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Iron

Nutrient Name: Iron.
Synonyms: Iron salts; fer; ferric sulfate; ferrous carbonate anhydrous, ferrous citrate, ferrous fumarate, ferrous gluconate, ferrous glutamate, ferrous glycinate, ferrous glycine sulphate, ferrous lactate, ferrous picolinate, ferrous pyrophosphate, ferrous succinate, ferrous sulfate; carbonyl iron; iron-polysaccharide, iron dextran, iron-ovotransferrin, iron sorbitol, iron sucrose, sodium ferric gluconate.
Elemental Symbol: Fe.

Summary Table
nutrient description

Chemistry and Forms

  • Oxidation states: Ferric (Fe3+) iron, ferrous (Fe2+) iron.
  • Heme and nonheme.

Physiology and Function

Iron is an essential mineral that plays a vital role in numerous essential biochemical pathways. The principal functions of iron involve DNA synthesis and cell formation, oxygen sensing and cellular uptake, oxygen transport and storage within blood and muscle, electron transfer and the conversion of glucose to adenosine triphosphate (ATP), both antioxidant and beneficial pro-oxidant functions, and regulation of intracellular iron. Within the human body, iron occurs primarily in functional forms, such as proteins, particularly hemoglobin and myoglobin, and in transport and storage forms, such as transferrin, ferritin, and hemosiderin. Iron is also a constituent of numerous enzymes, amino acids, hormones, and neurotransmitters. Iron is a key component of enzymes responsible for oxidative phosphorylation and ATP generation in the mitochondria and for synthesis of serotonin and dopamine. Iron is essential for the synthesis of carnitine, a critical compound in fatty acid metabolism, and for the operation of the cytochrome P450 system and other cytochromes. It also acts as a cofactor in the synthesis of collagen and elastin.

Iron absorption is highly dependent on maintenance of the normal biochemical environment and coordination of upper gastrointestinal (GI) function. Iron must be in ferrous form to be absorbed. When iron is found in meat, it is in the heme form. When the source of iron is from plants or from animal products such as milk, eggs, and cheese, it is referred to as nonheme iron. In the heme form, once it is cleaved from the food, iron may be converted to hemin (Fe3+), which can be directly absorbed intact by the mucosal cell into the blood. Absorption of heme iron is about 10 times that of nonheme iron, depending on whether body stores are replete. In the nonheme form, iron must be cleaved from its food source, then reduced from the ferric to the ferrous form, facilitated by gastric hydrochloric acid, before it can be absorbed. Likewise, ascorbic acid, found in foods and supplements, increases absorption by keeping the ferrous form from oxidizing to ferric in the gastric environment. Iron absorption is a slow process, taking between 2 and 4 hours, and occurring principally in the duodenum and proximal jejunum. Iron is absorbed from the small intestine in different forms at 5% to 15% of intake. Absorption percentages, as opposed to excretion, are largely responsible for regulation of body iron content and respond to levels of body iron stores. Thus, low body iron levels lead to improved absorption.

Iron is oxidized back to ferric state for transport and then transported within the mucosal cell and in the blood bound to the protein transferrin. Transferrin is usually saturated to about one-third its total iron-binding capacity (TIBC). If no iron is needed, transferrin remains saturated and less is absorbed from the intestinal mucosal cells. The transferrin that remains in the cells eventually is sloughed away with the mucosal cells at the end of their 2- to 3-day life cycle. If iron is needed, the transferrin is less saturated when it reaches the intestinal mucosal cells, and more iron passes from the mucosal cell to the transferrin. Thus, the degree of saturation of transferrin is also used as a measurement of body stores of iron. Iron is stored in the liver, spleen, and bone marrow as ferritin and hemosiderin. The normal human body contains 3 to 4 grams of iron (40-50 mg/kg body weight), 75% of which (∼36 mg/kg) is present in metabolically active compounds. A storage pool maintains the remaining 25% (∼10 mg/kg in men and ∼ 5 mg/kg in menstruating women) in a form that is readily available for use if metabolically active iron is depleted for any reason.

The body's capacity to eliminate iron is limited and, once absorbed, largely occurs through blood loss. Under normal conditions, the largest loss of iron is through bleeding in menstruating women; although considerably greater than other channels, these iron losses vary widely from individual to individual. Very small amounts of iron are also excreted through sweat and normal exfoliation of hair, skin, and nails. Most iron expelled in the feces is nonabsorbed iron from dietary intake.

Hemoglobin and myoglobin are proteins involved in the transport and storage of oxygen that contain heme, an iron-based compound. Hemoglobin is the primary protein responsible for oxygen transport in red blood cells (RBCs) and constitutes approximately two thirds of the iron in the human body. Hemoglobin functions to acquire oxygen efficiently and rapidly during its short contact in oxygenated lung tissue, transporting that oxygen from the lungs throughout the circulatory system and releasing it as needed into the target tissues. Myoglobin is the primary protein responsible for oxygen transport and regulation of short-term oxygen storage within myocytes and for the coordination of oxygen influx with the physiological demands of muscle function. Iron's ability to shift between its ferrous or reduced state (Fe2+) and its oxidized ferric state (Fe3+) enables it to hold or release oxygen and empowers its functional activity in electron transport and energy production.

Iron plays a critical role in the body's ability to sense oxygen and dynamically respond to variable conditions. Prolyl hydroxylase is an iron-dependent enzyme that participates in regulating the body's response to hypoxic conditions, such as high altitude or impaired function caused by lung disease. In particular, hypoxia inducible factors (HIFs) are transcription factors that respond to decreases in cellular oxygen tension characteristic of hypoxic conditions, by binding to genetic response elements that encode various proteins involved in compensatory responses to hypoxia, and increase their synthesis. Thus, in response to cellular oxygen tension, prolyl hydroxylase will either rapidly degrade HIF-alpha subunits or bind them to HIF-beta subunits to create an active transcription factor capable of entering the nucleus and binding to specific response elements on genes.

Iron, in both heme and nonheme forms, is part of several enzymes involved in electron transport, cellular energy production, and cellular detoxification. Cytochromes are heme-containing compounds critical to mitochondrial electron transport in the synthesis of ATP. In the liver the cytochrome P450 family of enzymes, in particular, metabolizes a wide range of biological molecules and exogenous toxins, including detoxification and metabolism of pharmaceuticals. NADH dehydrogenase and succinate dehydrogenase are among several enzymes containing nonheme iron involved in energy metabolism. Iron is also prominent in the synthesis of carnitine, an amino acid that plays an essential role in the metabolism of fatty acids. Thus, in a state of iron deficiency, an individual will fatigue more readily because of inadequate accessible oxygen and impaired synthesis of ATP.

Iron is well known for its tendency to cause oxidative damage, but it is also part of the antioxidant enzymes catalase and peroxidase, which serve to quench potentially damaging reactive oxygen species (ROS). These heme-containing enzymes catalyze the conversion of hydrogen peroxide to water and oxygen and thus prevent its buildup within cells. Myeloperoxidase, another heme-containing enzyme, catalyzes neutrophils to synthesize hypochlorous acid, an ROS, to be used within the immune system's response to pathogenic bacteria.

