There is about 4 g of iron in the body of a healthy adult male and approximately 2.8 g in a female. The iron-containing compounds in the body are grouped into two categories. About 75% of body iron is considered functional. The majority of this is present in hemoglobin of red blood cells whereas small portions occur in myoglobin, in certain respiratory enzymes that catalyze oxidation–reduction processes within the cell, and in other iron-containing enzymes. The remaining 25% of body iron is stored in the reticuloendothelial system chiefly in the liver, spleen, and bone marrow as storage or nonessential iron. The storage form is present as a soluble iron complex, ferritin, which contains about 20% iron, and as insoluble iron protein complex, holding about 35% iron. Both forms can release iron as needed.
Food Sources
The best food sources of iron (>5 mg/100 g) include organ meats such as liver and heart, brewer’s yeast, wheat germ, egg yolks, oysters, and certain dried beans, dried fruits (e.g., figs and dates), and green vegetables. Iron, as ferrous sulfate, is added to some foods such as flour. Milk and milk products and most nongreen vegetables are low (<1 mg/100 g) in iron.
Absorption
Iron in foods is present as heme iron, which is found in animal products, and nonheme iron, present mainly in plant products. The efficiency of absorption of heme iron is much higher than nonheme iron. Two substances, ascorbic acid and meat, facilitate the absorption of nonheme iron. Ascorbic acid forms complexes with and/or reduces ferric iron to ferrous iron. Meat facilitates absorption of iron by stimulating the production of gastric acid, which helps reduce ferric iron to the ferrous state. Iron seems to be more readily absorbable in the ferrous state. Absorption takes place chiefly in the upper part of the small intestine. Some foods (e.g., bran, vegetable fiber, and those with phytates, polyphenols, oxalates, taurine, or phosphates) tie iron up so that it is absorbed poorly.
Iron uptake is influenced by the amount of storage iron. As stores decrease the amount of iron absorbed increases and as the stores increase the amount absorbed decreases. This regulatory mechanism in the intestinal mucosa helps maintain iron homeostasis and in large part protects against both iron deficiency and iron overload. It is estimated that in a normal healthy adult, only 5–10% of the dietary iron is absorbed, but it increases to 10–
20% in iron-deficient individuals.
The regulation occurs primarily at the translational level where the amounts of transferrin, its receptor, ferritin, and the first enzyme of the heme synthesis pathway are regulated by an iron-responsive element (IRE), a stem loop structure 5V to the coding region of the messenger RNAs for ferritin and transferrin, and in the 3V untranslated region of the receptor. Binding of a regulatory protein to the IRE in the presence of low intracellular iron decreases ferritin formation. By contrast, in the presence of high intracellular iron protein binding increases ferritin formation and decreases transferrin synthesis. Increasing ferritin decreases iron absorption because the incoming iron is sequestered and does not enter the circulation. The iron-containing mucosal cell is then sloughed into the intestine in the normal manner.
Plasma transferrin delivers iron to the cells where cell membrane receptors bind the iron–transferrin complex and carry it into the cells by receptor-mediated endocytosis.
There the iron is released. The receptor then returns the apotransferrin to the cell surface for release into the extracellular environment to function once again. In humans, there is no way to excrete excess iron. Less than 1 mg is excreted per day, 67% of it from the gastrointestinal tract as extravasated cells, iron in the bile, and iron in exfoliated mucosal cells. The other 33% accounts for the small amount of iron in desquamated skin and urine.
Functions
Hemoglobin is the most abundant of the heme proteins and accounts for 62% of the body iron. It transports oxygen via the blood stream from the lungs to the tissues. Hemoglobin is a tetramer made of four globin chains, each associated with a heme group that contains one iron atom. Hemoglobin makes up over 95% of the protein of the red cell and accounts for more than 10% of the weight of whole blood. Myoglobin, the red pigment of muscle, has a structure similar to the monomer unit of hemoglobin. It contains one globin chain, one heme group, and one atom of iron. It transports and stores oxygen for use during muscle contraction. Myoglobin accounts for about 8% of the body iron. The myoglobin content of human muscle is approximately 5 mg/g of tissue. Heme iron is also found in the cytochromes that are located in the mitochondria and other organelles. Cytochromes a, b, and c are present within the cristae of mitochondria in all aerobic cells and are essential for the oxidative production of cellular energy in the form of ATP. Cytochrome c is made up of one globin chain and one heme group containing one atom of iron. The cytochromes P-450 are a family of proteins located primarily in the microsomal membrane and are involved in the oxidative degradation of drugs and endogenous substrates. Cytochrome b5 is a component of many membranes.
