Physiological Role
Tissue Distribution
Absorption and Excretion
Homeostatic Control
Interactions with Other Elements
Fe Requirements
Dietary Sources
Iron Deficiency
Fe Toxicity

I.  Physiological Role

  1. Iron is present in all cells of the body and plays a key role in many biochemical reactions
  2. Transport of oxygen
    1. Hemoglobin is an iron-protein complex which carries oxygen from the lungs to the tissues and CO2 on the return trip
      1. Complex of globin and four ferroprotoporphrin moieties with a molecular weight of 65,000 and an Fe content of about 0.35% (see Ganong, 1981, Review of Medical Physiology, Lang Medical Publications, Low Altos, CA. page 414)
        Bonds between Fe and globin stabilize Fe in the ferrous (Fe2+) state and allow it to be reversibly bonded to oxygen
      2. When the Fe atom is oxidized to the ferric (Fe3+) state (as in methemoglobin), it loses its capacity to carry O2
      3. Composition (amino acids) of b-polypeptide chain of hemoglobin is extremely important. For example, replacement of glutamate in the No. 6 position with valine results in sickle cell anemia (hemoglobin is very insoluble at low 02 tensions and this causes the red cells to become sickle shaped.)
    2. Myoglobin is the heme-protein found in muscle.
      1. It has an Fe content of about 0.12%
      2. Structure is like that of hemoglobin but it contains only one ferrous porphyrin group per molecule and has a molecular weight of only 16,500
      3. It has a greater affinity for 02 than hemoglobin and thus can accept 02 released by hemoglobin and serve as an oxygen reservoir
  3. Biological oxidations (oxidation is combination with 02, loss of hydrogen, or loss of electons
    1. Flavoprotein-cytochrome sytem
      1. A chain of enzymes in the cell mitochondria which transports hydrogen to oxygen, forming water
      2. Each enzyme in the chain is reduced and then reoxidized as hydrogen is passed down the line
      3. Each of the enzymes is a protein with an attached nonprotein prosthetic group
      4. The prosthetic groups of the cytochromes contain Fe in a porphyrin configuration similar to hemoglobin
      5. Cytochromes provide a system for protein transfer through the capacity of the Fe atom to undergo reversible oxidation
    2. Oxidative phosphorylation
      1. Transfer of proteins across an insulating membrane is driven by oxidation in the respiratory chain
      2. This creates an electrochemical potential difference across the membrane which drives a reversible ATPase in the membrane in the direction which converts ADP and Pi to
        1. Transfer of hydrogen from NADH to flavoprotein is associated with formation of ATP from ADP
        2. Further transfer along the flavoprotein-cytochrome system generates 2 more molecules of ATP per pair of protons transferred
  4. Fe plays a key role in other enzymes involved in oxygen transport and the oxidative process
    1. Oxidases and oxygenases activate oxygen
    2. Peroxidase and catalase provide protection against peroxide ions, an unavoidable byproduct of oxygen reduction
    3. Non-heme metallo-flavoproteins: xanthine oxidase, succinic dehydrogenase, NADH reductase
    4. Other Fe binding proteins
      1. Phosvitin - binds Fe in plasma of laying hens and transports it to be ovocytes and egg yolk
      2. Conalbumin - found in egg white. No evidence for Fe transport function. May have bacteriostatic activity
      3. Lactoferrin - present in milk
        1. May increase absorption of Fe and other metals in milk
        2. It may also have bacteriostatic activity

