The use of iron for anemia may be the wrong approach and even dangerous in some instances. During inflammation and immunological signaling, the body’s utilization of iron can be shifted from constructive processes to destructive. In cases where anemia is caused by the acute phase and inflammation, the objective should be the restoration of the body’s healing so that normalization of iron activities is accomplished. Giving iron when inflammatory processes are occurring can be seen as harmful and iatrogenic because of iron’s ability to drive hydroxyl radical formation via the Fenton reaction. Moreover, the administration of oral and intravenous iron has been shown in several clinical studies to increase a very toxic form of iron, known as NTBI (non-transferrin bound iron). This form of iron is responsible for generating intracellular reactive oxygen species, which damage cellular organelles and molecules, as well as create tissue and organ damage in a variety of disease states. Because of the complexity of iron in biology and its proclivity to participate in destructive, inflammatory processes, it is critical to develop a more nuanced and refined approach to the age-old problem of anemia. It is now understood that aberrant iron metabolism and anemia can be corrected without the use of iron. The use of both direct and indirect treatment protocols offers a more effective and safer approach for anemias that are driven by inflammatory and immunological signaling.
Iron-Deficient Anemia: More Than Meets The Eye
Iron and copper researcher Morely Robbins asks the question: “How can anemia exist on a planet with 36% iron?” The question is provocative because it implies that other factors can cause anemia, and that the issue of iron deficiency is much more complex than what it seems. Indeed, during inflammatory states, the body shuttles and sequesters iron to prevent it from being taken up by pathogens and inflammatory processes. Giving iron when these conservation mechanisms are underway is counterproductive, and can even be harmful.
Iron is a complex element that exists in different valence states. In organisms this is Fe2+ (ferrous) and Fe3+ (ferric). The different valence states of iron confer its redox properties. Fe2+ acts as an electron donor, whereas Fe3+ exists as an electron acceptor. The ferrous form of iron (Fe2+) is prone to being more toxic because of its ability to participate in oxidative bursts and form hydroxyl radicals through the Fenton reaction. Giving more iron during inflammation is not only counterproductive, it may be harmful.
Iron & Inflammation: Acute Phase Proteins
The mechanisms of iron shuttling and sequestration during inflammation has ancient evolutionary origins. These derive from the ability to prevent iron utilization by different types of pathogens, which also utilize iron. Good examples of these complex sequestration mechanisms can be seen in the genetic conditions, ß-thalassemia, hemochromatosis and sickle cell anemia. In thalassemia, the hepcidin-induced hypoferremia has been identified as a defense mechanism to prevent iron uptake by pathogens. Hemochromatosis, a condition characterized by elevated Ferritin and NTBI (non-transferrin bound iron), actually features deficiencies of iron in macrophages. This macrophage deficit of iron is a survival strategy to prevent the multiplication of intracellular bacteria inside this white blood cell type (Reuben, et al; 2017). In the case of sickle cell anemia, carriers of this genotype suffer deformity of red blood cells and aberrant hemoglobin, but with the survival advantage of having immunity from plasmodium, the parasite that causes malaria. This mechanism involves the host’s ability to sequester hemoglobin during polymerization, and prevent the parasite from generating haemozoin (Uzoigwe, 2010). Clearly, the acquired and inherited strategies involving iron sequestration are elaborate and necessary for maintaining homeostasis during infection and inflammatory signaling.
The acute phase relates to how inflammatory signaling alters various transport proteins in the blood. There are 6 iron-regulatory, acute phase proteins. That is, these proteins will either increase or decrease during inflammatory states. There are 2 types of acute phase proteins: positive (tending to increase during inflammation) and negative (tending to decrease during inflammation). The acute phase is mediated by immunological signaling molecules such as cytokines, and the 4 most influential in these regards are: IL-6, TNF-a, IFN-g and IL-1.
Transferrin, the most abundant iron-binding protein in plasma, has a much higher affinity for Fe3+ iron than Fe2+. Importantly, Transferrin is a negative acute phase protein; that is, it tends to decrease during certain inflammatory states. This is why a low TIBC (total iron binding capacity) is often reduced in inflammatory conditions; because the TIBC is mostly comprised of transferrin.