Other iron porphyrin enzymes include peroxidase, which, in conjunction with hydrogen peroxide, catalyzes the oxidation of certain organic compounds, and catalase, which is involved in the decomposition of hydrogen peroxide. There are also a group of iron-containing enzymes in which iron is not present in the form of heme. These enzymes contain iron–sulfur complexes and include reduced nicotinamide adenine dinucleotide (NAD) dehydrogenase, succinate dehydrogenase, and other components of electron transport pathways. The enzymes that contain heme and nonheme iron account for about 3% of the body iron. In addition, there are enzymes such as aconitase and phospho-enolpyruvate carboxykinase, which require iron as a cofactor for enzymatic function.
Deficiency
The body is very efficient in conserving iron supplies. Simple iron deficiency occurs only during the growth period or when intake fails to meet needs after blood loss or in women
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who have experienced frequent pregnancies in rapid succession. During the deficiency, iron depletion occurs in three phases. In the first phase, there is depletion of iron stores (decrease in serum ferritin) and a compensatory increase in iron absorption, transferrin, and iron binding capacity. This is followed by a phase in which iron stores are exhausted and transferrin saturation is reduced. The amount of heme precursor, protoporphyrin, in erythrocytes increases but the blood hemoglobin remains near normal level. In the third phase, anemia characterized by a low hemoglobin level develops. In the absence of adequate heme synthesis, there is failure of the cells to grow and this leads to the production of small cells. Nutritional anemia is characterized by hypochromic and microcytic cells.
In addition to these changes, iron deficiency is associated with a drop in iron-containing enzymes, which play critical roles in cellular metabolism and in the functioning of enzymes that require iron as a cofactor. Evidence of these deficiencies shows up in decreased work capacity and altered behavior such as apathy and irritability.
Hypotransferrinemia, also called atransferrinemia, is a condition in which little or no transferrin is produced. This rare disorder leads to severe iron deficiency anemia that does not respond to iron therapy. Intravenous administration of transferrin normalizes iron kinetics. Individuals with this disorder are susceptible to infection (transferrin inhibits the growth of certain bacteria probably by binding iron required for the growth of these organisms). Patients with rare congenital defect in the uptake of iron by red cell precursors have normal plasma iron and transferrin levels but have severe hypochromic anemia that does not respond to iron therapy.
Iron Overload
There are a number of conditions that cause excessive accumulation of iron in the body.
The term hemosiderosis denotes an increase in iron storage without associated tissue damage. Hemochromatosis indicates that such damage is present, particularly in the liver, that the iron overload is generalized, and that the amount of iron is generally increased.
The best defined is hereditary hemochromatosis (HH), an autosomal recessive disorder characterized by an increase in the rate of dietary iron absorption by the small intestine.
People with the disease absorb approximately 3–4 mg of iron per day— compared to the normal rate of 1–2 mg per day. Because the body has no mechanism to increase the excretion of iron beyond that which occurs by normal daily skin desquamation and gastrointestinal and genitourinary tract sloughing, the excess absorbed iron accumulates at a rate of approximately 0.5–1 g per year. During adulthood, total body iron stores in HH patients can reach 20–40 g, compared to a normal of 3–4 g. The capacity of cells to sequester iron through complexing with ferritin, the major intracellular iron storage protein, is eventually exceeded. This leads to excess intracellular ‘‘free’’ iron.
The onset of clinical signs and symptoms of HH usually occurs in mid to late adulthood and commonly consists of fatigue, malaise, and vague abdominal pain. As the disease progresses, more serious clinical sequelae develop, and include gonadal and cardiac failure, diabetes mellitus, cirrhosis of the liver, and arthritis. There is an increased incidence of hepatocellular carcinoma after substantial damage to the liver has occurred.
HH is one of the most common genetic disorders, clinically presenting in men twice as frequently as in women. The reduced clinical presentation in women is thought to be a result of menstrual iron loss and extra iron demands from pregnancy. HH is predominantly a disorder of Caucasians, with a prevalence of 1 in 200–400. The
treatment of hemochromatosis involves the removal of excess iron as quickly as possible.