II.  Tissue Distribution

  1. Content of whole body only about 50-60 ppm
    1. Above figure quoted by W. J. Miller for dairy cow
    2. Body of 70 kg. man contains 4 to 5 g of Fe
      (4 g ¸ 70 kg = 4 g ¸ 70,000 g = .00006 = .006% = 60 ppm)
  2. Of total Fe in body:
    1. 60-70% is in hemoglobin
    2. 3% is in myoglobin
    3. Remainder is in storage in equilibrium with plasma
      1. Ferritin, the primary Fe storage compound when the total level of  stored Fe is Iow, contains up to 20%
      2. Hemosiderin, containing up to 35% Fe, may predominate at higher storage levels
    4. Total Fe stores:
      1. 500 to 1000 mg in adult men
      2. 0 to 500 mg in adult, premenapausal woman. A great proporation of women in both industrialized and developing countries have no Fe stores at all
  3. Plasma level (human) 50-150 mg/dl (9.0-26.9 mmol/L)
    1. Most of the Fe in plasma is transported bound to tranferrin (or siderophilin), a B1 globulin normally about 30% saturated with Fe
      1. Transferrin may also participate in defense mechanisms of the body against infection
      2. In normal individuals, only 30-40% of the Fe binding capacity of transferrin in serum is utilized, the remainder representing an unbound reserve
      3. Percentage saturation of plasma transferrin is much-lower than this when dietary Fe is insufficient

III.  Absorption and Excretion

  1. Fe metabolism can be described as two loops
    1. One internal loop with a continuous reutilization of Fe from cells catabolized in the body
      1. Reutilization of Fe from catabolized RBC
      2. Fe released from hemoglobin in the reticuloendothelial system is then taken up by a transferrin and is transported to the bone marrow for formation of hemoglobin in new RBC
    2. One external loop
      1. Losses of Fe from the body
      2. Absorption of Fe from the diet
  2. Most dietary Fe is in the ferric (Fe3+) form but Fe is absorbed in the ferrous (Fe2+) state
  3. Sites of absorption of Fe
    1. Little Fe is absorbed in the gastric stomach but gastric secretions dissolve the Fe and are favorable for its reduction to Fe2+. (Anemia often accompames partial gastrectomy)
    2. Most of the Fe absorption occurs in the duodenum and adjacent jujunum. (Can. J. Anim. Sci. 62:979.1982). Amounts of Fe entering the sheep small intestine about equal to amounts eaten, indicating no net absorption of Fe from the forestomachs
  4. Mechanism of Fe absorption.  Fe absorption is an active process
    1. Nonheme Fe absorption
      1. In the stomach Fe is released from food in a soluble form and reduced to Fe2+
      2. Soluble Fe is bound to mucoproteins found in the gastric juice
      3. Absorption occurs mainly in the duodenum in the ferrous (Fe2+) form
      4. Binding of Fe to mucoproteins in the stomach results in Fe remaining soluble at the higher pH in the small intestine
      5. It is believed that the mucoproteins are detached before the Fe enters the small intestinal epithelial cell
    2. Mucosal transport
      1. Mucosal transferrin binds Fe in the gut lumen and transports it across the brush border of the intestinal mucosa
        1. Mucosal transferrin is an Fe binding protein similar to plasma transferrin
        2. Its synthesis responds to Fe status of the individual
        3. Fe absorption is determined by the amount of this protein present
      2. Fe is released into the cell for incorporation into ferritin or for transport into the blood stream
        1. Within the mucosal cells, Fe exists in two pools
        2. Transferrin like pool is rapidly exchangeable
        3. Ferritin like pool is slowly exchangeable
        4. Normally, Fe exchanges with the slowly exchangeable pool; in Fe deficiency the rapidly exchangeable pool may predominate
    3. Serosal transfer
      1. At the serosal surface, Fe is attached to plasma transferrin
      2. Ceruloplasmin (ferroxidase) is a Cu containing serum protein which catalyzes the oxidation of Fe for binding to plasma transferrin
      3. Plasma transferrin mediates Fe exchange between body tissues
      4. Functions of trensferrin
        1. Fe transport between sites of Fe absorption, body stores, and sites of Fe utilization. Only transferrin bound Fe is efficiently utilized for hemoglobin synthesis by the erythroid cell
        2. Fe transport to and from the liver
        3. Fe uptake by the placenta and transfer to the fetus
        4. Role in defense against infection - many bacteria require Fe for growth. A low Fe saturation of transferrin serves as a defense mechanism against infection. During infection, there is a redistribution of Fe from serum to the liver
      5. Heme Fe absorption
        1. Heme Fe is absorbed more efficiently than nonheme Fe (25% for heme Fe vs 10% for nonheme Fe)
        2. Heme is split from globin in the small intestine lumen
        3. Heme enters the intestinal epithelium where Fe is released from heme by heme oxygenase
        4. After release from heme, the Fe follows the same pathways as nonheme Fe
      6. Dietary factors affecting Fe absorption
        1. Ascorbic acid and other reducing substances favor conversion of Fe 3+ to Fe 2+. Ascorbic acid enhances nonheme Fe absorption
        2. In human, bioavailability of heme and nonheme dietary Fe must be considered separately
        3. – Absorption of heme Fe tends to be greater than that of nonheme Fe
          1. The only bioavailability factor that may influence absorption of heme Fe may be the amount of meat in the meal
        4. – Absorption of nonheme Fe is greatly altered by meal components
          1. Increased by ascorbic acid, meat, fish and poultry, and low molecular weight organic acids that form soluble complexes with Fe
          2. J. Nutr. 119:446. 1989. The apparent absorption of Fe by rats fed diets containing beef tended to be higher, compared to rats fed diets containing lactalbumin
          3. J. Nutr. 119:1418. 1989. Meat contains factor(s) that solubilize Fe independent of proteolytic digestion
          4. Fe absorption decreased by synthetic complexing agents or by complexing agents endogenous to foods: phytic acid, oxalic acid, phosphoprotein, fiber
          5. Chelating agents may thus either inhibit or enhance absorption of Fe
            1. Agents which form stable Fe chelates in the Gl tract may prevent uptake of Fe by acceptor sites on mucosal cells thus inhibiting absorption
            2. Weaker agents which form chelates of lower stability may release their Fe to the acceptor sites. These weaker agents may keep Fe available for absorption by reducing formation of poorly absorbed hydroxides and phosphates
          6. Nonheme Fe absorption is decreased by wheat bran, soy products, egg, and cow's milk
          7. Decreased by tea and coffee
        5. – The generality that nonheme Fe of plant origin is of low bioavailability may be true for cereals and legumes but does not hold for all vegetables
      7. Only small amounts of Fe are excreted in urine

