What Is Known
- Anemia frequently complicates inflammatory bowel disease and adversely effects patients’ quality of life.
- Anemia can be caused by iron deficiency or due to chronic disease inhibiting erythropoiesis. In either case, it proves difficult to treat.
What Is New
- Anemia is common and persists even after a year of treatment in many patients with inflammatory bowel disease.
- Prevalence of anemia is greater in Crohn disease compared with ulcerative colitis or indeterminate colitis.
- Anemia of chronic disease is characteristic of Crohn disease while iron deficiency anemia is more a feature of ulcerative colitis.
The prevalence of inflammatory bowel disease (IBD) is increasing in both adult and pediatric populations (1,2). The prevalence of IBD in the United States is 0.6% (1) making it one of the most common chronic diseases of childhood. The worldwide spread of IBD parallels industrialization. The risk of IBD seems to be associated with change in environment and diet that may alter the microbiome leading to IBD in genetically susceptible individuals (1). Anemia is the most common extra-intestinal manifestation of IBD and can adversely affect quality of life (3,4). The 2 types of anemia associated with IBD are iron deficiency anemia (IDA) and anemia of chronic disease (ACD). These anemias can occur separately or can be present simultaneously.
IDA: The reason for IDA in IBD is multifactorial. The most obvious reason is gastrointestinal (GI) blood loss; however, sloughing of cells that line the GI tract, malabsorption and decrease in oral iron due to poor appetite can also contribute to IDA in IBD.
ACD: ACD frequently accompanies IBD, but is not specific to IBD, occurring in many other chronic inflammatory processes. In ACD hepcidin activity is increased resulting in a decrease in red blood cell production at the level of the erythron and a decrease in iron absorption via the small intestine. In many ways ACD mimics IDA including microcytosis and decreased reticulocyte count. Many indices of iron status are also acute phase reactants, making interpretation of test results problematic in the face of concurrent inflammation. The fact that IDA and ACD often occur together further complicates the diagnosis and planning the treatment (5). The aim of this study is to examine the prevalence and types of anemia in pediatric patients with IBD at diagnosis and at approximately 1 year follow-up.
The study was approved by the Children and Youth Institutional Review Board, University at Buffalo, Women and Children's Hospital. It is a retrospective chart review of patients diagnosed with IBD from 2005 to 2012, ages 1 to 18 years. Patients who had hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), and iron indices obtained at the time of diagnosis and at approximately 1 year follow-up were included in the study. A total of 213 charts were reviewed and 153 patients were found to fit these criteria. In this study group the following data was sought: albumin, serum iron, ferritin, total iron binding capacity (TIBC), transferrin, soluble transferrin receptor (sTR), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). World Health Organization's (WHO) Hb thresholds were used to define anemia (6). The sTR/log ferritin index (sTR Index) was employed to differentiate the type of anemia, IDA from ACD (7,8). This index can differentiate IDA from ACD; however, it cannot separate IDA from the combination of IDA/ACD. IDA or IDA/ACD were considered to be present if the sTR index value was greater than 1.03. An sTR index of <1.03 was taken to be indicative of the presence of ACD. Total body iron was calculated as follows: total body iron = −[log(sTR/Ferritin) − 2.8229]/0.1207 (9). The Pediatric Crohn's Disease Activity Index (PCDAI) and the Pediatric Ulcerative Colitis Activity Index (PUCAI) were recorded at diagnosis and at follow-up.
All of the statistical analyses were performed by a professional statistician using the SAS System (SAS Institute, Cary, NC). Results are expressed as mean values +/− standard deviation. A P value of 0.05 or less was taken to indicate a significant difference.
The characteristics of the study subjects are given in Table 1. The prevalence of IBD in boys and girls was not found to be statistically different. Crohns disease (CD) occurred more frequently than ulcerative colitis (UC) or indeterminate colitis (IC). The severity of disease for most IBD patients was moderate or less. The severity improved at the time of follow-up. The majority of the patients received iron therapy, most frequently oral therapy.
Table 2 lists the parameters at baseline and at follow-up. All parameters improved except serum ferritin and serum soluble transferrin receptor; those 2 values remained unchanged. The calculated value for total body iron did not change.
