat the primary disease. The broad prevalence range in paediatric studies reflects the different methods used to define anaemia including various cut-offs for haematocrit and haemoglobin values and potentially the duration and severity of disease in the children studied. The clinical significance of anaemia in children with IBD and the extent to which correcting anaemia is associated with improvements in disease activity or growth has not been determined. However, in adult studies improvements in quality of life, independent of disease activity, have been attributed to improvements in haemoglobin concentration. 6 We can only assume that this is also true in children and adolescents. If anaemia is not being adequately treated in children with IBD then its detection and subsequent treatment may lead to strategies to improve quality of life. Revel Vilk and Goodhand suggest iron deficiency is responsible for 40% 4 and 88% 5 of the cases of anaemia in children with IBD. However data is scarce on the prevalence of iron deficiency per se. Serum ferritin, transferrin and percentage transferrin saturation are commonly used to determine iron deficiency as bone marrow biopsy to determine the amount of stainable iron in the bone marrow cannot be widely performed. However, the interpretation of iron indices in children with disease requires adequate consideration of inflammation. Serum ferritin is a positive acute phase reactant and increases with inflammation which may mask underlying functional iron deficiency. In the context of IBD interpreting serum ferritin relative to the C reactive protein has been proposed as a method of detecting iron deficiency in patients with IBD. 7 The aim of this study was to establish the prevalence of anaemia and of iron deficiency at diagnosis and while under follow up from children attending a regional paediatric gastroenterology service. 2. Methods This was a retrospective cohort study and data were gathered from electronic records. Children diagnosed following the Porto criteria 8 with disease extent recorded following Paris classification 9 were recruited from the regional service to studies examining nutritional status in IBD 10,11 approved by the local research ethics committee. The management of children with IBD in our centre follows published guidelines, 12 the aims of treatment are to control disease activity and optimise growth. No specific guideline is followed for the investigation and treatment of children with IBD who are anaemic or iron deficient. Blood results from diagnosis, and at follow up one and two years later were recorded where available. Children with haemoglobinopathies and those who had received blood transfusions were excluded. Anaemia was defined using cutoffs for haemoglobin concentration specific to age groups and gender in accordance with WHO standards (Table 1). Iron deficiency was identified using two approaches, firstly; a transferrin saturation of b16% and secondly; a serum ferritin of b30 μg/l (for children with a CRP b10 mg/l) or b100 μg/l (for children with a CRP 10 mg/l). 7 These criteria for iron deficiency were chosen as they are specific to this patient group and attempt to correct for the role of ferritin as an acute phase reactant. Data are quoted as median (25th, 75th centile). Statistical analysis was performed using SPSS 18.0 (SPPS Inc. Illinois). 3. Results 3.1. Crohn's disease 46 children (16 girls) with Crohn's disease were studied. Median age of 12, range 4 to 16 years. 11 children had colonic disease, 32 had ileo-colonic disease. Upper GI disease was 175 150 Ulcerative Colitis Crohn s disease 125 100 75 50 25 0 At diagnosis One year Two years Figure 1 Haemoglobin concentration of children with IBD grouped by disease type at time of diagnosis, and at follow up one and two years later.