IV.  Homeostatic Control

  1. Changes in Fe absorption compensate for differences in Fe consumption, state of body stores and rate of erythropoiesis
    1. Mucosal transfer of Fe increases or decreases over several days in response to Fe status
      1. Absorption of dietary Fe is regulated in normal individuals by physiological need or Fe status
      2. As one writer puts it, populations of receptors during mucosal cell formation increase or decrease over several days in response to Fe status
      3. Another way of putting it is synthesis of mucosal transferrin, which determines the amount of Fe absorbed, responds to Fe status of the individual
    2. Changes in serosal transfer occur over a relatively short time
      1. Ingestion of large quantities of Fe increases binding of Fe in the mucosal cells but not absorption of Fe
      2. Fe bound in mucosal cells is lost with the cells when they are shed into the intestinal lumen
      3. Mucosal block - the ability of the mucosa to prevent excess Fe from being absorbed
  2. Tissue deposition in harmless or readily useable reserve forms
    1. Ferritin, which is easily mobilizable, is the primary Fe storage compound
    2. Fe is also stored as hemosiderin, which is less readily mobilized, at higher levels of Fe storage
  3. Conservation and recycling
    1. Fe from hemoglobin and old red blood cells recovered in the spleen and liver
    2. Since RBC life span is 120 days, every day in adult male human some 20 mg of Fe is liberated and recycled

