iron kinetics

• After studying the material in this chapter, the reader will be able to respond to the following case study
• In 1995, Garry, Koehler, and Simon assessed changes in stored iron in 16 female and 20 male regular blood donors aged 64 to 71
• Measurements taken


  • Hemoglobin
  • Hematocrit
  • Serum ferritin concentration
  • Percent transferrin saturation
• The donors gave an average of 15 units (approximately 485 mL/unit) of blood over 3.5 years
• Comparable data was collected from nondonors
• 10 women and 6 men took a dietary supplement providing approximately 20 mg of iron per day
• Mean dietary iron intake was 18 mg/day for the women and 20 mg/day for the men
• Over the period of the study, mean iron stores in women donors decreased from 12.53 to 1.14 mg/kg of body weight
• Mean iron stores in male donors declined from 12.45 to 1.92 mg/kg
• Nondonors' iron stores remained unchanged
• Based on hemoglobin and hematocrit results, no donors became anemic
• As iron stores decreased, the calculated iron absorption rose to 3.55 mg/day for the women and 4.10 mg/day for the men more than double the normal rate for both women and men
• Among the metals that are required for metabolic processes, none is more important than iron
• It is critical to energy production in all cells, being at the center of the cytochromes of mitochondria
• Oxygen needed for energy production is carried by iron in the hemoglobin molecule in red blood cells
• Iron is so critical to the body that there is no mechanism for active excretion, just minimal daily loss with exfoliated skin and hair and sloughed intestinal epithelia
• Iron is even recycled to conserve as much as possible in the body
• To insure against times when iron may be scarce in the diet, the body stores iron as well
• Distribution of body iron

  • Nearly 70% in hemoglobin in red blood cells
  • Almost 20% in storage, mostly within hepatocytes and macrophages in the spleen and bone marrow
  • Remaining approximately 10% divided among the muscles, the cytochromes, various iron-containing enzymes, and the plasma
• Functional compartment


  All iron that is functioning within cells including iron in hemoglobin, myoglobin (in muscles), and cytochromes (in all cells other than mature red blood cells)
• Storage compartment


  Iron that is not currently functioning but is available when needed. The major repositories are the macrophages and hepatocytes, but every cell, except mature red blood cells, stores some iron for its own use
• Transport compartment


  Iron that is in transit from one body site to another in the plasma
• The reactivity of iron ions makes them central to energy production processes, but it also makes them dangerous to the stability of cells
• The body regulates iron carefully at the level of the whole body and also within individual cells, maintaining levels that are necessary for critical metabolic processes, while avoiding the dangers of excess iron accumulation
• The conditions that develop when this balance is perturbed are described in Chapter 17
• The routine tests used to assess body iron status are discussed here
• The metabolic functions of iron depend on its ability to change its valence state from reduced ferrous (Fe²+) iron to the oxidized ferric (Fe³+) state
• Ferrous iron can react with peroxide via the Fenton reaction, forming highly reactive oxygen molecules
• The resulting hydroxyl radical (OH•), also known as a free radical, is especially reactive as a short-lived but potent oxidizing agent, able to damage proteins, lipids, and nucleic acids
• There are various mechanisms within the body and individual cells to reduce the potential for this type of damage
• Iron Compartments in Normal Humans

  • Functional: Hemoglobin iron in the blood, Myoglobin iron in muscles, Peroxidase, catalase, cytochromes, riboflavin enzymes in all cells
  • Storage: Ferritin and hemosiderin mostly in macrophages and hepatocytes; small amounts in all cells except mature red blood cells
  • Transport: Transferrin in plasma
• The total amount of iron available to all body cells, systemic body iron, is regulated by absorption into the body because there is no mechanism for excretion
• Absorption of Iron in the Intestines

  1. Iron can be absorbed as heme from animal food sources or as ionic iron, mostly from vegetable sources

  2. Heme is absorbed by enterocytes, likely by receptor-mediated endocytosis, and the iron is freed from protoporphyrin by heme oxygenase

  3. Nonheme ionic iron in the ferric form must be reduced by duodenal cytochrome b (Dcytb) before it can enter the enterocyte and be carried across the luminal side by divalent metal transporter 1 (DMT1)

  4. Iron can be stored as ferritin or chaperoned through the cytoplasm to the basolaminal side of the enterocyte for transport into the plasma by ferroportin
• Ferroportin


  The only known protein that exports iron across cell membranes
• Regulation of systemic body iron

  1. Hepatocytes sense body iron status and increase production of hepcidin when iron stores are adequate, leading to inactivation of ferroportin and decreased iron absorption

  2. When body iron begins to drop, the liver decreases hepcidin production, allowing ferroportin to be active and transport iron into the blood
• Iron exported from the enterocyte into the blood is ferrous and must be converted to the ferric form for transport in the blood by hephaestin
• Apotransferrin (ApoTf)


  A specific protein that binds up to two molecules of ferric iron to form transferrin (Tf) for plasma transport
• Regulation of hepcidin production

  Involves transferrin receptor 1 (TfR1), the hemochromatosis receptor (HFE), transferrin receptor 2 (TfR2), hemojuvelin (HJV), bone morphogenic protein (BMP) and its receptor (BMPR), sons of mothers against decapentaplegic (SMAD), and matriptase-2
• When body iron is replete and transferrin is well saturated, there is more diferric transferrin available to bind to the TfR1 and TfR2 on hepatocytes
• Diferric transferrin


  Also known as holotransferrin