Iron in Senescent Erythrocytes Is Recycled by Macrophages

Erythrocytes normally have a half-life of approximately 28 days, a turnover rate that requires the catabolism of ≈200 billion erythrocytes per day. Senescent or damaged erythrocytes are phagocytosed in the spleen and liver by macrophages of the reticuloendothelial system (RES). Within these macrophages, hemoglobin-derived heme groups are oxidized to biliverdin by the enzyme heme oxygenase (see Figure 1), releasing carbon monoxide and iron. The liberated iron is exported from phagocytic vesicles in the macrophage by NRAMP 1 (natural resistance–associated macrophage protein 1), a trans porter homologous to DMT1. Iron is subsequently secreted into the circulation by the transmembrane protein ferroportin (Figure 2). Thus, ferroportin plays a central role in both iron absorption by the intestine and iron secretion from macrophages.

Fig1. Diagrammatic representation of the three major processes (uptake, conjugation, and secretion) involved in the transfer of bilirubin from blood to bile. Certain proteins of hepatocytes bind intracellular bilirubin and may prevent its efflux into the bloodstream. The processes affected in certain conditions that cause jaundice are also shown.

Fig2. Recycling of iron in macrophages. Senescent erythrocytes are phagocytosed by macrophages. Hemoglobin is degraded and iron is released from heme by the action of the enzyme heme oxygenase. Ferrous iron is then transported out of the macrophage via ferroportin (Fp). In the plasma, it is oxidized to the ferric form by ceruloplasmin before binding to transferrin (Tf). Iron circulates in blood tightly bound to Tf.

In the blood, Fe2+ is oxidized to Fe3+ in a reaction catalyzed by the ferrioxidase ceruloplasmin (see later), a copper containing plasma enzyme synthesized by liver. Once oxidized, Fe3+ is then bound by transferrin in blood. The iron released from macrophages in this way (about 25 mg/d) is recycled, thereby reducing the need for intestinal iron absorption, which averages only 1 to 2 mg/d.

Haptoglobin Scavenges Hemoglobin That Has Escaped Recycling

During the course of red blood cell turnover, approximately 10% of an erythrocyte’s hemoglobin escapes into the circulation. This free, extracorpuscular hemoglobin is sufficiently small at ≈65 kDa to pass through the glomerulus of the kidney into the tubules, where it tends to form damaging precipitates. Haptoglobin (Hp) is a plasma glycoprotein that binds extra corpuscular hemoglobin (Hb), forming a tight noncovalent complex (Hb-Hp). The large size of the resulting Hb-Hp com plex (≥ 155 kDa) prevents its passage through the glomerulus, thereby protecting the kidney from the formation of harmful precipitates and reducing the loss of the iron associated with extracorpuscular hemoglobin. Normally, a deciliter of human plasma contains sufficient haptoglobin to bind 40 to 180 mg of hemoglobin.

Human haptoglobin exists in three polymorphic forms, known as Hp 1-1, Hp 2-1, and Hp 2-2, that reflect the patterns of inheritance of two genes, designated Hp¹ and Hp². Homozygotes synthesize Hp 1-1 or Hp 2-2, respectively, while Hp 2-1 is synthesized by heterozygotes. Other plasma proteins bind free heme rather than hemoglobin. They include hemopexin and albumin, the latter of which binds metheme (ferric heme) to form methemalbumin. Methemalbumin subsequently transfers this metheme to hemopexin.

Haptoglobin Can Serve as a Diagnostic Indicator

 In situations where hemoglobin is constantly being released from red blood cells, such as occurs in hemolytic anemias, the level of haptoglobin can fall dramatically. This decrease reflects the marked difference in the half-lives of free haptoglobin, approximately 5 days, and the Hb-Hp complex, approximately 90 minutes. In some cancer patients the level of haptoglobin related protein, a homologue of haptoglobin also present in plasma, becomes elevated. However, its significance is not yet understood.

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