Iron is most readily removed by weekly phlebotomy of 500 ml until body stores return to normal as indicated by serum ferritin level. Thereafter, one phlebotomy once in every 3 months usually suffices to maintain normal iron stores. Patients are advised to restrict intake of a) vitamin C, because it facilitates iron absorption, b) red meat, a rich source of heme iron, and c) alcohol.
Repeated transfusion leads to rapid iron loading, because each unit of blood contains 200 to 250 mg of iron and can cause what is known as transfusional siderosis.
Reticulendothelial macrophages become iron loaded and, ultimately, iron is deposited in the same sites as in other iron-overload disorders (liver, heart, and endocrine tissues).
Cardiomyopathy is more prevalent in patients with transfusional siderosis. Therapy consists of the administration of deferoxamine, an iron-chelating agent, by continuous infusion. The deferoxamine–iron complex is excreted in urine (iron is not normally excreted by this route).
Neonatal hemochromatosis is characterized by iron loading in the liver, heart, and pancreas, and liver failure in the perinatal period. The disease may be associated with metabolic disorders such as hypermethioninemia but the mechanism is poorly under-stood. Liver transplantation is the primary treatment but is often unsuccessful. In another disorder, termed juvenile hemochromatosis, patients at a young age present with cardiomyopathy and endocrinopathy but not severe liver disease. Patients usually die of heart failure before the age of 30. The genetic basis of this disorder is unknown.
Aceruloplasminemia is a rare autosomal recessive condition caused by mutations in the ceruloplasmin gene. This disorder is distinct from Wilson’s disease, in which low serum ceruloplasmin levels result from a copper transport defect. Patients with acer-uloplasminemia have low serum iron but have massive accumulation of iron in neural and glial cells of the brain, hepatocytes, and pancreatic islet cells. Treatment with plasma or ceruloplasmin concentrate may be helpful.
Hemosiderosis results when iron is present in excessive quantities in a diet that permits its maximum absorption. A distinct iron-loading disorder is prevalent in Africa, affecting up to 10% of some rural populations. Formerly termed Bantu siderosis, iron overload results from ingestion over many years of large amounts of highly bioavail-able iron derived from cooking pots and from drinking beer brewed in nongalvanized steel drums. In adult males, the intake may exceed 100 mg iron per day. The condition frequently becomes manifest in early adulthood and reaches severity after the age of 40. The pathological pattern of the iron overload is one of hepatic and reticuloendo-thelial involvement. Hemosiderosis can progress to hemochromatosis, cirrhosis, and diabetes. Serious iron overload does not develop in all beer drinkers, and not all patients with iron overload consume excessive amounts of beer. Some investigators have suggested that there is also a genetic predisposition, but the defective gene has not yet been identified.
The production of tissue-damaging free radicals is an essential component of the pathogenesis of chronic diseases, and iron may help form free radicals, resulting in lipid peroxidation, low density lipoprotein (LDL) oxidation, and DNA damage. Iron overload is associated with a greater incidence of cancer. Patients with HH have 200 times greater risk of hepatocellular carcinoma than those with around normal iron stores. Several studies have suggested that even a modest increase in iron status may be a risk factor for the development of heart disease. Serum ferritin concentration is considered to be the best measure of body iron stores and is the most feasible to use in epidemiological studies. In
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a cohort study of over 1900 Finnish males, from 40 to 64 years of age, males with serum ferritin greater than 200 Ag/l had a 2.2 times greater risk of myocardial infarction compared to males with lower ferritin levels. Furthermore, serum ferritin was observed to be one of the strongest indicators of the presence and prognosis of carotid artery disease.
Blood donations, which deplete iron stores in the donors, were associated with reduced risk of myocardial infarction and cardiovascular disease. In premenopausal women, the incidence of cardiovascular disease is less than half that of age-matched men. Depletion of iron stores by regular menstrual blood loss may be a source of protection in premenopausal subjects.
Excess iron is quite toxic, even to healthy individuals. Ferrous sulfate tablets are a cause of infant morbidity and mortality. Human clinical data support the concept that high iron stores impose additional risk of many types of diseases.