V.  Interactions with Other Elements

  1. Fe absorption reduced by cadmium or excess cobalt
  2. Phosphates and phytate react with Fe to form insoluble compounds
  3. Copper required for hemoglobin formation in bone marrow
    1. Cu as ceruloplasmin catalyzes the oxidation of Fe for binding to plasma transferrin
    2. Cu deficiency may impair liver Fe mobilization if dietary Fe is Iow (J. Nutr. 115:633. 1985)
      1. Decreased ceruloplasmin activity
      2. Decreased Fe reduction by ascorbate or xanthine dehydrogenase (J. Nutr. 115:633-649, 1985)
  4. Fe accumulates in the liver when Mo is severely deficient (J. Nutr. 114:1652. 1984)
  5. Chronically high Sn may reduce hematocrit, hemoglobin, and serum Fe (J. Nutr. 115:615. 1985)
  6. Biologically important interactions among chemically similar metal ions were predicted in 1970 by Hill and Matrone (See Fed. Proc. 29:1474-1481. 1970)
    1. Fe (atomic no. 26, atomic wt. 55.85) and Zn (atomic number 30, atomic weight 65.37) are both in the first transition series of the periodic table of elements but Zn is not a transition element (it exists only as Zn+2 whereas Fe exists as Fe2+ or Fe3+)
    2. Fe and Zn have identical outer electron shell configurations
    3. Zn absorption is enhanced in Fe depleted animals
    4. Fe absorption is enhanced in Zn depleted animals
    5. Excessive Fe intakes (as supplements or in formulated foods) can impair indices of Zn status such as growth and circulating Zn levels
    6. Efforts to ensure Fe repleted conditions in members of populations with greater propensity to develop Fe depletion must be tempered by concern for adverse effects on Zn status
  7. Maize and wheat fibers (see J. Nutr. 116:1007-1017. 1986)
    1. Decrease retention of ferrous Fe by binding and by promoting autoxidation and formation of poorly soluble Fe polymers
    2. Decrease retention of ferric Fe, presumably as a result of polymerization

VI.  Fe Requirements

  1. Measurement of requirements
    1. Growth rate, anemia, hemoglobin and packed cell volume are relatively insensitive measurements of requirement
    2. Measurements of iron reserves, such as percent saturation of transferrin, are a much more sensitive way of determining Fe requirement
      1. In normal individuals, transferrin is 30-40% saturated
      2. When transferrin saturation falls to 15% or less, insufficient Fe is available to the erythroid marrow to support normal Hb synthesis
  2. Fe requirements
    1. Humans:
      1. Infants, adult males & 51+ yr females.....10 mg/day
      2. Children 1-3 yrs........................................15 mg/day
      3. Males 11-14 & females 11-50 yrs............18 mg/day
    2. Poultry.........50 to 80 ppm in diet DM
    3. Swine..........70 ppm
    4. Dairy cattle:
      1. Calves to 3 mo. of age.......100 ppm (30 to 40 ppm for pale veal)
      2. Other dairy cattle................50 ppm.

VII.  Dietary Sources

  1. Most feeds of animal origin except milk are excellent sources. Heme Fe is more available than nonheme Fe
  2. Plant sources:
    1. Legumes forage......200-400 ppm
    2. Oilseeds..................100-200 ppm
    3. Cereal grains...........30-60 ppm
    4. Grasses...................40 ppm
  3. Fe supplements (in order of availability): Fe-AA complex, ferrous sulfate, ferrous carbonate, ferric chloride, ferric oxide, Fe phytate