Iron is intimately involved in a number of other physiological and biochemical processes at cellular and systemic levels. DNA synthesis requires the activities of ribonucleotide reductase, an iron-dependent enzyme. Iron storage and metabolism are managed by key proteins within self-regulatory processes coded by short sequences of nucleotides found in the messenger RNA (mRNA), known as “iron response elements,” in response to changing iron storage levels. In particular, iron regulatory proteins (IRPs) can bind to iron response elements and affect mRNA translation, thereby regulating the synthesis of specific proteins. Thus, iron binds to IRPs to a greater or lesser degree, depending on iron supply to influence relative levels of ferritin, the central iron storage protein; translation of mRNA that regulates enzymatic control of heme synthesis in immature RBCs; and synthesis of transferrin receptors. Iron is also a constituent of the enzymes that initiate the synthesis of serotonin and dopamine. Lastly, iron is essential in the synthesis of collagen and elastin.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Treatment of iron deficiency anemia constitutes the dominant use of supplemental iron within conventional medicine. Standard practice recognizes the increased risks of iron depletion associated with menstrual blood loss but typically responds only reactively and in the narrowest sense of anemia. Modern schools of natural medicine more often recognize the potential value of iron-rich foods and botanical preparations as a tonic therapy within a comprehensive strategy.

Historical/Ethnomedicine Precedent

In the classical medical tradition of Western culture, iron was considered the metal of Mars, and associated with vitality, the qualities of heat and fire, the blood, and inflammatory processes. Historically, traditions of natural medicine have emphasized enhancement of iron intake as part of a broader approach toward enriching the blood through provision of multiple minerals within the context of single herbs, herbal formulae, and nutrient-rich foods. Herbal formulae that “build the blood” have played central roles within many classical and folk herbal traditions around the world, especially in conjunction with strategies to regulate the menstrual cycle and improve hormonal balance, treat or prevent fatigue, and improve stamina and fertility.

Possible Uses

Alzheimer's disease, anemia, athletic performance (with deficiency only), attention deficit–hyperactivity disorder (ADHD), canker sores, celiac disease (with deficiency only), childhood cognitive development (with deficiency), cough, depression (with deficiency), dermatitis herpetiformis, human immunodeficiency virus (HIV) support, infertility (female) (with deficiency only), iron deficiency anemia, lactation support, menorrhagia (heavy menstruation) (with deficiency only), presurgery and postsurgery support (with deficiency, or after major surgery), pregnancy and postpartum support, restless legs syndrome (with deficiency).

Deficiency Symptoms

Iron deficiency is the most common nutrient deficiency in the United States (U.S.) and the world. Mild degrees of iron deficiency are common in U.S. toddlers, teenage girls, and women of childbearing age, although full-fledged iron deficiency anemia remains rare. 1 Most cases of iron deficiency appear according to well-known patterns of susceptibility, malnutrition, depletion, and exacerbation. Nevertheless, because of the numerous risk factors associated with excess iron intake, use of supplemental iron to prevent or treat any of these patterns associated with iron deficiency must be assessed based on individual characteristics, needs, and susceptibilities.

Although iron deficiency is the primary nutritional disorder among humans and perhaps the most studied form of nutritional deficit within conventional medicine, a comprehensive and coherent understanding of its effects and influences, both frank and subtle, immediate and long-term, is just beginning to emerge into a coherent and comprehensive model. Iron deficiency anemia is the most overt and well-known symptom of iron deficiency. However, several gradations of iron depletion, including stages below the threshold and before the appearance of overt pathology, may contribute to physiological dysfunction and adversely affect quality of life. Thus, contrary to common assumptions, an individual does not have to be anemic to be iron deficient. 2 Furthermore, it is also critical to remember that iron deficiency anemia is not the only form of anemia, that other forms of anemia tend to appear in the same population(s), and that factors other than iron status contribute to iron deficiency anemia. In particular, folate and vitamin B12status, as well as confounding factors such as drug-induced depletion patterns, must be considered to adequately diagnose suspected anemia.

Cellular responses to iron deprivation are poorly understood. Emerging evidence indicates that iron deficiency reprograms cellular genetic expression. Puig, Askeland, and Thiele 3 found that a deficiency of iron altered the expression of more than 80 genes in Saccharomyces cerevisiae (yeast) cells, which were chosen because of the similarity of their genome to that of humans. They observed that Cth2, a protein overproduced by iron-deficient cells, binds to the mRNA of over 80 genes and targets it for degradation or destruction by specifically downregulating mRNAs encoding proteins that participate in many iron-dependent processes. Through this proposed mechanism, iron deficiency controls a posttranscriptional regulatory process that coordinately drives widespread metabolic reprogramming. The authors concluded: “We discovered that iron deprivation actually reprograms the metabolism of the entire cell. Literally hundreds of proteins require iron to carry out their proper function, so without this nutrient, there is a complete reorganization of how cellular processes occur.” 3

Iron deficiency may be modeled in the following three levels of increasing severity 4,5

  1. Storage iron depletion. Tissue iron stores are depleted, but the functional iron supply is not limited.
  2. Early functional iron deficiency. The supply of functional iron is low enough to impair RBC formation, but not sufficiently low to cause measurable anemia.
  3. Iron deficiency anemia. Available iron is insufficient to support normal RBC formation, resulting in the microcytic and hypochromic anemia characteristic of iron deficiency. Both inadequate oxygen delivery due to anemia and suboptimal function of iron-dependent enzymes can produce symptoms at this more severe stage of iron deficiency.
  4. Most of symptoms associated with iron deficiency result from the associated anemia; these include fatigue, weakness, pallor, tachycardia, palpitations, dyspnea on exertion, decreased endurance, and excess lactic acid production. Reduced hemoglobin and myoglobin levels associated with iron deficiency will impair physical exertion capacity and athletic performance by limiting oxygen delivery to tissues, reducing oxidative metabolism in mitochondria, diminishing mitochondrial content of cytochromes and other iron-dependent enzymes, and undercutting electron transport and ATP synthesis. Nonhematological effects resulting from iron deficiency include glossitis, taste bud atrophy, canker sores, nail spooning (koilonychia), brittle nails, hair loss, diminished immune function and increased susceptibility to infection, impaired intellectual performance, neurological dysfunction, and increased sensitivity to chill. Plummer-Vinson syndrome, characterized by the formation of webs of tissue in the throat and esophagus and difficulty swallowing, can occur in some advanced cases, possibly corresponding to a genetic predisposition. Children may also manifest behavioral disturbances such as attention deficit–hyperactivity disorder (ADHD) and breath-holding spells. Restless legs syndrome, initial seizure, pica, and pagophagia (excessive ice consumption, characterized in particular by chewing of ice) have also been associated with iron deficiency. Fatigue, weakness, anorexia, and pica may be caused by tissue depletion of iron-containing enzymes and not by decreased levels of blood hemoglobin.

