12.7 Iron

Iron

There are 2 major dietary forms of iron: heme iron and non-heme iron. Heme iron is only found in foods of animal origin, within hemoglobin and myoglobin. The structure of heme iron is shown below.

Figure 12.71 Structure of heme iron1

Approximately 40% of iron in meat, fish, and poultry is heme-iron, and the other 60% is non- heme iron2.

Non-heme iron is the mineral alone, in either its oxidized or reduced form. The 2 forms of iron are:

• Ferric (Fe3+, oxidized)
• Ferrous (Fe2+, reduced)

It is estimated that 25% of heme iron and 17% of non-heme iron are absorbed2. Approximately 85-90% of the iron we consume is non-heme iron2,3.

In addition to getting iron from food sources, if food is cooked in cast iron cookware, a small amount of iron can be transferred to the food. On the next page you will find a link to a story about the iron fish that is being used in Cambodia to increase iron intake in an area with prevalent iron deficiency. However, they found that the iron fish was not effective in reducing anemia4.

Web Link Canadian’s lucky iron fish saves lives in Cambodia

Many breakfast cereals are fortified with reduced iron, which looks like iron filings, as the following video shows.

Web LinkVideo: Iron for breakfast (1:02)

While the iron bioavailability of this reduced iron is low, some is absorbed5.

Supplements

Most iron supplements use ferrous (Fe2+) iron, because this form is better absorbed, as discussed in the next section. The figure below shows the percent of elemental iron in different supplements. This is the percentage of elemental iron that is in each compound.

Figure 12.72 Elemental iron in different iron supplements3

Vitamin C does not increase absorption of ferrous supplements because they are already in reduced form, as discussed in the following subsection2. Iron chelates are marketed as being better absorbed than other forms of iron supplements, but this has not been proven6. It is recommended that supplements are not taken with meals, because they are better absorbed when not consumed with food2.

For more information on vitamin K, see the Required Web Link below.

Required Web LinkIron Dietary Supplement Fact Sheet

Subsections:

• 12.71 Iron Uptake & Absorption
• 12.72 Iron Transport & Storage
• 12.73 Iron Functions
• 12.74 Iron Deficiency & Toxicity

References & Links

• http://en.wikipedia.org/wiki/File:Heme.svg
• Whitney E, Rolfes SR. (2011) Understanding nutrition. Belmont, CA: Wadsworth Cengage Learning.
• http://foodfix.ca/health.php#en65
• Rappaport AI, Whitfield KC, Chapman GE, Yada RY, Kheang KM, Louise J, Summerlee AJ, Armstrong GR, Green TJ. Randomized controlled trial assessing the efficacy of a reusable fish- shaped iron ingot to increase hemoglobin concentration in anemic, rural Cambodian women. (2017) Am J Clin Nutr 106 (2): 667-674.
• Garcia-Casal M, Layrisse M, Pena-Rosas J, Ramirez J, Leets I, et al. (2003) Iron absorption from elemental iron-fortified corn flakes in humans. role of vitamins A and C1-3. Nutr Res 23(4): 451-463.
• Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing.

Link

Canadian’s lucky iron fish saves lives in Cambodia – http://www.therecord.com/news/local/article/624229–canadian-s-lucky-iron-fish-saves-lives- in-cambodia

Iron Dietary Supplement Fact Sheet – https://ods.od.nih.gov/factsheets/Iron- HealthProfessional/

Video

Iron for breakfast – https://www.youtube.com/watch?v=pRK15XSqtAw

Iron Uptake & Absorption

There are 2 transporters for iron, one for heme iron and one for non-heme iron. The non-heme transporter is the divalent mineral transporter 1 (DMT1), which transports Fe2+ into the enterocyte. Heme iron is taken up through heme carrier protein 1 (HCP-1), and then metabolized to Fe2+. Fe2+ may be used by enzymes and other proteins or stored in the enterocyte bound to ferritin, the iron storage protein. To reach circulation, iron is transported through ferroportin1,2. This process is summarized in Figure 12.711.