The portion of patients with abnormal hematologic parameters decreased significantly from diagnosis to follow-up for most values recorded (Fig. 1). Percent of patients with abnormal serum iron and abnormal ferritin levels appeared to decrease but did not reach statistical significance. Percent with abnormal sTR did not decrease.
The proportion of patients who were anemic by WHO criteria decreased significantly from diagnosis to follow-up. This was true for the entire IBD cohort and for the IBD phenotypes CD and UC. Anemia decreased among the patients with IC; however, this group represented only 4 patients precluding meaningful statistical analysis (Fig. 2A). Figure 2B shows the percentage of patients with IDA or IDA/ACD initially and at 1-year follow-up. There were significant decreases in these categories of anemia for IBD and for CD as well as UC. Figure 2C shows the percentage of patients with ACD alone (without IDA). For the group as whole and for CD there was a dramatic decrease in this category of anemia. For UC at follow-up none of the patients had ACD alone. There were insufficient numbers of patients with IC to compare.
We created a correlation table (Supplemental Table 1, Supplemental Digital Content, http://links.lww.com/MPG/B366) crossing all of the parameters we measured at diagnosis. Some interesting correlations were apparent. Albumin correlated with most measures of anemia as well as with nutritional parameters (weight, body mass index [BMI] and BMI z) and measure of clinical indices of disease severity (ESR, CRP, PDCAI, and PCUAI). Interestingly, clinical severity scores (PDCAI and PUCAI) were poor predictors of anemia.
In the management of IBD patients with anemia it is important and helpful to determine the type of anemia as treatment options depend on the type of anemia. In IBD, IDA and ACD frequently occur simultaneously, complicating interpretation and treatment.
Iron is present in all mammalian cells and is of essential importance not only for oxygen transport but also for many nonhematological functions (10). In IBD, iron deficiency is the result of reduced iron uptake from the enterocyte and chronic blood loss from the GI tract. Ongoing daily losses of >10 mL of blood will result in iron deficiency (10).
ACD is due to inflammatory cytokine-mediated mechanisms thought to be due, at least in part, to hepcidin. Hepcidin is a circulating peptide, which plays a major role in iron homeostasis. Hepcidin reduces the quantity of circulating iron by preventing its exit from the cells, especially from enterocytes and macrophages. Hepcidin expression is controlled by iron and inflammation. The pro-inflammatory cytokines induce the hepcidin gene. In states of inflammation, high hepcidin levels lead to inhibition of iron release from enterocytes decreased iron levels in the circulation, and decreased utilization of iron at the level of the erythron (11).
Different parameters have been used to evaluate anemia in IBD, such as Hb, ferritin, serum iron, TIBC, and transferrin saturation (12). Outside the context of IBD, IDA and ACD are differentiated by using iron indices (13,14). These tests are, however, affected by chronic inflammatory disease. Ferritin levels are typically reduced in IDA, but may be increased by the chronic inflammation. When both iron deficiency and the ACD are present, many of the laboratory measures of iron status become unreliable (8).
Hb: When IDA accounted for most cases of anemia in children, “anemia” and “IDA” were roughly synonymous, and a simple measurement of Hb concentration was sufficient to make a presumptive diagnosis of anemia attributable to iron deficiency. Particularly in industrialized nations, the prevalence of iron deficiency and IDA has decreased, and other causes of anemia, such as hemolytic anemias, ACD, and anemia attributable to other nutrient deficiencies have become proportionately more common (15). Based on body iron measurements, however, only 20% of women with presumptive IDA had total body iron deficiency as defined by a total body iron deficit >4 mg/kg (9).
Serum iron: Serum iron is not an accurate tool to study the IDA. Iron levels change rapidly and serum iron show extensive fluctuations. Serum iron turns over many times daily (11). In our study, iron levels did not correlate with clinical activity but did correlate with the degree of anemia (Supplemental Table 1, Supplemental Digital Content, http://links.lww.com/MPG/B366). There was no correlation between serum iron level and total body iron perhaps reflecting the fact that serum iron represents only a fraction of the total body iron.