    Conditions contributing to iron deficiency, particularly from blood loss or malabsorption, include diarrhea, ulcers, ulcerative colitis, Crohn's disease, celiac disease, parasitic infections, hemorrhoids, GI cancers, menorrhagia, accidents, injuries, and surgery. Other factors influencing iron absorption and deficiency include hydrochloric acid secretion and gastric pH, decreased dietary intake, blood loss (both internal and external, as in menorrhagia), calcium intake, caffeine intake, high–phytic acid fiber foods, vitamin A, genetic variability, and iron storage levels.

    Populations particularly at risk for compromised iron status include infants and children, age 6 months to 4 years, especially those living in inner cities or other impoverished circumstances; rapidly growing adolescents, especially females after menarche; pregnant women; individuals with acute or chronic blood loss due to medication-induced ulcers or intestinal parasites; frequent blood donors; individuals, especially children, with Helicobacter pylori infection (even without GI bleeding); populations exposed to environmental contaminants, especially lead; and individuals who engage in regular, intense exercise, particularly daily endurance training. All these factors are exacerbated in the context of ongoing menstrual cycles; menstruating women require approximately twice as much iron intake as men to replace their monthly losses due to menses. Although iron deficiency is not usually caused by a lack of iron in the diet alone, vegan or vegetarian diet or dietary intake may increase the risk of deficiency because of less relative bioavailability of iron from plant versus animal sources, at least in some individuals. Nutriture status of all nutrients, including iron, is compromised with poverty or lifestyle choices characterized by high intake of processed and refined foods or other forms of malnutrition.

    Dietary Sources

    The hemoglobin and myoglobin consumed within meat, poultry, oysters, and fish are the primary sources of heme iron in the diet. Approximately 40% of the iron in animal foods is heme iron and 60% is nonheme iron. Heme iron provides up to one third of total absorbed dietary iron, even though it accounts for only 10% to 15% of the iron potentially available in the diet. Nonheme iron is an inorganic compound, less easily absorbed, and derived from plant foods, dairy products, dried fruit, molasses, leafy green vegetables, and wine. Overall, absorption of heme iron can be up to 10 times that of nonheme iron, depending on whether body stores are replete. In the U.S., most grain products are fortified with iron. Iron fortification of cereal, using microencapsulated ferrous fumarate flakes, appears to achieve high iron bioavailability and can serve as an effective means of enhancing hemoglobin nutriture for infants and children. 6

    Many foods, beverages, and supplements have been shown to affect the bioavailability and absorption of iron. Foods that contain heme iron usually also provide nonheme iron, and the presence of the heme iron will enhance absorption of nonheme iron within the same foods or from foods consumed concurrently. In contrast to heme iron, the absorption of which is influenced less by other dietary factors, the absorption of nonheme iron is strongly influenced by enhancers and inhibitors ingested at the same time. Iron absorption, especially nonheme iron, can be inhibited by concomitant intake of phytate (phytic acid, as found in unleavened wheat products, whole-wheat bran, wheat germ, oats, some rye crackers, nuts, beans, cacao powder, vanilla extract, and many other high-fiber foods), tannins (found in tea and coffee), polyphenols (as in green tea, rosemary, and red wine), calcium-rich foods, soy protein, and egg yolk. Conversely, the absorption of nonheme iron is also enhanced by concurrent ingestion of various organic acids, particularly ascorbic acid, but also citric, malic, tartaric, and lactic acids. Certain soy-containing foods (e.g., tofu, miso, tempeh), some soy sauces, vitamin A, and alcohol (other than red wine) can also increase iron absorption. In general, iron absorption from all forms may be influenced most by relative iron nutriture and storage status.

    Ferrous salts are more efficiently absorbed than ferric salts. Acidic foods (e.g., tomato sauce) cooked in iron cookware may also provide a source of dietary iron, although not necessarily the optimal form. Alcohol, but not red wine, can increase the absorption of ferric, but not ferrous, iron.

    Nutrient Preparations Available

    Ferrous citrate, ferrous fumarate, ferrous gluconate, ferrous glutamate, ferrous glycinate, ferrous glycine sulfate, ferrous lactate, ferrous picolinate, ferrous succinate, ferrous sulfate; carbonyl iron; ferric sulfate.

    A number of supplemental iron preparations are available, and different forms provide different proportions of elemental iron, with differing bioavailability characteristics. Ferrous fumarate is 33% elemental iron, ferrous sulfate (monohydrate) 33%, ferrous sulfate (heptahydrate) 23%, and ferrous gluconate 12% elemental iron. In general, absorption of elemental iron is very poor. Ferrous iron is much better absorbed than ferric iron. Heme iron is far better absorbed than nonheme. Absorption of organic chelates is probably the next highest, followed by organic salts (e.g., ferrous gluconate). Inorganic salts (e.g., ferrous sulfate) are the least well absorbed.

    Diverse users absorb, tolerate, and respond to the various forms of iron to varying degrees and with differential responses. Iron supplements can be challenging to those who need to take them because when isolated, the nutrient is not easy to digest and can readily lead to nausea, constipation, or both. Nonheme iron is the predominant type of iron present in nutritional supplements. Ferrous forms (usually as the sulfate, gluconate, or fumarate salt) are readily absorbed without the need for acid. Although ferrous sulfate is the form of nonheme iron used most frequently, ferrous succinate is more often recommended. Ferrous fumarate and iron-EDTA may be more bioavailable than ferrous sulfate, particularly in individuals with low (or impaired) gastric acidity. Enteric coating is sometimes used with ferrous sulfate to delay tablet dissolution and moderate adverse effects, but bioavailability may be compromised. Combining iron with certain mineral-rich herbs, such as yellow dock (Rumex crispus), dandelion root (Taraxacum officinale), alfalfa leaf (Medicago sativa), and nettles tops (Urtica dioica), may enhance absorption, buffer irritant effects, and expand the nutritive effect beyond iron alone.

    Dosage Forms Available

    • Capsule; capsule, time-release; liquid; tablet.
    • Intravenous (IV) iron forms: Iron dextran (DexFerrum, Imferon), iron sucrose (Venofer), sodium ferric gluconate (Ferrlecit).

    Source Materials for Nutrient Preparations

    Most are inorganic and organic salts, chelates, and synthetic polymeric matrices. Botanical extracts of iron-rich plants. Some heme iron concentrates have been used in clinical trials, but generally are not commercially available.

    Dosage Range

    The doses of iron discussed in this monograph represent elemental iron unless stated otherwise.

    Adult

    Dietary: In the U.S. the average adult daily diet of premenopausal and postmenopausal women provides 12 mg/day and of pregnant women about 15 mg/day. In the United Kingdom (U.K.) the average daily dietary intake for adult women is 12.9 mg/day. For men in the U.S. the average adult daily diet provides 16 to 18 mg elemental iron daily; in the U.K., 14.5 mg.

