Management of iron deficiency anemia in inflammatory bowel disease - a practical approach

Abstract

Although anemia is the most common systemic manifestation of inflammatory bowel disease (IBD), among the broad spectrum of extraintestinal disease complications encountered in IBD, including arthritis and osteopathy, it has generally received little consideration. However, not only in terms of frequency, but also with regard to its potential effect on hospitalization rates and on the quality of life and work, anemia is indeed a significant and costly complication of IBD. Anemia is multifactorial in nature, the most prevalent etiological forms being iron deficiency anemia (IDA) and anemia of chronic disease. In a condition associated with inflammation, such as IBD, the determination of iron status using common biochemical parameters alone is inadequate. A more accurate assessment may be attained using new iron indices including reticulocyte hemoglobin content, percentage of hypochromic red cells or zinc protoporphyrin. While oral iron supplementation has traditionally been a mainstay of IDA treatment, it has also been linked to extensive gastrointestinal side effects and possible disease exacerbation. However, many physicians are still reluctant to administer iron intravenously, despite the wide availability of a variety of new IV preparations with improved safety profiles, and despite the recommendations of international expert guidelines. This article discusses improved diagnostic and therapeutic strategies based on new clinical insights into the regulation of iron homeostasis.

Keywords: Inflammatory bowel disease; anemia; extraintestinal manifestations; iron deficiency; iron supplementation.

Figure 1

Hepcidin as the master regulator of iron homeostasis in inflammatory bowel disease. Hepcidin gene expression is up-regulated during inflammation by proinflammatory cytokines - mainly IL-6 (involving JAK-dependent activation of STAT3). Hepcidin binds to ferroportin and triggers its lysosomal degradation, leading to a reduction in iron release from enterocytes and macrophages. Hepcidin may also inhibit DMT1 directly. Hepcidin levels are correlated with the body’s iron stores. BMP regulates hepcidin by sensing enteric iron status. Iron absorption in enterocytes leads to activation of BMP6 expression and, subsequently, to the delivery of BMP6 to the liver. In the liver, BMP6 binds to type I and II receptors (BMPR1 and BMPR2) and to the co-receptor HJv, leading to phosphorylation of SMAD1, SMAD5 and SMAD8, and complex formation with SMAD4. This complex translocates to the nucleus to activate the HAMP gene promoter, leading to synthesis of hepcidin BMP, bone morphogenetic protein; DMT1, divalent metal transporter 1; HJv, hemojuvelin; IL-6, interleukin 6 (adapted from [4]).

Figure 2

Response Rates at Week 12. Primary (Hb increase ≥ 2 g/dL) and secondary (Hb increase ≥ 2 g/dL or normal Hb) end points [49]

Figure 3

Work-up for the management of iron deficiency anemia in patients with inflammatory bowel disease Hb, Hemoglobin; TSAT, Transferrin saturation; HYPO, hypochromic erythrocytes; Chr, reticulocyte-Hb; ESA, Erythropoiesis stimulating agent (adapted from [4])