Requirement
The RDA for adults is based on the assumption that an adult male must obtain about 1 mg of iron per day to replace body losses, and the adult female approximately 1.2–2 mg. Because the average amount of absorption is about 10% of ingested iron, it is recommended that men obtain 10 mg and women obtain 18 mg from dietary sources.
Iron needs for women are higher than for men because of menstrual loss and the demands of pregnancy and lactation. During pregnancy, about 300 mg are needed for the growth of the fetus, 70 mg for the placenta, and 500 mg for the synthesis of hemoglobin associated with increase in blood volume that occurs at this time. As a result, it is recommended that pregnant women take a supplement providing 30–60 mg of iron, in addition to obtaining 18 mg from the diet. Human milk contains 0.2 Ag/ml.
Because only 0.5–1 mg is transferred to milk the recommended intake during lactation is the same as for adult women.
B. Copper
The adult human being weighing about 150 lbs has on the average about 80 mg of copper (70–120 mg), with about a third of it evenly divided between the liver and the brain, a third in the muscle, and the rest dispersed in other tissues.
Food Sources
The amount of copper in foods of plant origin varies according to the soil in which they are grown, but green leafy vegetables, legumes, whole grain, and almonds are good sources. Raisins and other dried fruits rank fairly high in copper content. Meats, especially liver, and seafoods including shellfish such as oysters, are rich in copper whereas dairy products are low in copper.
Absorption
Copper is absorbed from the upper part of the small intestine and possibly from the stomach. Absorbed copper is transported in combination with albumin to the liver where it is incorporated into ceruloplasmin, an a2globulin, and released into the blood where it constitutes about 90% of the plasma copper pool. One molecule of ceruloplasmin contains six atoms of copper. The major route of copper excretion is via the bile and ultimately in the stools. Trace amounts are lost through the urine, hair, nails, sweat, and desquamation of skin.
Functions
Several cuproenzymes play critical metabolic roles, including ceruloplasmin, cytochrome c oxidase, lysyl oxidase, superoxide dismutase, tyrosinase, dopamine hydroxylase, and others. Ceruloplasmin is necessary for the oxidation of iron in the plasma for binding to transferrin, and thus it plays a role in the transport of iron to sites where hemoglobin synthesis can occur. Cytochrome c oxidase governs the terminal reaction in the electron transport chain and is essential for energy production. Lysyl oxidase catalyzes the deamination of lysine residues and is the key enzyme for cross-linking in collagen and elastin. When the activity of lysyl oxidase is low, pathological changes in connective tissue occur. This ultimately leads to vascular disease and spontaneous rupture of major vessels, as well as defective bone matrix and osteoporosis. Superoxide dismutase decomposes superoxide free radicals, which can cause membrane damage and cell death.
Tyrosinase is important in the formation of melanin, and dopamine hydroxylase participates in the conversion of dopamine to norepinephrine.
Deficiency
Deficiency of copper is extremely rare in humans because the amount present in foods is more than adequate to provide the average needs. Copper deficiency has been demon-strated in malnourished infants, in those with prolonged diarrhea or malabsorption disorders, in individuals who have undergone intestinal bypass surgery, and in those who are receiving long-term total parenteral nutrition (TPN). Prolonged high doses of zinc can also induce copper deficiency because of the antagonistic relationship between zinc and copper. Excess zinc stimulates the synthesis of intestinal metallothionein, which chelates copper and inhibits its absorption.
The outstanding findings in copper deficiency are leukopenia, particularly neutro-penia and granulocytoneutro-penia, and microcytic anemia that is unresponsive to iron therapy.
Copper deficiency shortens the life span of erythrocytes. This may be related to the plasma membrane because of free radical accumulation when superoxide dismutase activity is low. Other changes seen in copper deficiency include a fall in serum copper and ceruloplasmin, failure of iron absorption and of erythropoiesis, and bone demineraliza-tion. Neutropenia and leukopenia are early indications of copper deficiency in children.
There are two hereditary syndromes related to the disruption of copper homeostasis: Wilson’s disease and Menke’s kinky hair syndrome. Wilson’s disease is an autosomal recessive disorder of copper metabolism. It occurs in every ethnic and geographical population, with a worldwide prevalence of 1 in 30,000 live births.
Patients with this disease have a defect in the ability to excrete copper via the bile. This
Patients with this disease have a defect in the ability to excrete copper via the bile. This