    Supplemental/Maintenance:

    • Men: 8 mg/day
    • Women, nonpregnant, nonlactating, age 19 to 50 years: 18 mg/day
    • Women, age 19 to 51 and older: 8 mg/day

    During pregnancy, the metabolic needs of the developing fetus and placenta, as well as a significant expansion of blood volume, increase iron utilization. Conversely, iron requirements are potentially reduced during pregnancy by cessation of menstruation and increased efficiency of absorption. Consequently, iron intake may not need to be any greater than for other adult women, and routine iron supplementation is not necessarily required in pregnancy. Nevertheless, within context of care by a qualified health care professional, pregnant women may benefit from iron supplementation during the last 3 to 6 months of pregnancy. In particular, prenatal prophylactic iron supplementation before 20 weeks’ gestation may help pregnant women increase the birth weight of their infants. 7 Iron status should be monitored in all pregnant women.

    In general, routine supplementation of iron on a daily basis is not recommended. It is generally advised that use of iron supplements be avoided unless clinically indicated, such as low serum ferritin or microcytic, hypochromic anemia. Excess iron has been implicated in free-radical damage. These cautions do not extend consumption of iron-rich foods in moderation for most individuals. Notably, the dietary iron intake of the majority of premenopausal and pregnant women in the U.S. is lower than the recommended dietary allowance (RDA) and the dietary intake of many men is greater than the RDA. Many multivitamin-mineral preparations contain 18 mg of iron, which may result in excessive iron intake for certain individuals.

    Pharmacological/Therapeutic: 10 to 200 mg/day.

    In treatment of iron deficiency, 100 mg/day is a common recommended amount for an adult; dosage is generally reduced after the frank deficiency is corrected. Administration of therapeutic levels is generally recommended for 3 to 4 months after correction of iron deficiency anemia, to replace iron stores.

    Toxic: 100 mg/day (in absence of iron deficiency).

    The tolerable upper intake level (UL) for iron is 45 mg/day for non-iron-deficient adolescents and adults over age 14 years, including pregnant and breastfeeding women, according to standards set by the Food and Nutrition Board (FNB) of the U.S. Institute of Medicine. This UL is based on the prevention of GI distress and is generally understood not to apply to individuals being treated with iron under supervision of a qualified health care professional.

    Pediatric (<18 Years)

    Dietary (AI, adequate intake):

    • Infants, birth to 6 months: 0.27 mg/day (AI, adequate intake)
    • Infants, 7 to 12 months: 11 mg/day (AI)
    • Children, 1 to 3 years: 7 mg/day (AI)
    • Children, 4 to 8 years: 10 mg/day (AI)
    • Children, 9 to 13 years: 8 mg/day (AI)
    • Adolescents, 14 to 18 years: 15 mg/day (for females); 11 mg/day (for males)

    Supplemental/Maintenance: Otherwise-healthy infants born without iron deficiency benefit from iron supplementation, according to the findings of an intervention trial. 8

    Pharmacological/Therapeutic: 10 to 50 mg/day, depending on body weight, condition, and other individual factors, under medical supervision.

    Toxic: 2.0 to 2.5 g can be lethal in a 10-kg child. Deaths in children have occurred from ingesting as little as 200 mg to as much as 5.85 g of iron. 9

    Laboratory Values

    Current diagnostic markers for iron deficiency are not highly sensitive, unless the deficiency is severe. Bone marrow iron is often considered the “gold standard” of iron stores but is rarely practical in most clinical situations. Serum ferritin concentration provides the most accurate diagnostic method to assess iron stores and confirm iron deficiency, but only if the values are low. Iron deficiency can accompany elevated serum ferritin levels when acute or chronic inflammatory states are present, because ferritin is one of the acute-phase reactants.

    One can traditionally obtain a serum iron and serum iron-binding capacity and divide the former by the latter to determine the transferrin saturation. If iron/iron-binding capacity is less than 10%, there is a probability of iron deficiency. A more modern approach to this diagnosis is to measure the serum ferritin; iron deficiency can usually be excluded as a diagnosis if serum ferritin is more than 220 µg/L. However, if it is less than 220, it is judicious to obtain a serum transferrin receptor (sTfR) level. This measures the soluble receptors of transferrin in the circulation, receptors that bind to the available iron. If this value is 28 mg/L or higher, there is a significant probability of iron deficiency. 10 Ongoing developments in knowledge of how iron deficiency influences cellular genetic expression may soon provide diagnostic markers of increased sensitivity by pinpointing the genes affected by iron deprivation to provide a genetic fingerprint of how varying levels of iron deprivation are expressed in different patients. 3

    It is often necessary to assess ferritin, percentage transferrin saturation, and sTfR levels for an accurate assessment of iron status, because ferritin can be falsely elevated by a number of conditions, including pregnancy, inflammatory conditions (e.g., arthritis), malignancy, skin conditions, irritable bowel disease, and acute/chronic infections, both viral and bacterial.

    Areas to exclude as causes of anemia include iron deficiency anemia, nutritional anemias due to B12and folic acid deficiency, drug-induced anemia, alcohol-induced bone marrow toxicity, acute and chronic hemolysis, other illnesses affecting RBC production, and malignant infiltration of the bone marrow.

    Serum Ferritin

    Normal: 12 to 200 µg/L.

    Serum ferritin is the measure of iron status that provides the most accurate indicator of tissue stores and can serve as an effective screening tool. However, it can be elevated with inflammation or infection independent of iron status. Serum ferritin greater than 225 µg/L can generally be interpreted as ruling out iron deficiency anemia. When serum ferritin is less than 220 µg/L, the soluble transferrin receptor (sTfR) level can be used to determine if the patient has upregulated transferrin receptors. Some practitioners of natural therapeutics recommend that males ideally should not have a ferritin level much more than 80 µg/L, unless they are actively engaged in strenuous athletic training or exercise regimens, to minimize iron-catalyzed oxidative stress.

    Serum Iron

    Normal: 9 to 29 mmol/L.

    Serum iron provides an insensitive indicator of iron status, declining only after tissue stores are completely exhausted.

    Transferrin Saturation

    Transferrin saturation of less than 16% of available binding sites indicates iron deficiency.

    Some practitioners of natural therapeutics recommend that transferrin saturation not be greater than 45%, especially with a history of heart disease, diabetes, or cancer. Transferrin saturations greater than 60% are highly suggestive of hereditary hemochromatosis, or another form of iron overload, and should be thoroughly investigated with genotyping and/or liver biopsy to assess hepatic iron stores.

    Serum Transferrin Receptor

    Also known as soluble transferrin receptor (sTfR). Levels greater than 8 mg/L indicate deficiency in standard diagnostic usage. However, some experienced practitioners of nutritional therapeutics use 28 mg/L as the level for demarcating iron deficiency. Values greater than 28 mg/L are also consistent with iron deficiency with corrections for altitude.

