Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD) and is frequently overlooked as a complication. Patients with IBD are commonly found to have iron deficiency anemia (IDA) secondary to chronic blood loss, and impaired iron absorption due to tissue inflammation. Patients with iron deficiency may not always manifest with signs and symptoms; so, hemoglobin levels in patients with IBD must be regularly monitored for earlier detection of anemia. IDA in IBD is associated with poor quality of life, necessitating prompt diagnosis and appropriate treatment. IDA is often associated with inflammation in patients with IBD. Thus, commonly used laboratory parameters are inadequate to diagnose IDA, and newer iron indices, such as reticulocyte hemoglobin content or percentage of hypochromic red cells or zinc protoporphyrin, are required to differentiate IDA from anemia of chronic disease. Oral iron preparations are available and are used in patients with mild disease activity. These preparations are inexpensive and convenient, but can produce gastrointestinal side effects, such as abdominal pain and diarrhea, that limit their use and patient compliance. These preparations are partly absorbed due to inflammation. Non-absorbed iron can be toxic and worsen IBD disease activity. Although cost-effective intravenous iron formulations are widely available and have improved safety profiles, physicians are reluctant to use them. We present a review of the pathophysiologic mechanisms of IDA in IBD, improved diagnostic and therapeutic strategies, efficacy, and safety of iron replacement in IBD.

Inflammatory bowel disease (IBD) describes a set of chronic gastrointestinal illnesses, including Crohn’s disease (CD) and ulcerative colitis (UC), of multifactorial etiology, which proceed with periods of relapse and remission. Extraintestinal complications are common in IBD, and are reported in more than 25% of patients[1]. Anemia is one of the most common manifestations of IBD[2]. One-third of patients with IBD have hemoglobin levels below 12 g/dL[3]. The anemic state is strongly correlated with quality of life, and is an important problem in the therapeutic management of patients with chronic disease[4].

Most cases of anemia in patients with IBD result from functional or absolute iron deficiency. Functional iron deficiency is a state in which there is insufficient availability of iron for incorporation into erythroid precursors despite normal or increased body iron stores[5,6]. In patients with absolute iron deficiency, iron is stored in the bone marrow. Other parts of the monocyte-macrophage system in the liver and spleen become depleted, making iron unavailable for normal or increased rates of erythropoiesis. This may occur as the result of poor dietary intake of iron, reduced iron absorption, and/or increased blood loss.

Signs and symptoms of iron deficiency depend on the severity and chronicity of the anemia, in addition to the usual signs of anemia, including fatigue, pallor, and reduced exercise capacity. Cheilosis and koilonychia are signs of advanced tissue iron deficiency which are not frequently seen in the modern world, due to early diagnosis and timely correction.

Key symptoms of anemia, such as dyspnea and tachycardia, are caused by decreased blood oxygen levels and peripheral hypoxia. Compensatory blood shifting from the mesenteric arteries may worsen perfusion of the intestinal mucosa[7]. Motility disorder, nausea, anorexia, and even malabsorption have been attributed to anemia. Reduced metabolic and energy efficiency during physical activity also contribute to weight loss in anemia[8].

Central hypoxia may lead to symptoms such as headache, dizziness, vertigo, or tinnitus. Several studies have confirmed that treatment of anemia improves cognitive function[9]. Iron is a component of hemoglobin myoglobin, cytochromes, and many other enzymes. Thus, anemia negatively impacts almost every aspect of daily life in patients with IBD. Men with iron deficiency anemia (IDA) may suffer from impotence. Loss of libido contributes to impaired quality of life in both sexes[10]. In addition, latent iron deficiency may be responsible for “non-hematological” symptoms such as hair loss, paresthesias of the hands and feet, and reduced cognitive function, and may also be significantly associated with restless leg syndrome.