Total body iron: Calculations of total body iron using the formula: total body iron = −[log (sTR/Ferritin) − 2.8229]/0.1207, is not dependent on Hb and thus measures iron status rather than anemia. Approximately half of the total body iron is circulating as serum iron or as Hb, the remainder is found in myoglobin, heme- and nonheme enzymes and in storage forms, ferritin and hemosiderin. Thus, small changes in serum iron may not be reflected in changes in total body iron. The total body iron level did not correlate with gender, terminal ileum involvement, type of IBD or the severity of the disease (Supplemental Table 1, Supplemental Digital Content, http://links.lww.com/MPG/B366). It also did not correlate with the Hb level.
Serum ferritin is the most accessible measure of storage iron, and a subnormal concentration is indicative iron deficiency. Ferritin, however, is also an acute-phase reactant, and in the context of IBD, a normal or high value does not exclude iron deficiency. In our study, most patients had normal ferritin levels at the time of the diagnosis (72%). Ferritin levels were found to be lower in UC, and higher in CD (P < 0.05) (Table 2), possibly due to more blood loss in UC and relatively more inflammation in CD. In this study, ferritin levels did not correlate with the Hb levels, serum iron levels or disease activity, but did correlate with inflammatory markers (Supplemental Table 1, Supplemental Digital Content, http://links.lww.com/MPG/B366), sTR, and total body iron. Overall, ferritin alone is not a useful marker to estimate the type of anemia in IBD patients.
Transferrin and TIBC: Serum transferrin (sTF) and TIBC are reciprocal measurement. Transferrin is synthesized in the liver and mediates the transfer of iron between the enterocytes and the erythron. Serum TF generally carries about one-third of its iron binding capacity as a mixture of apo-, mono- and di-ferric forms. Serum TF levels go up in iron depletion and decrease as in iron overload. TIBC is a rough a measure of the amount of iron it takes to saturate sTF. Because TIBC measures nonspecific binding to other proteins, TIBC often overestimated the binding capacity. Serum TF is the more accurate of the 2; nevertheless, our data showed that both values increased significantly with treatment.
sTR and Soluble Transferrin Receptor Index (sTR-index): Serum sTR is an indicator of iron deficiency and is unaffected by chronic disease and inflammation (16). The transferrin receptor is a protein expressed in cells that require iron, and the soluble form is elevated in serum in cases of iron deficiency (17). Serum ferritin levels reflect iron stores while sTR levels reflect the degree of availability of iron for cells. The sTR Index, developed by Skikne et al (18), represents the relationship between 2 variables influenced by iron deficiency, sTR and ferritin. In this study, we used the sTR index to differentiate the ACD from IDA. At the time of the diagnosis, IDA or (IDA + ACD) prevalence was 28%. The ACD prevalence was 38%. In our study, sTR correlates with PCDAI, not with PUCAI score, possibly due to the degree of inflammation in CD compared with UC. There was no correlation with inflammatory markers and there is no difference in the sTR level between the type of IBD or the terminal ileum involvement (Supplemental Table 1, Supplemental Digital Content, http://links.lww.com/MPG/B366).
Intuitively, degree of anemia and clinical indices of disease severity should correlate. In our study, there is no such correlation (Supplemental Table 1, Supplemental Digital Content, http://links.lww.com/MPG/B366). This suggests that clinical indices of disease severity and anemia are not related. A possible explanation is that cytokines can lead to subclinical anemia before the laboratory signs and clinical symptoms of anemia are apparent. Alternatively, the indices of clinical indices of disease severity (PUCAI and PCDAI) may be inaccurate. Supporting the last of these possibilities is our finding that inflammatory markers (ESR and CRP) are consistent with the degree of anemia. Among all parameters examined, albumin is the single factor that correlates with most of the iron indices.
We found that the degree of anemia is consistent with inflammatory markers, not with clinical measures of disease activity. Anemia may exist even with mild inflammatory disease. Perhaps because activation of the inflammatory cascade is enough to cause anemia in the absence of the clinical picture of severe IBD. In states of inflammation, high hepcidin levels block iron release from enterocytes and decrease iron availability. This may explain our finding of lack of correlation between total body iron and the severity of the clinical activity.
Anemia is frequently encountered in both CD and UC. Measures of clinical indices of disease severity, PDCAI and PUCAI, were poor predictors of anemia. In CD and UC anemia due to IDA and ADC occur, either singly or together. The anemia of IBD proves difficult but not impossible to treat. The anemia in CD and UC does not follow the same pattern, perhaps pointing to differing pathogenesis.
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