    Measurement of serum transferrin receptor is a new marker of iron metabolism that reflects body iron stores and total erythropoiesis. Unlike serum ferritin, the sTfR is not an acute-phase reactant, so it is not elevated in response to acute or chronic inflammatory disease. 10 Thus, it serves as a reliable marker of iron status when iron deficiency is associated with chronic disorders, such as inflammation, infection, or malignancy. In situations of iron deficiency, the avidity and number of soluble transferrin receptors (i.e., sTfR) increases in proportion to tissue iron deficit. Thus, soluble TfR levels are decreased in situations characterized by diminished erythropoietic activity and are increased when erythropoiesis is stimulated by hemolysis or ineffective erythropoiesis. Measurements of sTfR are very helpful in investigating the pathophysiology of anemia, quantitatively evaluating the absolute rate of erythropoiesis and the adequacy of marrow proliferative capacity for any given degree of anemia, and to monitor the erythropoietic response to various forms of therapy, in particular allowing one to predict the response early, when changes in hemoglobin are not yet apparent. Iron status also influences sTfR levels, which are considerably elevated in iron deficiency anemia but remain normal in the anemia of inflammation, and thus may be particularly valuable in the differential diagnosis of microcytic anemia, especially when identifying concomitant iron deficiency in a patient with inflammation, because ferritin values are then generally normal. Elevated sTfR levels are also the characteristic feature of functional iron deficiency, a situation defined by tissue iron deficiency despite adequate iron stores. The sTfR/ferritin ratio can thus describe iron availability over a wide range of iron stores. With the exception of chronic lymphocytic leukemia (CLL), high-grade non-Hodgkin's lymphoma, and possibly hepatocellular carcinoma, sTfR levels are not increased independent of iron status in patients with malignancies. 11

    Erythrocyte Protoporphyrin

    Recent research indicates that erythrocyte protoporphyrin (EP) can provide a useful screening tool for determining iron deficiency. Using the receiver operating characteristic (ROC) curve to characterize the sensitivity and specificity of hemoglobin and EP measurements in screening for iron deficiency, Mei et al. 12 found EP “consistently better than measurements of hemoglobin for detecting iron deficiency” in preschool children, age 1 to 5 years. However, in nonpregnant women, they found “no significant difference between EP and hemoglobin in ROC performance for detecting iron deficiency.”

safety profile

Overview

Adverse effects resulting from ingestion of iron supplements occur frequently and often manifest with common dosage levels. However, iron toxicity is relatively rare and predominantly occurs acutely as a result of overdose. In the U.S., iron is the leading cause of accidental poisonings in children. In response, child-resistant safety packaging is legally required for all iron-containing products. Even so, the incidence of iron poisonings in young children increased dramatically in 1986. Many of these children obtained the iron from a child-resistant container opened by themselves or another child, or left open or improperly closed by an adult. 13

Nutrient Adverse Effects

General Adverse Effects

In adults, early symptoms of supplemental iron toxicity include GI irritation, nausea, vomiting, and abdominal pain. Constipation is the most frequently reported adverse effect associated with some forms of iron, even when therapeutically indicated, and may lead to fecal impaction, particularly in the elderly. Conversely, an exacerbation of diarrhea can occur in individuals with inflammatory bowel disease and may be accompanied by bleeding. Liquid iron preparations may blacken the teeth. Signs and symptoms of overload include grayish skin, headache, shortness of breath, fatigue, dizziness, and weight loss. More advanced toxic effects associated with acute excessive iron intake include weakness, fatigue, pallor, arrhythmia, tachycardia, cardiovascular collapse, cyanosis, seizures, and coma.

Intravenous iron, administered in some cases of severe anemia in an inpatient setting, can lead to headache, fever, lymphadenopathy, joint pain and inflammation, hives, exacerbation of rheumatoid arthritis, hemolytic reactions (often associated with acute back pain and renal injury), and (rarely) anaphylaxis.

Adverse Effects Among Specific Populations

Individuals with insulin resistance syndrome, diabetes, or hepatitis C may be particularly susceptible to iron overload. Iron overload triples mortality in people with elevated transferrin saturation. 14

Supplementing iron can be quite dangerous for individuals with hereditary hemochromatosis, hemosiderosis, polycythemia, iron-loading anemias, and other conditions involving excessive storage of iron. Excessive absorption of iron from dietary sources may occur in response to excessive formation of red blood cells. Hereditary hemochromatosis (HH) is a genetic disorder that affects up to 1 in 200 individuals of northern European descent and is characterized by increased intestinal absorption of iron leading to progressive deposition of iron-containing pigments in the liver and other tissues. If untreated, tissue iron accumulation may lead to bronzing of skin, cirrhosis, cardiomyopathies, diabetes, conduction irregularities, testicular atrophy, and arthritis. The HFE gene and the mutation resulting in HH were identified in 1996, but the precise role of the protein encoded by the HFE gene in intestinal iron absorption has yet to be fully elucidated. 15,16Supplemental iron is generally contraindicated in individuals with HH, but they are usually not advised to avoid iron-rich foods, depending on their degree of iron overload at diagnosis and their response to iron unloading on repeated phlebotomies. Sub-Saharan African hemochromatosis is a variant that appears to require both high iron intake and an as-yet unidentified genetic factor. 17

Hemosiderosis is characterized by excessive iron deposits in hemosiderin, the normal iron storage protein. Long-term use of iron at high dosage levels can cause hemosiderosis that clinically resembles hemochromatosis.

Patients with sideroblastic anemia, pyruvate kinase deficiency, thalassemia major, and similar conditions are particularly at risk of iron overload when treated for anemia with numerous transfusions. Iron overload is significantly less common in individuals with hereditary spherocytosis and thalassemia minor, unless they are administered excessive amounts of iron after being misdiagnosed as iron deficient. Emerging information suggests the existence of a Mediterranean form of hemochromatosis, not involving the HFE gene, and with a genetic association unknown at this time, distinct from HH and thalassemias. Treatment for iron overload is by phlebotomy, typically weekly removal of 500 mL of blood until mild iron deficiency is induced. Transfusion-dependent states, however, require iron chelation, generally with regular overnight subcutaneous infusions of deferoxamine mesylate (Desferal).

In a randomized, placebo-controlled trial involving children age 1 to 35 months living in Zanzibar, Sazawal et al. 18 found that “supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death.” Routine prophylactic iron supplementation in such situations should be avoided pending further research. However, within the context of an active program “to detect and treat malaria and other infections, iron-deficient and anaemic children can benefit from supplementation.”

Pregnancy and Nursing

Low-dose iron supplements are generally safe and effective in pregnancy. 19 Iron supplementation during pregnancy and lactation should be undertaken only under the supervision of a health care professional trained and experienced in nutritional therapeutics.

Infants and Children

Infants and children are especially vulnerable to iron toxicity. Doses as low as 60 mg/kg can be fatal.