Anemia and iron deficiency have a dramatic impact on patients’ quality of life, yet anemia in patients with IBD is still underdiagnosed and undertreated. In the United States, annual emergency room visits for anemia average around 209000[11], drastically maximizing health care costs. In a patient population with the predisposition for anemia, like patients with IBD, early diagnosis and management of iron deficiency can promptly reduce hospital visits, improve quality of life, reduce loss of work, and, ultimately, lower health care costs.

Anemia in IBD patients involves multiple pathogenic mechanisms resulting in low hemoglobin levels and compromised quality of life. Although ongoing blood loss from chronically inflamed intestinal mucosa and micronutrient deficiency (iron and B12) are the main mechanisms underlying the development of anemia in patients with IBD, chronic inflammation, hemolysis, and medication-induced myelosuppression may also play important roles in both the development of anemia and the management of this condition[12,13]. Anemia of chronic disease (ACD) and IDA are the two most common causes of anemia in patients with IBD[14,15]. Patients with IDA and concomitant ACD tend to have more severe anemia compared with patients with ACD alone[14]. Table 1 presents the causes of anemia in patients with IBD. Figure 1 outlines causes of IDA.

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Figure 1 Causes of iron deficiency anemia. GI: Gastrointestinal; NSAIDs: Nonsteroidal anti-inflammatory drugs.

Up to 3-4 g of iron is stored in the human body. Around 1-2 mg of iron is lost every day through desquamation of epithelial cells of the skin, gastrointestinal tract, bile ducts, and urinary tract, and through blood loss in menstruating women[16].

Iron homeostasis is strictly maintained by iron absorption from the duodenal enterocytes, and is tightly regulated by hepcidin (Figure 2). Hepcidin is a 25-amino-acid peptide hormone, has intrinsic antimicrobial activity, and is an acute-phase protein that is primarily synthesized by hepatocytes[17]. Cellular targets for hepcidin and iron-exporting cells are villous enterocytes, reticuloendothelial macrophages, and hepatocytes. Hepcidin binds to the basolateral transporter and iron exporter ferroportin 1, leading to its phosphorylation, internalization by binding to JAK 2, and lysosomal degradation, thus preventing iron release into the plasma[16]. Increased hepcidin levels downregulate ferroportin, thereby reducing iron efflux from the enterocytes and macrophages, causing hypoferremia. The increase in enterocyte iron content reduces the expression of enterocyte brush border reductase (Dcytb) and divalent metal transporter 1 (DMT1) on villous enterocytes, inhibiting dietary iron absorption causing iron deficiency anemia[18]. Therefore, by regulating the expression of DMT1 and ferroportin, hepcidin acts as a negative regulator of iron absorption in the duodenum and of iron release from the enterocytes and macrophages.

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Figure 2 Role of hepcidin in the regulation of iron homeostasis. Fe³⁺ is reduced to Fe²⁺ by enterocyte brush border reductase Dcytb, transported across brush border membrane by DMT1. If iron demand is low, Fe²⁺ is stored as ferritin and sloughed with enterocytes. If iron demand is high, iron is oxidized by oxidase hephaestin and then exported into the plasma at the basolateral membrane by ferroportin[23]. Hepcidin binds to iron exporter, ferroportin 1, leading to its phosphorylation, internalization by binding to JAK 2 and lysosomal degradation, thus preventing iron release into the plasma[16]. DcytB: Duodenal ferric reductase; DMTI: Divalent metal transporter 1.

Hepcidin expression is upregulated by iron overload, infection, and inflammation, through proinflammatory cytokines such as interleukin (IL)-6 via the JAK 2 mediated STAT 3 signaling, thus limiting iron absorption[16,19]. Hepcidin expression is downregulated by hypoxia, oxidative stress, iron deficiency anemia, and ineffective erythropoiesis, thus increasing iron availability (Figure 2)[20].