VIII.  Iron Deficiency

  1. Occurence of deficiency
    1. Uncomplicated nutritional Fe deficiency more likely in baby pigs and milk fed calves than in adult animals
    2. Blood loss due to parasites can result in Fe deficiency
    3. Fe metabolism in humans is unique in comparison with other mammals
      1. Fe balance in infancy and adolescence, and in menstruating and pregnant women is borderline
      2. Fe deficiency is widespread in these categories
  2. Negative effect of Fe deficiency on working performance is not due entirely to anemia as such
    1. Work capacity of Fe deficient subjects is rapidly improved by treatment with Fe but results could not be accounted for totally by elevation of hemoglobin concentration
    2. A variety of Fe-containing or Fe-dependent enzymes or tissue compounds are depleted in Fe deficiency anemia
      1. Cytochromes
      2. Peroxidase
      3. Catalase
      4. a-glycerophosphate dehydrogenase
      5. Succinic acid dehydrogenase
      6. Xanthine dehydrogenase
    3. Lack of Fe-containing enzymes responsible for oxidative phosphorylation could lead to incomplete metabolism of pyruvate and increased formation of lactate during work
  3. Deficiency signs
    1. Anemia - also caused by inadequate copper or cobalt, or by excess molybdenum, zinc, selenium, lead or cadmium
    2. Reduced appetite and lower weight gain
    3. Listlessness
    4. Decreased resistance to infection
    5. Inability to withstand circulatory strain
    6. Higher than normal pulse rate
    7. Labored breathing after mild exercise
    8. Blanching of visible mucous membranes
    9. Pale color of muscle (decreased myoglobin content)
    10. Atrophy of papilla of tongue
    11. Less than 30% saturation of transferrin
    12. Reductions in hemoglobin levels and tissue concentrations-of-Fe and cytochrome C
    13. Thyroid hormone deficiency in Fe-deficient anemic rats (J. Nutr. 119:439-445 and 772-778. 1989). It was suggested that concentrations of metallothionein in blood cells reflect erythropoietic activity
    14. Fe deficient rats could dispose of almost twice the glucose per unit of insulin when compared with control rats. (J. Nutr. 118:1140-1109. 1988)
    15. Insulin sensitivity is increased in Fe deficient rats
    16. Fe deficient rats cannot metabolize exogenous insulin as well as control rats