Anaemia and iron deficiency in childhood IBD 689 Table 2 Prevalence of anaemia and iron deficiency in children with Crohn's disease grouped by C reactive protein. CRPb10 CRP 10 CRPb10 CRP 10 CRPb10 CRP 10 Anaemia 5/8 (63%) 26/35 (74%) 11/20 (55%) 7/10 (70%) 4/20 (20%) 4/6 (67%) Iron deficient (transferrin saturation) 4/4 (100%) 20/22 (91%) 14/25 (56%) 8/9 (89%) 9/15 (60%) 4/4 (100%) Iron deficient (ferritin corrected for CRP) 6/7 (86%) 22/25 (88%) 23/28 (82%) 9/9 (100%) 13/16 (81%) 2/3 (67%) present in 18 children including two who had isolated upper GI disease. One child had perianal disease only. 37 children received thiopurines, 30 received aminosalicylates and 4 received biological agents. Median haemoglobin at diagnosis was 111 (99, 119) g/l and rose to 122 (116, 131) g/l at one year and 127 (121,131) at two years (Fig. 1). Median C reactive protein at diagnosis was 22 (12, 43) mg/l, at one year was 7(1, 9) mg/l and fell to 3 (1, 10) mg/l at two years. Median transferrin saturation and median ferritin at diagnosis were 6 (4, 9)% and 25 (15, 54) μg/l; at one year were 14 (8, 16)% 16 (9, 29) μg/l; and at two years were 13 (8, 25)% and 22 (17, 29) μg/l respectively. Prevalence of anaemia and iron deficiency at diagnosis, one year and two years is shown in Table 2. It has been suggested that the prevalence of anaemia may be directly related to the degree of untreated intestinal inflammation which may be reflected by treatment type as immunomodulators achieve better mucosal remission. Data showing the prevalence of anaemia in patients grouped by treatment type is shown in Table 3. 3.2. Ulcerative colitis 34 children (18 girls) with UC were studied. Median age of 11, range 10 to 16 years. 13 children had left sided disease, one child had proctitis and 20 children had pancolitis. During the two years evaluated, 30 children received aminosalicylates and 15 received thiopurines. No children received biological agents. Median haemoglobin at diagnosis was 110 (94, 122) g/l and rose to 124 (110, 127) g/l at one year and 123 (114, 139) at two years (Fig. 1). Median C reactive protein at diagnosis was 2 (1, 5) mg/l, at one year was 1 (1, 3) mg/l, and at 2 years was 1 (1, 2) mg/l. Median transferrin saturation and median ferritin at diagnosis were 8 (4, 17)% and 8 (5, 21) μg/l; at one year were 13 (8, 32)% and 12 (6, 24) μg/l; and at two years were 23 (19, 32)% and 20 (11, 35) μg/l. Prevalence of anaemia and iron deficiency at diagnosis, one year and two years is shown in Table 4. Data Table 3 Prevalence of anaemia in children with Crohn's grouped by treatment received. Aminosalicylate alone 7/8 (88%) 3/7 (43%) 0/2 Thiopurine alone 11/15 (73%) 5/14 (36%) 1/7 (14%) Aminosalicylate and 12/18 (67%) 7/18 (39%) 5/13 (39%) thiopurine showing the prevalence of anaemia in patients grouped by treatment type is shown in Table 5. Combining data from both disease groups there was poor agreement between the two methods in the classification of children as iron deficient (kappa 0.2 standard error 0.08, pb0.01). 4. Discussion Anaemia is common in this cohort of children with IBD with a prevalence of 74% at presentation, falling to 42% at one year, and 32% at two years and is similar between those with Crohn's or Ulcerative Colitis. Improvement in prevalence of anaemia occurs relative to decreased median CRP which raises two possibilities. Firstly, that haemoglobin concentration reflects disease activity and underlying inflammation and secondly that both of these parameters may reflect underlying nutritional status. It has been suggested that treatment given may be a proxy for underlying inflammation since immunomodulators produce better mucosal healing. However there may be a confounding effect as patients with mild disease are not given thiopurines and only those with most severe disease are given biologics. The degree of mucosal healing achieved in mild disease with less aggressive treatment is not known. In this study treatment given does not appear to relate to the prevalence of anaemia in Crohn's or Ulcerative Colitis although small numbers of children studied precludes detailed analysis. Whatever the cause the prevalence of anaemia at two years after diagnosis suggests persistent anaemia is common. In this cohort iron deficiency is more common than anaemia. Two years after diagnosis between 70% and 80% of children with Crohn's disease are iron deficient. There are several potential mechanisms for iron deficiency including decreased oral intake, increased loss from inflamed