Ferritin, is a protein that stores or sequesters high amounts of Fe3+ iron, and is also a positive acute phase protein; it is increased by inflammatory signals. The Fe3+ iron stored by ferritin is conserved and does not participate in redox reactions. However, another iron-related product known as hemosiderin forms as a result of the breakdown of ferritin. The form of iron contained within hemosiderin is redox reactive and can generate hydroxyl radicals (Ozaki, et al; 1988). The induction of ferritin during the acute phase by IL-1 has been proposed as a trap to prevent haematopoiesis (synthesis of RBC’s). It has also been proposed that Neopterin (BH2) may act to increase ferritin levels (Means, 2004).
Hepcidin, is a regulatory protein that controls iron entry into cells. It is also a positive acute phase protein, tending to rise during certain inflammatory states. Control of hepcidin activity is a key for correcting anemia, as well as conditions of iron excess, such as hemochromatosis. It is of importance that Hepcidin has been characterized as a defensin anti-microbial peptide. During inflammation, hepcidin levels rise in response to the cytokines IL-1 and IL-6, and this leads to the binding and activation of the cellular iron exporter, ferroportin. The net effect is the inhibition of iron uptake by intestinal cells, export of iron from different cell types, and the induction of hypoferremia and anemia (Deschemin, Vaulont, 2013). It is now widely understood that Hepcidin and Ferroportin activities during inflammation and infection is one of the main driving mechanisms of iron anemia in these situations.
Haptoglobin is a positive acute phase protein. During inflammation, when red blood cells are damaged or hemolyzed, haptoglobin levels rise in order to bind the liberated, free hemoglobin. Under extreme oxidative stress conditions, haptoglobin levels can become depleted, and free heme can readily oxidize and create tissue damage.
Hemopexin is a positive acute phase protein. During inflammation, damage of red blood cells can cause the release of hemoglobin and constituent free heme. Hemopexin avidly binds free heme in order to prevent cellular and tissue damage. Additionally, hemopexin possesses important anti-inflammatory properties. In experimental studies, hemopexin can prevent pathways leading to autoimmune TH17 (Rolla, et al; 2013). Additionally, hemopexin expression down-regulates inflammatory cytokine expression induced by LPS (lipopolysaccharides) from macrophages (Liang, et al; 2009).
Ceruloplasmin is known to transport more than 90% of circulating copper. Ceruloplasmin is also a ferrooxidase; it oxidizes reactive, and harmful ferrous iron (Fe2+) to ferric Fe3+ iron for incorporation into transferrin. Ceruloplasmin is a positive acute phase protein; it tends to rise during inflammation. Ceruloplasmin is also unique in that it possesses antioxidant properties, containing both glutathione peroxidase and superoxide dismutase. In vitro research has identified that during inflammation, ceruloplasmin prevents the damaging effects of iron by forming complexes with both lactoferrin and myeloperoxidase. The net effect of these interactions works to maintain ceruloplasmin’s ferroxidase properties, maintaining the pool of Fe3+, as well as preserving the protein’s antioxidant actions (Samygina, et al; 2013).
The changing redox states of an organism (due to infection, inflammation, immune activation, pathology, etc.) directly affect the quantities and fate of Fe2+ and Fe3+, as well as where iron will go and how it will be used. During conditions of oxidative stress, iron activities are conserved, diverted and augmented. Under such conditions, iron may be used to create more inflammation, or the body will conserve iron utilization, or alter iron activities through the acute phase proteins.
Iron Supplementation Can Increase Toxic NTBI Iron (non-transferrin bound iron)
Non-transferrin bound iron (NTBI) represents an intracellular form of iron that is understood to play an important role in iron toxicity, inflammation and disease processes. NTBI is a form of iron that is particularly harmful because of its ability to generate intracellular ROS (reactive oxygen species), react with organelles within cells, and to create cellular damage (Brissot, et al; 2012). NTBI is not directly measurable on routine lab tests, so it’s detection is somewhat elusive.
NTBI represents a form of iron that is not bound to transferrin or ferritin, but accumulates in cells when transferrin proteins reach saturation. NTBI iron is bound to citrate, ATP and other organic molecules. NTBI is responsible for the intracellular and tissue damage observed in a variety of conditions such as cancer, neurodegenerative disease, autoimmune conditions, hemochromatosis, organ damage, ß-thalassemia, just to name a few.
Importantly, oral intake of ferrous iron supplements has shown the ability to increase the accumulation of NTBI iron, in both anemic and in normal subjects. In some studies, even low doses of iron were shown to cause elevations in NTBI iron (Dresow, Peterson, et al; 2007). Studies on the use of I.V. iron infusions have found similar elevations in toxic NTBI, and researchers in this area have begun to elucidate the molecular mechanisms of NTBI accumulation (Garbowski, Bansal, et al; 2021). Recognizing the potential harm to pregnant mothers and fetuses, a 2008 study called out the inherent risks of iron supplementation in pregnancy by way of increasing NTBI levels (Baron, David, Hallak; 2008). Moreover, oral use of ferrous iron in pregnancy is associated with a significant decrease in the antioxidant glutathione peroxidase (Khalid, et al; 2018).
