Although iron deficiency anemia can be easily recognized by a low hemoglobin and a low MCV, there are other causes of this picture and other tests for confirming iron deficiency. Looking at a stained blood film reveals red blood cells that are paler than usual. They are paler because they are thinner and thin cells let more light through. You can also measure the amount of iron in the blood: the serum iron level. Iron is carried in the blood on a carrier protein known as transferrin. Normally, the whole body plasma transferrin contains about 3mg of iron and it functions as a transit compartment. About 20mg of iron flows through it in a normal day. In iron deficiency there is spare carrying capacity and the serum transferrin is raised. Elsewhere in the body iron is bound to a storage protein called ferritin, so in iron deficiency the serum ferritin level is low. Finally, you can normally see bits of iron in macrophages in the bone marrow (they stain blue with a special stain called Perl’s stain). In iron deficiency the macrophages are empty.
However, in some apparent iron deficient anemias, although the serum iron is low the transferrin is also low and the ferritin high and there is plenty of stainable iron in the bone marrow macrophages. The red cells on the blood film are still pale and indeed the blood film is indistinguishable from any other case of iron deficiency. These cases often have chronic inflammatory conditions like rheumatoid arthritis, ulcerative colitis or Crohn’s disease, or chronic infections like TB or perhaps certain types of cancer. Sometimes the condition comes on very quickly, especially in severe acute infections. We call these anemias, the anemias of chronic disorders or sometimes the anemias of inflammation. We used to say that something was preventing the release of iron from the macrophages. We now know what that ‘something’ is, and as we might have expected it is more complicated than that.
The ‘something’ is now known to be Hepcidin (pronounced ‘hep – side – in’; ‘hep’ comes from the Greek for liver – ‘hepar’; ‘sidero’ is the Greek for iron). Hepcidin is a small peptide consisting of 25 amino-acids. As you might expect from its name, it is made mainly in the liver, though it can be made by both granulocytes and macrophages. A knockout mouse has been produced that lacks hepcidin and from studying this we know that hepcidin controls intestinal iron uptake and the retention of iron in macrophages. If you inject hepcidin it produces a 75% reduction of serum iron levels within an hour and the effect persists for two days. A diet laden with iron produces an increase in the production of hepcidin, and anemia or a shortage of oxygen reduces hepcidin production.
During inflammation, inflammatory cytokines are produced and one of the most important of these is interleukin-6 (IL-6) which is an important inducer of hepcidin production. Other cytokines including IL-1 and TGF-beta are also involved in hepcidin regulation.
There are several mechanisms for the absorption of iron from the diet. Dietary iron is either in the ferric form (Fe+++) or as heme (myoglobin, the respiratory pigment of muscle [otherwise known as meat] contains heme). Fe+++ must be reduced to the ferrous form (Fe++) for absorption and this is done with a ferric reductase enzyme. Fe++ is absorbed using DMT1 (a silly name that just stands for divalent metal transporter 1) and heme absorption uses the equally obviously named heme carrier protein 1 (HCP1). Both these mechanisms only take the iron as far as the lining cells (or enterocytes) of the duodenum. From here they have to pass into the plasma and thence to macrophages in the bone marrow and elsewhere for the manufacture of hemoglobin, myoglobin and other iron-dependent proteins. The protein responsible for getting iron out of cells into the plasma is called ferroportin (Latin this time meaning iron-door). Ferroportin is equally important for enterocytes and macrophages. Without it iron would be stuck in the enterocytes and lost when they migrate up the duodenal villi and are shed into the intestinal lumen, and iron that had entered the macrophages would be trapped there and never get to the developing red blood cells.
Hepcidin binds to ferroportin in the cell membrane and causes it to be internalized and degraded (to put it another way, hepcidin locks the iron door). So hepcidin acts as a regulator of iron absorption and usage. In anemia, when there is a shortage of iron, or when the patient is short of oxygen, hepcidin production is suppressed so that more iron is absorbed and more iron is released from macrophages. Of course, if the anemia is not caused by a shortage of iron there can be inappropriately increased absorption of iron and this occurs in some types of thalassaemia.
Hepcidin is produced when iron absorption is sufficient, when there is no anemia or hypoxia, so as to stop excessive iron absorption. Hepcidin is also produced in response to some inflammatory cytokines, particularly IL-6; hence in the anemia of chronic disorders iron gets trapped in macrophages and not released to the developing red cells. Thus in the anemia of chronic disorders, because the iron-door is bolted, the anemia has the appearance of iron deficiency.
Added later. I need to say that there is no point in trying to treat the anemia of chronic disorders with either oral or intravenous iron. It just won't work.