GI mucosa, impaired absorption, and altered metabolism as part of the inflammatory response. Some of these effects may be mediated by hepcidin. Hepcidin is a peptide involved in iron homeostasis. Following signalling from pro-inflammatory cytokines hepcidin production is upregulated in the liver. Hepcidin decreases the activity of ferroportin preventing the transport of iron out of the enterocyte, and thereby promoting excretion from the body. 13 Clinicians require suitable investigations to define iron deficiency in order to determine which patients may benefit from iron therapy. A recent review in this journal examined the role of markers to differentiate iron deficiency anaemia from anaemia of chronic disease. The authors suggest that iron regulators such as hepcidin and classic erythrocyte parameters are not useful. 14 The two criteria proposed by Gasche 7 have been used in this study although it is not entirely

690 A.E. Wiskin et al. Table 4 Prevalence of anaemia and iron deficiency in children with Ulcerative Colitis grouped by C reactive protein. CRPb10 CRP 10 CRPb10 CRP 10 CRPb10 CRP 10 Anaemia 21/29 (72%) 2/2 (100) 10/27 (37%) 1/3 (33%) 5/19 (26%) 1/2 (50%) Iron deficient (transferrin saturation) 13/17 (76%) 0/0 (0%) 13/23 (57%) 1/3 (33%) 3/17 (18%) 0/1 (0%) Iron deficient (ferritin corrected for CRP) 18/19 (95%) 1/1 (100%) 19/24 (79%) 3/3 (100%) 11/16 (69%) 0/1 (0%) clear how well these parameters reflect functional iron deficiency. It is clear from this study that the agreement between the two methods proposed by Gasche is poor. The ratio of transferrin receptors to log ferritin (TfR-F Index) is an outstanding parameter for identifying patients with depleted iron stores, determined by stainable iron in bone marrow 15 and has recently been evaluated in patients with IBD. 16 The use of this parameter in further studies may be appropriate to determine improvements in iron status in response to treatment of underlying inflammation, improvements in nutritional status and iron supplementation. Treatment of iron deficiency in IBD is not straightforward. In this study nine children with Crohn's and four with Ulcerative Colitis received an iron supplement at some stage during the study interval. However the prescription of these supplements was not consistent and this study was unable to observe their efficacy. It is proposed that oral iron supplementation may generate radical oxygen species, provoke inflammation, and thereby exacerbate gastro-intestinal symptoms 17 leading to intolerance. However there is also evidence to the contrary from a prospective trial of adults with IBD. 18 Intra-venous iron preparations avoid the problem of gastro-intestinal side effects and appear efficacious in adult studies. 19 There are few studies which report the use of intra-venous iron in children. One retrospective study suggests the use of intra-venous iron in children with IBD is safe. 20 Another has demonstrated that intra-venous iron may be of benefit in children who have not responded to therapy with oral iron. 21 However data on the tolerability and efficacy of iron supplementation (oral and intra-venous) in children with IBD is scarce. The authors recognise that the retrospective nature of this study may introduce bias as children with the most apparent deficit are those most likely to have bloods requested. While this may be the case it is notable that the prevalence of anaemia in this study is comparable to previous work. This study suggests that iron deficiency and anaemia are significant on-going issues in the care of children with IBD and highlights the scale of the problem even in children under follow up. Reliable diagnostic criteria are needed to help identify children who may be suitable for therapeutic intervention which in turn may make significant improvements in quality of life. Table 5 Prevalence of anaemia in children with Ulcerative Colitis grouped by treatment received. Aminosalicylate 12/17 (71%) 5/16 (31%) 1/9 (11%) Aminosalicylate and thiopurine 10/13 (77%) 5/13 (39%) 4/10 (40%) Conflict of interest The authors have no conflicts of interest to declare. Acknowledegments This project received no specific funding. AEW is funded by the NIHR Biomedical Research Unit (Nutrition, Diet & Lifestyle) Southampton. AEW conceived of the study, assisted in data collection and analysis and drafted the manuscript. BJF completed data collection and analysis and assisted in drafting the manuscript. 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