Figure 12.711 Iron uptake into the enterocyte

Since only the reduced form of non-heme iron (Fe2+) is taken up, Fe3+ must be reduced. There is a reductase enzyme on the brush border, duodenal cytochrome b (Dcytb), that catalyzes the reduction of Fe3+ to Fe2+, as shown below. Vitamin C enhances non-heme iron absorption because it is required by Dcytb for this reaction. Thus, if dietary non-heme iron is consumed with vitamin C, more non-heme iron will be reduced to Fe2+ and taken up into the enterocyte through DMT1 as shown in Figure 12.712.

Figure 12.712 Reduction of non-heme iron by Dcytb

In addition to vitamin C, there is an unidentified factor in muscle that enhances non-heme iron absorption if consumed at the same meal3. This unidentified factor is referred to as meat protein factor (MPF).

Inhibitors of non-heme iron absorption typically chelate, or bind, the iron to prevent absorption. Phytates (phytic acid), which also inhibit calcium absorption, chelate non-heme iron decreasing its absorption.

Figure 12.713 Structure of phytic acid4

Other compounds that inhibit absorption are: Polyphenols (coffee, tea)1

Figure 12.714 Structure of gallic acid, a polyphenol5

Oxalate (spinach, rhubarb, sweet potatoes, and dried beans)2

Figure 12.715 Structure of calcium oxalate6 Calcium is also believed to inhibit iron uptake.

References & Links

• Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing.

• Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins.
• Hurrell R, Reddy M, Juillerat M, Cook J. (2006) Meat protein fractions enhance nonheme iron absorption in humans. J Nutr 136(11): 2808-2812.
• http://en.wikipedia.org/wiki/File:Phytic_acid.png
• http://en.wikipedia.org/wiki/File:Gallic_acid.svg
• http://en.wikipedia.org/wiki/File:Calcium_oxalate.png

Iron Transport & Storage

Transferrin is the major iron transport protein (transports iron through blood). Fe3+ is the form of iron that binds to transferrin, so the Fe2+ transported through ferroportin must be oxidized to Fe3+. There are 2 copper-containing proteins that catalyze this oxidation of Fe2+: hephaestin and ceruloplasmin. Hephaestin is found in the membrane of enterocytes, while ceruloplasmin is the major copper transport protein in blood. Hephaestin is the primary protein that performs this function in a coupled manner (need to occur together) with transport through ferroportin. This means that the Fe2+ needs to be oxidized to be transported through ferroportin. Evidence suggests that ceruloplasmin is involved in oxidizing Fe2+ when iron status is low1. Once oxidized, Fe3+ binds to transferrin and is transported to a tissue cell that contains a transferrin receptor.

Transferrin binds to the transferrin receptor and is endocytosed, as shown in Figure 12.7212.

Figure 12.721 Transport and uptake of iron

Once inside cells, the iron can be used for cellular purposes (cofactor for enzyme etc.) or it can be stored in the iron storage proteins ferritin or hemosiderin. Ferritin is the primary iron storage protein, but at higher concentrations, iron is also stored in hemosiderin2.

Figure 12.722 Fates of iron within cells

There are 3 major compartments of iron in the body3:

• Functional Iron
• Storage Iron
• Transport Iron

Functional iron consists of iron performing some function. There are 3 functional iron sub- compartments.

• Hemoglobin
• Myoglobin
• Iron-containing enzymes

The functions of these sub-compartments are discussed in the next section. Iron Stores consist of:

• Ferritin
• Hemosiderin

The liver is the primary storage site in the body, with the spleen and bone marrow being the other major storage sites.

Circulating iron is found in transferrin3.

The majority of iron is in the functional iron compartment. The figure below further reinforces this point, showing that most iron is found in red blood cells (hemoglobin) and tissues (myoglobin).