Contraindications

Iron preparations are generally contraindicated for individuals diagnosed with a variety of conditions, including hemochromatosis, hemosiderosis, transfusion-dependent thalassemia or other transfusion-dependent states, other conditions associated with iron overload, peptic ulcer, inflammatory bowel disease or other GI disease, diverticulitis, and intestinal stricture. Patients receiving hemodialysis for end-stage renal disease (ESRD) are particularly susceptible to oxidative stress and carotid artery intima media thickening as a result of iron administration, especially without concomitant vitamin E. 20,21

Prophylactic iron (and folic acid) may be contraindicated for children in malarial environments. 18

Iron supplements are generally inappropriate for individuals with a history of any unusual or allergic reaction to iron, or medicines, foods, dyes, or preservatives containing iron.

Precautions and Warnings

Conservative principles of practice suggest that regular iron supplementation be avoided in any individual who has not demonstrated iron deficiency anemia or low iron stores. Such caution is warranted because of the frequency of undetected HH, the pervasive pathophysiology of inflammation and oxidative stress, and emerging concerns about the more subtle effects of chronic excess iron intake. Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis. 22 Thus, for example, iron supplementation appears particularly to increase risks of vascular disease and thrombosis for smokers with hypercholesterolemia. 23

Some patients have a serious allergic reaction to IV iron dextran (Imferon), and therefore patients must be monitored especially closely during the first two Imferon administrations using a test dose of 25 mg for each session. After the second test dose is given, the administered dose can be increased to 100 mg. Intravenous sodium ferric gluconate (Ferrlecit) does not contain dextran, and this significant concern regarding anaphylactic reactions is essentially negligible.

Numerous researchers and reviewers have proposed, and sometimes proved, links between excess iron and the development or exacerbation of numerous pathological conditions, including increased risk of infection and inflammatory processes (e.g., pulmonary tuberculosis, pelvic endometriosis), heart disease (e.g., carotid atherosclerosis, coronary disease, myocardial infarction), autoimmune processes (e.g., diabetes, rheumatoid arthritis, systemic lupus erythematosus), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease), and cancer (especially hepatocellular carcinoma and colorectal cancer). 23-46Most of these associations are not conclusively supported by a review of well-done human studies, and some have been disproved, but many are consistent with known patterns of physiology, epidemiology, and pathogenesis. This important area of conflicting data, experience, and opinions will undoubtedly continue to be the subject of clinical trials and meta-analyses.

interactions review

Strategic Considerations

Iron deficiency is the most common micronutrient deficiency in the world, and iron is the nutrient most often prescribed by conventional physicians as an active therapeutic intervention. However, the principles underlying and clinical practices framing such administration have not yet matured into a comprehensive and coherent approach for safe and effective prescribing in daily clinical practice. As with the inflammation it can induce and the free radicals it often generates, the classical metaphor of iron as a “hot” mineral can be applied therapeutically, serving well in suitable circumstances at the appropriate amounts, but just as easily causing a ripple of multiple adverse effects when insufficient, excessive, or simply inappropriately situated. Given the risks of iron depletion and iron overload and the multiple interaction patterns involving iron, deeper analysis of the research data and clinical practices reveals that universal declarations of efficacy, risk, and response patterns do not adequately convey the complexity of individual variability, patient subgroups, and conflicting needs. Thus, iron exemplifies the need for personalized and evolving therapeutic strategies within an integrative model when multiple therapies and coordinated care among various health care providers are involved.

Iron might be seen as a warrior whose sword cuts both ways. It produces heat, agitation, and invigoration, which can convey vitality, sustain activity, and embody vigor, but also carries the risk of oxidative stress, irritation, inflammation, and infection. Although iron depletion is common and has been given more attention than any other nutrient deficiency in conventional medical practice, the methods of evaluation and the standards for augmentation (or reduction) remain controversial. Depleted tissue iron stores are often missed in susceptible individuals because the clinical focus almost exclusively centers on frank iron deficiency anemia rather than functional parameters. Conversely, iron excess or overload, or even inappropriately timed administration, will tend to increase susceptibility to, or aggravate inflammatory processes and promote an environment favorable to, pathogenic microorganisms. The physiological response to infection and neoplasm is to make iron as unavailable as possible to the invading cells, which results in the functional iron deficiency, often seen with acute or chronic infections, and malignancies. Although not rigorously investigated with careful clinical research, much clinical experience suggests that it is often unwise to override this physiological adaptation with oral, and particularly parenteral, iron administration.

Accurate laboratory evaluation of iron status is multifactorial, often making it difficult and elusive to assess functional iron levels, metabolic processes, and depletion and overload states. It is often necessary to assess ferritin, percentage transferrin saturation, and sTfR levels for an accurate assessment of iron status, because ferritin can be falsely elevated by a number of conditions, including pregnancy, inflammatory conditions (e.g., arthritis), malignancy, skin conditions, irritable bowel disease, and chronic infections, both viral and bacterial.

Many minerals and metals are known to bind with a wide range of medications to form insoluble complexes that impair absorption and bioavailability, but with no other common nutrient as much as with the iron salts. Although this phenomenon has been studied widely, the body of evidence indicates that adverse effects on therapeutic efficacy of either agent involved can usually be effectively avoided by separating oral intake by at least 2 hours. Nevertheless, direct inquiry and frank discussion with patients regarding supplement use is critical because simultaneous intake over an extended period could adversely impact therapeutic action and confuse monitoring. Further, unsupervised alterations in intake habits, especially sudden discontinuation of iron that had been taken simultaneously, could result in a rapid elevation in effective dose levels of other agents, thus creating unintended consequences. As always, physician-patient communication, interdisciplinary collaboration, and reinforcement of trust, honesty, and respect for patient choices will always enhance the therapeutic process and support positive clinical outcomes.

The volatility of iron within human physiology, its complex interactions with a wide range of medications and nutrients, and the adverse implications of not maintaining dynamic equilibrium all attest to the critical importance of attentiveness to the changing needs of the individual patient whenever dealing with iron, its intake, and reverberations throughout the economy of the organism.

nutrient-drug interactions
Acetylsalicylic Acid (Aspirin)
Angiotensin-Converting Enzyme (ACE) Inhibitors
Antacids and Gastric Acid–Suppressive Medications
Bile Acid Sequestrants
Bisphosphonates
Carbidopa, Levodopa, and Related Antiparkinsonian Medications
Cefdinir and Related Cephalosporin Antibiotics
Chloramphenicol
Chlorhexidine
Clofibrate
Desferoxamine
Dimercaprol
EDTA
Erythropoiesis-Stimulating Agents
Epoetin alpha (EPO, epoetin alfa, recombinant erythropoietin; Epogen, Eprex, Procrit), epoetin beta (NeoRecormon), darbepoetin alpha (darbepoetin alfa; Aranesp). See also Vitamin C monograph.
Beneficial or Supportive Interaction, with Professional Management
Bimodal or Variable Interaction, with Professional Management
Minimal to Mild Adverse Interaction—Vigilance Necessary
Potentially Harmful or Serious Adverse Interaction—Avoid

Probability: 2. Probable
Evidence Base: Emerging , Mixed

Effect and Mechanism of Action

Erythropoietin is an endogenous peptide, produced primarily by the kidneys, which drives erythropoiesis in the bone marrow. It became available as a recombinant peptide hormone for therapeutic use in the 1980s.

