INTRODUCTION

The regulation of iron metabolism involves the interaction of a number of specific proteins as well as the interplay between iron absorption, recycling, and iron loss. This topic review will discuss these factors. Disorders of iron balance, both iron deficiency and iron overload, are discussed separately.

ROLE OF SPECIFIC PROTEINS

Our current understanding of iron metabolism and the hallmarks of iron deficiency and excess is based upon the biology of a number of critical proteins including, but not limited to, the following [1-4]:

• Transferrin (Tf)
• Transferrin receptor (TfR)
• Ferritin (Ft)
• Iron regulatory protein 1 and 2 (IRP1 and IRP2), the cellular iron sensing proteins
• Divalent metal transporter 1 (DMT1, Nramp2, DCT1, Solute carrier family 11, member 2 (SLC11A2)), the duodenal iron transporter
• Ferroportin (Ireg1, SLC11A3, Mtp1), the cellular iron exporter
• Hephaestin, which likely cooperates with ferroportin for exporting iron from enterocytes to transferrin
• Ceruloplasmin, a plasma metalloprotein required by ferroportin to export iron from macrophages, hepatocytes, and glial cells
• HFE, mutations of which are responsible for the common form of hereditary hemochromatosis
• TFR2, mutations of which are responsible for a rare form of hereditary hemochromatosis
• Hemojuvelin, a hepcidin regulator, mutations of which are responsible for the common form of juvenile hemochromatosis
• Hepcidin, the key negative regulator of intestinal iron absorption as well as macrophage iron release. Mutations of hepcidin cause a rare form of juvenile hemochromatosis [5].
• Bone morphogenetic protein 6 (BMP6), a cytokine produced in iron overload, responsible for the main pathway of hepcidin activation [6]

Transferrin — The gene for apotransferrin is on the long arm chromosome 3. It codes for a protein (mol wt 80 kDa) that tightly binds one or two ferric (Fe3+) molecules and is the major transporter for iron trafficking through the plasma. Most of the Tf, which has a half life of eight days, is made in the liver where its synthesis is considerably increased in states of iron deficiency by unknown mechanisms [1,2].

• Tf can be measured in the plasma using an ELISA or turbidometric method to determine the mg of the transferrin protein/dL of plasma.
• The total iron binding capacity of Tf (ie, TIBC) can be measured directly using iron binding methodology (ie, mg of iron binding capacity/dL of plasma), or it can be calculated by multiplying the results of the chemical or immunologic method by a conversion factor calculated by the individual laboratory.