Hepcidin expression is mediated by two signaling pathways that involve bone morphogenetic protein (BMP) and transferrin receptor 2 (TfR2; Figure 3). The BMP signaling pathway includes BMP 6, hemojuvelin (HJV), and SMAD4, which constitute the major signaling pathway for hepcidin expression; TfR2 and the hereditary hemochromatosis protein (HFE)-dependent signaling pathway modulate this response[21,22]. In high iron conditions, transferrin-iron in the plasma forms a complex with HFE and TfR2 to promote hepcidin expression[21]. In iron-deficient conditions, there is downregulation of TfR2 and upregulation of TfR1. HFE is sequestered by TfR1, preventing its interaction with TfR2, thereby downregulating hepcidin expression (Figure 3)[21,23].

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Figure 3 Signaling pathways regulating hepcidin expression in the liver. Enterocyte iron induces BMP6 expression. BMP6 is released via the portal vein to act on cell-surface receptors in the liver, BMPR-I, BMPR-II, and HJV, a co-receptor of BMP, leading to phosphorylation of cytosolic transcription factors, SMAD 1/5/8, which complex with SMAD 4[16,21]. This heteromeric complex translocates to the nucleus and enhances transcription of hepcidin gene, HAMP. In iron deficiency, HJV is cleaved by matriptase-2 activation reducing BMP signaling, and BMP is sequestered by s-HJV, preventing its interaction with plasma membrane HJV, decreasing hepcidin expression[21]. IL-6: Interleukin 6; BMP: Bone morphogenetic protein; HJV: Hemojuvelin; s-HJV: Soluble HJV; TfR2: Transferrin receptor 2; HFE: Hereditary hemochromatosis protein; BMPR: Bone morphogenetic protein receptors.

Healthcare providers screen for IDA by measuring hemoglobin, serum ferritin, and C-reactive protein (CRP). Based on expert opinion and common clinical practice, screening is recommended at least every 3 mo for outpatients with active disease, and once every 6 to 12 mo for patients in remission or with mild disease; screening is not applicable to hospitalized patients[24].

The World Health Organization (WHO) definitions of anemia also apply to patients with IBD. WHO defines anemia as hemoglobin levels < 13 g/dL (hematocrit < 39%) in males, < 12 g/dL (hematocrit < 36%) in nonpregnant females, and < 11 g/dL (hematocrit < 33%) in pregnant females[25]. Severe IDA is defined as hemoglobin levels < 10 g/dL.

If a patient meets WHO criteria for anemia, a basic anemia workup should be initiated to determine the cause of anemia. The basic workup includes serum ferritin, transferrin, transferrin saturation, and CRP levels. If the cause of anemia is unclear despite the results of the above workup, more extensive testing is recommended. Further tests include vitamin B12, folic acid, haptoglobin, lactate dehydrogenase, creatinine, and reticulocyte counts[24].

Both IDA and ACD often coexist with IBD, and the treatment for each differs. There is no single laboratory parameter that differentiates one from the other. Consequently, supplementary laboratory tests are required to differentiate IDA from ACD. These tests include soluble transferrin receptor, soluble transferrin receptor-ferritin index, reticulocyte hemoglobin concentration, zinc protoporphyrin, the percentage of hypochromic red cells, and hepcidin levels[16]. IDA in IBD is diagnosed based on a combination of factors, taking inflammation into account. The laboratory findings in IDA, ACD, mixed IDA, and ACD are shown in Table 2[16,22].

Serum ferritin is a measure of stored iron content in the reticuloendothelial system; in absolute iron deficiency, the serum ferritin concentration is < 15 μg/L[16]. Serum ferritin is an acute-phase reactant; normal or high levels may be found in inflammatory conditions despite iron deficiency[26]. Therefore, the guidelines recommend that in patients with quiescent IBD without biochemical or clinical evidence of inflammation, iron deficiency is defined as serum ferritin < 30 g/L or transferrin saturation (TSAT) < 16%[24]. In the presence of active IBD with inflammation, as evidenced by elevated CRP, the guidelines give a cut-off level of serum ferritin < 100 g/L to increase sensitivity and specificity[24,27].

