Iron deficiency anemia in inflammatory bowel disease

Abstract

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.

Keywords: Ferritin; Hepcidin; Inflammatory bowel disease; Intravenous iron; Iron deficiency anemia; Oral iron.

Figures

Figure 1

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

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.

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.

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.