Approximately 50% of oncology patients develop anemia, with that incidence rising dramatically in patients with more advanced cancer or in those receiving chemotherapy and/or radiation therapy. Within conventional oncology, recombinant human erythropoietin(rHuEpo) represents the standard of care in managing cancer therapy-related anemia and fatigue, increasing hemoglobin levels, reducing transfusion need, and improving patient quality of life. Likewise, rHuEpo may correct anemia in chronic renal failure (CRF) patients, in iron-deficient erythropoiesis associated with the anemia of chronic disease (ACD), and in primary bone marrow dysfunction states, such as myelodysplastic syndrome. By stimulating erythropoiesis, erythropoietin may increase synthesis of RBCs, thereby increasing metabolic need for iron. Iron coadministration, intravenous/parenteral or oral, could improve the response to erythropoietin or rHuEpo in cases of iron-deficient erythropoiesis by delivering adequate iron to the bone marrow.

Research

Since the late 1980s, rHuEpo has provided a safe and effective option for treating cancer-related anemia and fatigue. Recent research confirmed that epoetin beta, 30,000 IU once weekly, is equally effective as the conventional 10,000 IU three times weekly in alleviating cancer-related anemia. 115 Nevertheless, erythropoietin therapy exhibits variable response rates, and 30% to 50% of patients did not respond adequately to treatment in some trials. True iron deficiency is the most common cause of an inadequate response to rHuEpo in CRF patients. However, in oncology patients, this failure may be caused by factors related to the underlying disease, adverse effects of chemotherapy or radiotherapy, functional iron deficiency, or some combination. 116,117 Thus, in cases of functional iron deficiency, patients may not respond to rHuEpo when iron availability is inadequate to the demands of erythropoietin-induced erythropoiesis, despite the presence of adequate bone marrow iron stores.

Since the emergence of rHuEpo as a standard treatment, concomitant iron has often been proposed as an important therapeutic option in optimizing the response of cancer-related anemia to rHuEpo. 118 Guidelines published by the American Society of Clinical Oncology and American Society of Hematology recommend iron repletion in patients receiving rHuEpo when functional iron deficiency is present, based on indirect evidence and biological inferences. 117 A growing body of literature regarding chronic renal failure patients has shown that iron coadministration can correct functional iron deficiency and may improve erythropoietin response, with IV iron doing so more effectively than oral iron.

Markowitz et al. 119 conducted a double-blind, placebo-controlled trial to evaluate the effectiveness of oral iron therapy in 49 hemodialysis patients receiving rHuEpo. They divided the subjects into two groups, based on adequate or deficient iron stores, and treated them for 3 months with 150 mg elemental iron (polysaccharide complex) or placebo, twice daily. Over 5 months they observed that iron-replete patients, in both oral iron and placebo subgroups, demonstrated decreasing iron stores; that is, oral iron failed to maintain their iron stores. Furthermore, compared to iron-replete patients, iron-deficient patients had a significantly greater dropout rate because of adverse effects, even though responses to the side effect questionnaire were equivalent, suggesting poor medication compliance. Beguin 116 found that oral iron is largely ineffective in the treatment of anemia in chronic diseases other than cancer, mainly because of the development of iron deficiency, which significantly limits the efficacy of rHuEpo therapy.

Oral iron products in patients with ESRD have been largely abandoned, and the safety of IV iron preparations has improved with the introduction of new-generation compounds that have significantly reduced incidence of allergenicity. Since its approval, sodium ferric gluconate complex (SFGC) has largely displaced iron dextran as the primary form of IV iron, which had been associated with significant adverse reactions, including anaphylaxis and death. Adverse reactions to SFGC are uncommon in hemodialysis patients, including both iron dextran–sensitive and dextran-tolerant patients. 120 These findings indicate that dextran, rather than iron, is the cause of most reactions to iron dextran administration.

Iron deficiency is the most common cause of suboptimal response to rHuEpo in chronic hemodialysis patients. Intravenous iron can improve hemoglobin response, help maintain adequate iron stores, and decrease erythropoietin dosage requirements in hemodialysis patients and patients with anemia of kidney disease. In 1997, Kooistra et al. 121 investigated the effects of iron availability, inflammation, and aluminum on iron absorption in 19 chronic hemodialysis patients on maintenance erythropoietin (rHuEpo) therapy. They concluded that iron absorption is decreased in hemodialysis patients with elevated C-reactive protein (CRP) values and higher levels of aluminum ingestion. Iron absorption correlated significantly with transferrin saturation and CRP in the iron-deficient group, and with serum ferritin in the iron-replete group. Auerbach et al. 122 conducted a randomized trial involving 43 hemodialysis patients receiving rHuEpo (epoietin alpha) to investigate three iron dextran infusion methods for anemia. They reported no significant differences in efficacy and safety (as measured by time to the maximum hemoglobin and adverse reactions) when they compared subjects who received IV iron dextran as a total-dose infusion, 500-mg infusion to total dose, or 100-mg bolus to total dose, in each case during the dialysis procedure.

In a trial involving 24 patients of an outpatient dialysis center, Vankova et al. 123 reported significant improvements obtained by tracking hematocrit, transferrin saturation, and ferritin levels and adjusting iron and rHuEpo dosage accordingly. In 23 patients (96%), transferrin saturation levels were within the recommended range after treatment. Hematocrit increased from 27.7% to 35.7%, with the recommended value of 33% being achieved in 18 patients. Overall, the weekly dose of rHuEPO fell from 3958 IU to 2042 IU, and the average dose of iron administered was 157 mg per week. Similarly, Chang et al. 124 conducted a 12-month IV iron substitution trial in 149 iron-replete chronic hemodialysis patients receiving subcutaneous rHuEpo therapy. They maintained the available iron pool with 100 mg iron every 2 weeks or 1 month, depending on serum ferritin and transferrin saturation levels, with the rHuEpo dosage titrated depending on hematocrit levels. After 12 months these researchers reported increases in the hematocrit, serum ferritin, and transferrin saturation along with a 25% reduction in rHuEpo requirement. The authors concluded that maintaining high levels of serum ferritin and transferrin saturation could further reduce the requirement of erythropoietin in chronic hemodialysis patients, but cautioned that “the long-term effect of iron overloading…must be further evaluated in contrast to the economic saving.” 124

However, oral heme iron may provide an effective option for iron therapy in hemodialysis patients because it is absorbed by patients with high ferritin levels, it has fewer adverse effects, and its absorption is stimulated by erythropoietin administration. In an open, 6-month, prospective evaluation of heme iron in 37 hemodialysis patients who had been on maintenance IV iron therapy, Nissenson et al. 125 discontinued the IV iron and replaced it with oral heme iron. Among the 28 subjects who completed the study, the authors observed an initial slight reduction in average transferrin saturation, which subsequently reversed, and a significant reduction in average serum ferritin level was seen at months 4 through 6. No significant changes were seen in average transferrin saturation or hematocrit. The authors concluded that heme iron polypeptide successfully replaced IV iron therapy in a majority of hemodialysis patients during the 6-month study period, maintained target hematocrits with no concomitant use of IV iron, and thus was associated with a significant increase in rHuEpo efficiency.

