Iron Deficiency and Anaemia in Heart Failure: Understanding the FAIR-HF Trial

José González-Costello; Josep Comín-Colet


Eur J Heart Fail. 2010;12(11):1159-1162. 

In This Article

Iron Deficiency in Chronic Heart Failure

It therefore seems reasonable to look further into the pathogenesis of anaemia in patients with CHF. Although vitamin B12 or folic acid deficiency must be assessed, as it may affect up to 19% of patients with CHF and anaemia, it seems to be of secondary importance.[1] Iron deficiency plays a critical role in the anaemia of CHF, and it can contribute to EPO resistance, as the bone marrow will not respond to EPO unless adequate iron stores are present.[20] An important point is that despite seemingly adequate iron stores assessed by serum iron and ferritin, up to 73% of patients with anaemia, normal kidney function, and advanced CHF had ID as assessed by bone marrow aspiration in a study by Nanas et al.[21] This study demonstrated that neither serum iron nor ferritin levels proved to be reliable markers of ID. The reason for this higher than expected serum ferritin may have been due to inflammatory mediators that accompany the CHF syndrome and this is why in these patients a higher value of ferritin (<100 µg/L) defines absolute ID.[16]

Iron is an essential trace element that can donate electrons in its ferrous form-Fe(II)-and accept electrons in its ferric form-Fe(III). This capability makes it a useful component of cytochromes and oxygen-binding molecules, such as haemoglobin and myoglobin, but can also promote the generation of free radicals and makes iron potentially toxic. For this reason iron is bound to proteins, yielding solubility in aqueous solutions such as blood, without the risk of free radical generation.[20] Since iron is not actively excreted from the body, iron haemostasis is mostly regulated by iron absorption in the duodenum and proximal jejunum (see Figure 1). There are two different iron absorption pathways: one for haem-bound iron, mostly bound to porphyrins in meat-based foods, and another for non-haem iron, mostly found in vegetables. Haem-iron constitutes only 10% of dietary iron, but because of greater bioavailability it represents 30% of the total absorbed iron and it is absorbed via a specific membrane transporter. Non-haem iron is mostly found in the Fe(III) state and is reduced to Fe(II) in the intestinal apical membrane by a ferrireductase, which is induced by ID. Fe(II) is then transported by a divalent metal transporter 1 (DMT1) into the enterocyte. Vitamin C, amino acids containing cysteines, and gastric acid reduce Fe(III) non-haem iron to the more easily absorbable Fe (II). On the other hand, tannins (tea, coffee), oxalates (spinach), phosphates (milk), antacids, and proton pump inhibitors reduce non-haem iron absorption.[20] The iron absorbed by DMT1 can be incorporated to enterocyte ferritin, and eventually lost when the enterocyte is replaced, or it can be exported by a transport protein called ferroportin, within the basolateral membrane.[22] Hepcidin is a peptide synthesized by the liver in response to an increase in transferrin saturation (TSAT), microbial infection, or inflammation. It blocks intestinal iron absorption and iron release from the liver and spleen by binding to ferroportin and degrading it.[23] Iron released into the bloodstream is bound to apotransferrin and yields transferrin, which transports iron to all body cells.[20] Transferrin levels correlate inversely with the amount of body iron stores. These transferrin molecules bind to transferrin receptors on the cell surface and this complex is internalized. In erythroid cells, iron moves mainly into the mitochondria to be used in haem synthesis for the subsequent formation of haemoglobin outside the mitochondria. In non-erythroid cells, iron is stored as ferritin and haemosiderin.[24] The concentration of soluble transferrin receptors in plasma is increased in absolute ID, but not by the acute phase response, helping to differentiate between ID anaemia and anaemia of chronic disease.[25]

Figure 1.

Possible mechanisms of iron deficiency in chronic heart failure. Fe(II), iron in ferrous form; Fe(III), iron in ferric form; DMT1, divalent metal transporter 1; TfR, transferrin receptor.