IX.  Fe Toxicity (see J. Dairy Sci. 70:2349-2354.)

  1. Not a common problem in cattle but a sufficiently high level in feed or water is detrimental. As little as 210-400 ppm may produce measurable effects
    1. Lower feed intake, weight gains and milk production
    2. Hemosiderinosis
    3. Diarrhea (See J. Nutr. 117:2072. 1987 for Fe overload in deer)
  2. Iron overload: more Fe is absorbed than is excreted
    1. Ferritin and hemosiderin accumulate in tissues when overload is prolonged
    2. Large ferritin and hemosiderin deposits are associated with hemochromatosis in humans
      1. Pigmentation of the skin
      2. Pancreatic damage with diabetes (bronze diabetes)
      3. Liver damage - cirrhosis, high incidence of hepatic carcinoma
      4. Lung injury due to lipid peroxidation (Fed. Proc. 45:13. 1986)
    3. Causes of hemochromatosis
      1. Prolonged excessive Fe intake (see Am. J. Clin. Nutr. 32:1272-1278. 1979)
        1. Prevalence of Fe overload in South African blacks has been very high
        2. Dietary Fe intake of affected individuals is very high
        3. Most of the dietary Fe is derived from the Fe containers used for preparation of beer
        4. Effects of Fe overload in South African blacks
        5. – hepatic fibrosis
        6. – hemochromatosis
        7. – disturbed ascorbic acid metabolism
        8. – subclinical and clinical scurvy
        9. – osteoporosis
        10. In one necropsy study, 20% of males were found to have hepatic Fe concentrations in the range of those found in idiopathic hemochromatosis
      2. Breakdown of the mucosal regulatory mechanism
      3. Idiopathic hemochromatosis is a congenital disorder
  3. Example of Fe involvement in lipid peroxidation: Adult respiratory distress syndrome (Fed Proc. 45:25-29, 1986)
    1. Direct pulmonary injury (aspiration of gastric contents) or abdominal sepsis can lead to the syndrome
    2. Polymorphonuclear leukocytes and platelets are activated.
    3. Toxic oxygen products of activated neutrophils are largely responsible for the lung microvascular injury (Fed. Proc. 45:13-18. 1986)
    4. The production of 02 - and H2 02 followed by their conversion in the presence of Fe ions to hydroxyl ion (OH') may ultimately lead to lipid peroxidation and tissue damage
    5. The Fenton reaction:
    6. Fe 3+ + 02 - ® Fe 2+ + 02
    7. Fe2+ + H202 ®Fe3+ + OH- + OH·
      1. Experimental damage in rats can be prevented by intervention with:
        1. Superoxide dismutase in combination with catalase
        2. Scavengers of hydroxyl radical (dimethyl sulfoxide)
        3. Fe chelators
      2. Infusion of nanomolar amounts of FeCI2 augmented pulmonary injury in a dose-dependent fashion
  4. Iron and the sex difference in heart disease risk (The Lancet, June 13, 1981)
    1. Pre-menopausal women in affluent societies are protected from heart diseases which kill large numbers of men
    2. This protection ends at menopause
    3. Incidence of heart disease doubles at menopause, even in comparisons between pre- and post-menopausal women of the same age
    4. At menopause, there is a remarkable lack of change in traditional cardiovascular risk factors
      1. Cholesterol and triglyceride levels rise but the increases seem to be far too small to be biologically meaningful
      2. Is it due to loss of estrogen? The Framingham study showed that protection is lost after surgical menopause whether or not the ovaries are removed
      3. Post menopausal estrogen use accelerates the increase in risk
    5. The hypothesis is proposed that the greater incidence of heart diseases in men and post-menopausal women compared with pre-menopausal women results from higher levels of stored iron
    6. The hypothesis is backed by the following observations:
      1. Myocardial failure in patients with Fe storage disease
      2. Accumulation of stored Fe with age in men after adolescense
        1. Men rapidly accumulate Fe after adolescense up to about age 30
        2. Accumulation continues after 30 at a decreased but relatively constant rate
        3. This suggests increasing heart disease risk in American men is associated with the progressive accumulation of stored Fe
      3. Serum ferritin remains low in women until age 45; from then it rises rapidly, as it does in men after adolescence
        1. Women under 45 have very little heart disease and very low Fe status
        2. Heart disease risk in men of the same age is approximately four times that for women.
        3. Removal of the uterus and thus the bleeding site enhances risk, with or without ovarectomy
      4. Serum ferritin > 80 ng/ml seems to be associated with sharp increases in rates of heart disease
      5. Ferritin (ng/ml)
      6.      Men 18-45............94
      7.      Women 18-45......25
      8.      Women > 45........89
    7. Diet and the third world
      1. Types of heart disease that kill large numbers of American men are rare in developing countries
      2. Cardiovascular disease seems to be inevitable in prosperity but poverty protects the heart
      3. Malnutrition which often includes Fe deficiency is a common problem in impoverished people
        1. Fe deficiency does not depend simply on amt. of Fe in diet
        2. Composition of diet is important
        3. – High dietary fiber and cereals inhibit Fe absorption
        4. – Meat enhances Fe absorption
        5. Chronic blood loss due to hookworm can produce Fe deficiency
        6. Low rates of heart disease are often associated with Fe deficiency
        7. Perhaps low Fe stores protect the impoverished from heart diseases of affluence
    8. The hypothesis can be tested since levels of stored Fe can be manipulated at will by phlebotomy
      1. Donation of I unit of blood/yr reduces serum ferritin approximately half in healthy adult male blood doner
      2. Three units/yr reduces stored Fe further, to about the level found in premenopausal women
      3. Men who give blood regularly could be compared with appropriate nondonor controls
    9. Our system for storing Fe probably developed by natural selection under conditions of Fe deficiency
      1. Complex mechanisms for conserving Fe have been developed
      2. Excessive amounts can be harmful
      3. The high risk of cardiovascular diseases in affluent societies may result from the inability of our system to adjust to a diet rich in Fe
  5. Maximum Fe tolerance (NRC 1980)
    1. Swine........3,000 ppm
    2. Cattle........1,000 ppm
    3. Poultry......1,000 ppm
    4. Sheep.......500 ppm

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