Ongoing research is examining the role of concomitant IV iron during epoetin therapy with the aim of further improving the effectiveness of epoietins in anemia treatment. A study published in 2004 was the first controlled trial confirming that iron should be coadministered intravenously rather then orally in cancer patients with chemotherapy-related anemia. In a prospective, multicenter, open-label, randomized trial involving 157 patients, Auerbach et al. 126 found that IV iron optimizes the response to rHuEpo in cancer patients with chemotherapy-related anemia. In addition to rHuEpo, 40,000 U subcutaneously once weekly, subjects received (1) no iron; (2) 325 mg iron orally twice daily; (3) iron dextran, repeated 100-mg IV bolus; or (4) iron dextran total-dose infusion (TDI). They reported that subjects in all four groups showed hemoglobin (Hb) increases from baseline with mean Hb increases for both IV iron groups were greater than for no-iron and oral iron groups. Patients in both groups receiving IV iron demonstrated higher hematopoietic responses (68%) than did those in the groups receiving no iron (25%) and oral iron (36%). Furthermore, subjects in the IV iron group showed increases in energy, activity, and overall quality of life from baseline, compared with a decrease in energy and activity for the no-iron group and no change in activity or overall quality of life for the oral iron group. The authors concluded that rHuEpo increases Hb levels and improves quality of life in patients with chemotherapy-related anemia, and that coadministration of IV iron significantly increased the magnitude of improvement for both outcomes. Patients were not followed long term to determine whether the therapy had any positive or negative impact on cancer specific survival. In a letter, Pedrazzoli et al. 127 responded with a cautionary approach: “Because of absence of iron stores, in this subset of patients, it is clinically cautious to postpone treatment with erythropoietic agents until iron stores are replenished or to treat iron deficiency aggressively along with rHuEpo therapy.” In contrast, in a randomized, double-blind, placebo-controlled trial involving 351 head and neck cancer patients with anemia undergoing radiotherapy, Henke et al. 128 found that epoetin beta corrected anemia but did not improve cancer control or survival, and in fact, locoregional progression-free survival was poorer with epoetin beta than with placebo. Moreover, whether concomitant iron can increase the proportion of patients without iron deficiency responding to erythropoietic agents remains the subject of ongoing controversy and an area in need of further elucidation within the field of rHuEpo therapy for anemia of cancer.

Anemia of chronic disease (ACD) is a frequent complication of chronic inflammation in rheumatoid arthritis and other conditions. The cytokine interleukin-6 (IL-6) mediates hypoferremia (anemia) of inflammation by inducing the synthesis of the iron-regulatory hormone hepcidin. 129,130 Arndt et al. 131 investigated the concomitant use of rHuEpo and parenteral iron to correct iron-deficient erythropoiesis (IDE) in patients diagnosed with anemia of chronic disease. They treated 30 rheumatoid arthritis patients with ACD using subcutaneous rHuEpo, 150 IU/kg twice weekly. Intravenous iron (200 mg iron sucrose once weekly) was coadministered in cases of IDE, as defined by the presence of two of three criteria: saturation of transferrin 15% or less, hypochromic erythrocytes 10% or more, and serum ferritin concentration 50 µg/L or less. The authors reported that all 28 subjects who completed the trial met the treatment goal of successful correction of anemia, with an increase of the median Hb concentration from 10.3 to 13.3 g/dL, and concluded that such coadministration of erythropoietin and iron was safe, effective, and well tolerated in all patients.

Nutritional Therapeutics, Clinical Concerns and Adaptations

Physicians administering erythropoietin are advised to exercise caution in the coadministration of iron, especially IV iron within the context of oncological care. Combination therapy using erythropoietin and iron is controversial and awaits greater evolution of clinical research, particularly specificity to individuals, conditions, and stages of treatment. 116 The erythropoietic response is a tactical element within the broader therapeutic strategy and, although evoking apparent short-term benefits using narrow parameters of hematological response, may be irrelevant or deleterious, even counterproductive, to achieving the desired clinical outcome, such as the strategic goal of eliminating cancer. 132 Thus, this intervention could be beneficial or adverse, depending on the particulars of the case.

Most anemia is cancer patients is the “anemia of chronic inflammation,” which although sometimes similar in presentation to iron deficiency, is part of a protective response, similar to that in acute infection; the body “locks down” iron to keep it out of circulation to counter the proliferative process, because most malignant cells and pathogenic bacteria require iron for rapid proliferation. Erythropoietin (EPO) is most appropriate in anemic cancer patients, and then only after assessing the endogenous EPO level and determining that it is not already extremely elevated. Iron is coadministered most safely and effectively only when there has been no or only minor response to initial EPO therapy. It is essential to monitor iron status and to address either true or functional iron deficiency before and during rHuEpo therapy to optimize the effect of rHuEpo in cancer patients. It must also be kept in mind that oncology patients with limited iron stores may become iron deficient as a result of erythropoiesis stimulated by EPO therapy, which then limits further response unless iron is supplied. The IV route shows significantly greater efficacy than the oral route with inorganic iron preparations. Oral administration of heme iron should also be investigated in this population.

Coadministration of ascorbic acid may also be indicated in certain cases, especially involving resistance to EPO in hemodialysis patients with functional iron deficiency.

Fluoroquinolone (4-Quinolone) Antibiotics
Hyoscyamine
Indomethacin and Related Nonsteroidal Anti-Inflammatory Drugs (NSAIDS)
Interferon Alpha
Levothyroxine and Related Thyroid Hormones
Methyldopa
Neomycin
Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)
Penicillamine
Sulfasalazine
Tetracycline Antibiotics
Trientine
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Allopurinol
Amphetamines and Related Stimulant Medications
Dipyridamole
Haloperidol
Methotrexate
Pyrimethamine/Sulfadoxine
Stanozolol
Warfarin
nutrient-nutrient interactions
Calcium
Copper
Fiber
Folate
Manganese
Pancreatic Enzymes
Phosphorus/Phosphate Supplements
Taurine
Vitamin A
Vitamin C (Ascorbic Acid)
Vitamin E
Zinc
herb-nutrient interactions
Herbs Containing Tannins And Polyphenols
Citations and Reference Literature
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