Figure 12.723 Iron distribution in different compartments4

Also notice how small oral intake and excretion are compared to the amount found in the different compartments in the body. As a result, iron recycling is really important, because red blood cells only live for 120 days. Red blood cells are broken down in the liver, spleen, and bone marrow and the iron can be used for the same purposes as described earlier: cellular use, storage, or transported to another tissue on transferrin2. Most of this iron will be used for heme

and ultimately red blood cell synthesis. The figure below summarizes the potential uses of iron recycled from red blood cells.

Figure 12.724 Iron recycling from red blood cells

Iron is unique among minerals in that our body has limited excretion ability. Thus, absorption is controlled by the hormone hepcidin. The liver has an iron sensor so when iron levels get high, this sensor signals for the release of hepcidin. Hepcidin causes degradation of ferroportin. Thus, the iron is not able to be transported into circulation5.

Figure 12.725 Action of hepcidin4

The iron is now trapped in the enterocyte, which is eventually sloughed off and excreted in feces. Thus, iron absorption is decreased through the action of hepcidin.

Figure 12.726 Enterocytes are sloughed off the villus and unless digested and their components reabsorbed, they will be excreted in feces

References & Links

• Yehuda S, Mostofsky DI (2010) Iron Deficiency and Overload: From Basic Biology to Clinical Medicine. New York, NY. Humana Press.
• Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing.
• Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier.
• http://en.wikipedia.org/wiki/File:Iron_metabolism.svg
• Nemeth E, Ganz T. (2006) Regulation of iron metabolism by hepcidin. Annu Rev Nutr 26: 323- 342.

Iron Functions

As we talked about in the previous subsection, there are 3 primary functional iron subcompartments:

• Hemoglobin
• Myoglobin
• Iron-containing enzymes

Hemoglobin contains heme that is responsible for red blood cells’ red color. Hemoglobin carries

oxygen to tissues. The function of hemoglobin can be seen in the Required Web Link below.

Required Web LinkHemoglobin

Myoglobin is similar to hemoglobin in that it can bind oxygen. However, instead of being found in blood, it is found in muscle. The color of meat products is a result of the state that myoglobin is in, as shown in the Required Web Link on the next page.

Required Web LinkMyoglobin & Meat Color

There are a number of enzymes that use iron as a cofactor. We’ve already talked about two in this class.

Iron is a cofactor for the antioxidant enzyme, catalase that converts hydrogen peroxide to water, as shown below.

Figure 12.731 Catalase uses iron as a cofactor

Iron is also a cofactor for proline and lysyl hydroxylases that are important in collagen cross- linking. This will be discussed further in the vitamin C section. The function of these enzymes is shown below.

Figure 12.732 Importance of ascorbic acid and iron to proline and lysyl hydroxylases.

Heme iron is also found in cytochromes, like cytochrome c in the electron transport chain as shown below1.

Figure 12.733 Cytochrome c in the electron transport chain contains iron2

References & Links

• Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing.
• http://wikidoc.org/index.php/File:ETC.PNG

Links

Hemoglobin – http://www.nlm.nih.gov/medlineplus/ency/imagepages/19510.htm Myoglobin & Meat Color – http://meatisneat.files.wordpress.com/2009/09/slide11.jpg

Iron Deficiency & Toxicity

The levels of iron in the different compartments is illustrated by the figure below. The red above the table is meant to represent the amount of iron in the different compartments. In early negative iron balance stage, iron stores are slightly depleted. Once the stores are almost completely exhausted, this state is referred to as iron depletion. In iron deficiency, stores are completely exhausted and the circulating and functional iron levels are also depleted. In iron anemia, the circulating and functional iron levels are further depleted from iron-deficiency.

1 Great measure, but invasive

2 Small amount are released from liver, bone, and spleen – proportional to body stores

3 Also referred to as total iron-binding capacity

Figure 12.741 Measures of iron status1-3

The most common measures of iron status are hemoglobin concentrations and hematocrit (described below) levels. A decreased amount of either measure indicates iron deficiency, but these two measures are among the last to indicate that iron status is depressed. This is because, as you can see in the figure above, circulating iron (plasma iron) levels are not altered until you reach iron deficiency. Thus, other measures are likely better choices1.