Microcytosis (low mean corpuscular volume, MCV) and hypochromia (low mean corpuscular hemoglobin, MCH), available from the complete blood count, are indicators of absolute iron deficiency. High MCV is found secondary to vitamin B12 and folate deficiency, the use of certain medications (thiopurines; azathioprine or 6-mercaptopurine), alcoholism, and hypothyroidism[24]. Therefore, normal or high MCV does not exclude IDA as a possibility. In patients with ACD, MCV may be low or normal.

Serum transferrin carries Fe³⁺ in plasma and delivers iron from the sites of iron absorption (duodenal enterocytes and macrophages) to all tissues. Therefore, its level is higher in IDA. However, as it is an acute-phase protein, its level can be decreased during inflammation, despite normal or low iron stores.

Transferrin saturation (TSAT), an indicator of the iron load of circulating transferrin, gives an indirect measure of extent of iron utilization[16]. TSAT is the ratio of serum iron and total iron-binding capacity, multiplied by 100. It is decreased in both IDA and ACD. Pregnancy and oral contraceptives increase plasma transferrin levels; therefore, TSAT may be low in such patients, despite normal iron stores[16]. Hepcidin is increased during inflammation and decreased in IDA. It prevents iron absorption, causes retention of iron in the macrophages, and inhibits erythropoiesis.

Soluble transferrin receptor (sTfR) is a measure of erythropoietic activity. It is directly proportional to erythropoietic activity and inversely proportional to tissue iron availability[28]. sTfR is used to differentiate iron deficiency (increased sTfR and low serum ferritin) from inflammation (normal sTfR and serum ferritin) and to diagnose a combination of iron deficiency and inflammation (increased sTfR and normal serum ferritin)[24,27]. However, its use is limited due to its cost and unavailability in many laboratories.

The sTfR/log ferritin ratio (sTfR-ferritin index) may be an early indicator of depletion of iron stores[29]. A ratio < 1 suggests ACD and excludes iron deficiency, while a ratio > 2 suggests either IDA or mixed IDA and ACD[27].

Functional iron deficiency is the imbalance between the iron requirements of the erythroid marrow and the iron supply, when the body cannot supply iron rapidly enough to maintain an increased erythropoietic rate. This leads to reduced reticulocyte and erythrocyte cellular hemoglobin (Hb) content[30]. Reticulocyte hemoglobin content (CHr) and the percentage of hypochromic RBC are indicators of red cell hemoglobinization and, thus, functional iron deficiency, regardless of inflammatory states[30]. In IDA, CHr > 40 and hypochromic RBCs > 5%[31].

Iron binds to protoporphyrin IX to form heme. In the absence of iron, zinc binds to protoporphyrin to form zinc protoporphyrin (ZPP). ZPP indicates iron levels in the bone marrow during erythropoiesis and is unaffected by ACD or inflammation[16].

IDA is the most common anemia in IBD. Therefore, anemic patients with IBD should be evaluated for IDA. IDA mandates adequate and appropriate treatment, as it influences the patient’s quality of life and morbidity. It should be considered as an extraintestinal manifestation of IBD. The basic workup may be insufficient to diagnose IDA in the presence of inflammation. Table 2 summarizes the laboratory parameters necessary to differentiate IDA from ACD. Recent clinical trials support IV iron therapy as a preferable option, especially in clinically active IBD and moderate-severe IDA. IV iron therapy was shown to have better tolerability and efficacy, with fewer infusions, a better safety profile, and, accordingly, improved patient compliance. Figure 4 summarizes the management of IDA in IBD[16]. The ultimate goal is to normalize hemoglobin levels.

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Figure 4 Management of iron deficiency anemia in patients with inflammatory bowel disease[16]. Hb: Hemoglobin; IDA: Iron deficiency anemia; TSAT: Transferrin saturation; CRP: C-reactive protein; IBD: Inflammatory bowel disease; IV: Intravenous; ESA: Erythropoiesis stimulating agents.