Anemia in inflammatory bowel disease: an under-estimated problem?

Abstract

Anemia is one of the most frequent complications and/or extraintestinal manifestations of inflammatory bowel disease (IBD). Iron deficiency is the most important cause of anemia in Crohn's disease and ulcerative colitis patients. Iron deficiency even without anemia may impact the quality of life of our IBD patients. In the last 10 years, the understanding of the pathology of iron-deficiency anemia and "anemia of chronic diseases" has increased; new diagnostic tools have been developed and new therapeutic strategies have been discussed. Hepcidin has been identified to be a central regulator of iron absorption from the intestine and of iron plasma levels. Hepcidin is regulated by iron deficiency but also as an acute phase protein by pro-inflammatory mediators such as interleukin-6. Innovative diagnostic tools have not been introduced in clinical routine or are not available for routine diagnostics. As iron substitution therapy is easy these days with a preference for intravenous substitution, the impact of differential diagnosis of anemia in IBD patients is underestimated.

Keywords: anemia; inflammatory bowel disease; iron desorption.

Figure 1

Distribution of iron in the human body (70 kg). Less than 10% of the daily iron uptake of around 20 mg is absorbed by the intestinal mucosa. The transferrin bound iron pool in the plasma consists of about only 3 mg in total. Around 1000 mg are bound to ferritin and hemosiderin as iron storage in the liver. One hundred to hundred and thirty milligrams are found in other tissues [bound to myoglobin (Mb) or to enzymes]. Erythrocytes (Ec) contain about 2000 mg iron in total bound to hemoglobin (Hb). Eighty milligrams are found in the reticulo-endothelial system (RES) in which senescent erythrocytes are degraded. From the RES, iron is released into the serum contributing to the pool bound to transferrin. Around 1 mg of iron is physiologically lost each day contributing to a balance of iron metabolism and making a higher uptake in the intestine normally unnecessary.

Figure 2

(A) Regulation of iron absorption by hepcidin. Hepcidin synthesis is increased upon iron or inflammation in the liver. Inflammation in the gut will lead to increased IL-6 serum levels followed by higher amounts of hepcidin in the circulation. Hepcidin then decreases iron absorption in the gut and iron recycling from the RES leading to reduced iron availability for hem formation in the bone marrow. (B) On a molecular level in the enterocytes – the absorptive cells of the intestinal brush border membrane – hepcidin prevents iron release from enterocyte cytoplasmic stores by binding to the iron exporter protein ferroportin. This is followed by ferroportin internalization and degradation. Thus, iron is trapped intracellulary without being able to reach the blood stream (DMT1, divalent metal transporter 1 is a protein by the SLC11A2 gene (solute carrier family 11, member 2). DMT1 is a metal ion transporter protein that binds a variety of divalent metals including copper (Cu²⁺) and zinc (Zn²⁺) but is best known for transporting ferrous iron (Fe²⁺).