The hematocrit, as illustrated in the figure below, is a measure of the proportion of red blood cells (erythrocytes) as compared to all other components of blood. The components are separated by a centrifuge. The red blood cells remain at the bottom of the tube. They can be quantified by measuring the packed cell volume (PCV) relative to the total whole blood volume.

w Figure 12.742 Hematocrit figures4,5

One of the best measures of iron status is bone marrow iron, but this is an invasive

measure, and is therefore not commonly used. Plasma ferritin, the iron storage protein, is also found in lower amounts in the blood (plasma) and is a good indicator of iron stores. Thus, it is a sensitive measure to determine if someone is in negative iron balance or iron depleted. It is not as useful of a measure beyond this stage because the iron stores have been exhausted for the most part. Transferrin iron binding capacity (aka total iron binding capacity), as it sounds, is a measure of how much iron transferrin can bind. An increase in transferrin iron binding capacity indicates deficiency (>400 indicates deficiency). But the best measure for deficiency or anemia is either percent serum transferrin saturation or plasma iron. A lower % saturation means that less of the transferrin are saturated or carrying the maximum amount of iron that they can handle. Plasma iron is easily understood as the amount of iron within the plasma1.

Iron deficiency is the most common deficiency worldwide, estimated to affect 1.6 billion people. In the US, it is less common, but an estimated 10% of toddlers and women of childbearing age are deficient. Iron deficiency often results in a microcytic (small cell), hypochromic (low color) anemia, that is a result of decreased hemoglobin production. With decreased hemoglobin, the red blood cells cannot carry as much oxygen. Decreased oxygen leads to slower metabolism. Thus, a person with this anemia feels fatigued, weak, apathetic, and can experience headaches6. Other side effects include decreased immune function and delayed cognitive development in children7.

Those who are particularly at risk are1,7:

• Women of childbearing age – because of losses due to menstruation
• Pregnant women – because of increased blood volume
• Vegetarians – because they do not consume heme iron sources
• Infants – because they have low iron stores that can quickly be depleted

To give you a better understanding of these risks, it is helpful to look at how much higher the RDAs are for women of reproductive age and pregnant women compared to men8.

Women of reproductive age18 mg/day Pregnancy27 mg/day

Men8 mg/day

To put this in perspective, 3 oz of beef contains ~3 mg of iron. Thus, it can be a challenge for some women to meet the requirement. The RDA committee estimates the iron requirements to be 80% and 70% higher for vegans and endurance athletes, respectively. The increased requirement for endurance athletes is based on loss due to “foot strike hemolysis”, or the

increased rupture of red blood cells due to the striking of the foot on hard surfaces3.

Iron toxicity is rare in adults, but can occur in children who consume too many supplements containing iron. Symptoms of this acute toxicity include nausea, vomiting, and diarrhea7.

50 out of 10,000 newborns in the United States are born with the genetic condition, hemochromatosis. In this condition, there is a mutation in a protein in the enterocyte that prevents the normal decrease of intestinal iron absorption. Without this protein these individuals cannot decrease iron absorption. Since the body cannot excrete iron, it accumulates in tissues, and ultimately can result in organ failure1.

References & Links

• Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing.
• Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier.
• McGuire M, Beerman KA. (2011) Nutritional sciences: From fundamentals to food. Belmont, CA: Wadsworth Cengage Learning.
• http://en.wikipedia.org/wiki/File:Illu_blood_components.svg
• http://en.wikipedia.org/wiki/File:Packed_cell_volume_diagram.svg
• Whitney E, Rolfes SR. (2011) Understanding nutrition. Belmont, CA: Wadsworth Cengage Learning.
• Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw’s perspectives in nutrition. New York, NY: McGraw-Hill.
• Anonymous. (2001) Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, D.C.: National Academies Press.