Efforts to modulate the underlying inflammatory conditions that are driving anemia is a safer and more effective treatment than using intravenous or parenteral iron, in many cases. This is because the indirect augmentation of iron metabolic pathways will not lead to the accumulation of toxic NTBI iron, but rather reduce and resolve the inflammatory mechanisms that are driving the anemia.
Indirect Mechanisms for Modulating Iron Homeostasis: Safer & More Effective than Using Iron
Colostrum & Lactoferrin: Colostrum is the first mammalian milk produced. Clinically, it is derived from bovine or goat sources. Emerging evidence has revealed that colostrum possesses numerous properties that act to mediate both inflammation and iron activities. Lactoferrin, a constituent colostrum protein is a notable transferrin family protein with numerous iron-binding, anti-inflammatory and immune-modulating properties. Bovine-derived lactoferrin avidly binds ferric iron (Fe3+), and recent clinical studies have found lactoferrin attenuates anemia via the Hepcidin-Ferroportin inflammatory signaling pathways, namely through down-regulating the cytokine IL-6 (Lepanto, et al; 2018).
A 2022 study involved 80 anemic children with IBD (Amrousy, et al; 2022). Children were given either Ferrous sulfate 6mg/kg per day (n=40) or Lactoferrin, 100mg/day (n=40), for 3 months. Both groups featured increased serum iron, MCV (mean corpuscular volume), transferrin saturation and ferritin. However, the lactoferrin group outperformed the ferrous sulfate group by greater hemoglobin elevation, greater transferrin saturation, greater serum iron levels, and greater ferritin. Moreover, the level of hepcidin was significantly lower in the lactoferrin group. Inflammatory IL-6 (which increases hepcidin) was unchanged in the ferrous sulfate group, but significantly lower in the lactoferrin group (S).
Other lines of research have found that the administration of lactoferrin has been shown to increase hemoglobin synthesis and increase circulating iron levels in pregnant women (Paesano, et al; 2006). Moreover, lactoferrin reduces and inhibits the inflammatory mechanisms that lead to anemia in various disease states (Artym, et al; 2021).
Importantly, bovine colostrum and lactoferrin possess anti-viral and anti-bacterial properties. Colostrum is well known to mediate intestinal infection through several immunological mechanisms. This includes inhibiting intestinal bacterial overgrowth, reducing IL-8 mediated intestinal inflammation and neutralization of bacterial endotoxins (Chae, et al; 2018). Colostrum has been studied as highly effective at resolving acute diarrhea of viral, bacterial and parasitic origins (Barakat, et al; 2020), (Rump, et al, 1990). Moreover, evidence suggests that colostrum’s immunological properties extend beyond the gut. For example, research in children has found colostrum is an effective prophylactic for preventing symptomatic episodes and hospitalizations for upper respiratory tract infections (Saad, et al; 2016).
Lactoferrin on the other hand has been shown to enhance the phagocytosis and clearance of pathogens, acting to enhance, rather than prolong the immune response. Several human studies have found that lactoferrin can prevent UTI’s (urinary tract infections), upper and lower airway infections, reduce allergies, including TH2-mediated asthma and eosinophila, reduce atopic dermatitis, reduce or resolve bacterial vaginosis, and effectively treat chronic and acute conditions (Presti, et al; 2021).
Testosterone: Testosterone and other androgenic steroid hormones have been studied as effective treatments for anemia, dating back to the 1950’s. Testosterone is a notable inhibitor of hepcidin, thereby leading to the incorporation of iron into RBC’s (Guo, et al; 2013). Moreover, testosterone induces erythropoiesis, the formation of new red blood cells, as well as increases hemoglobin synthesis. Moreover, literature going back nearly 50 years demonstrates that testosterone metabolites such as etiocholanone also increase hemoglobin synthesis (Levere, 1974).
Testosterone also possesses notable anti-inflammatory properties. For example, research in aging men found an inverse correlation between declining testosterone levels and elevations in the cytokine IL-6 (Maggio, et al; 2006). Remember that IL-6 induces the expression of Hepcidin, which can induce anemia. Moreover, testosterone administration lowers IL-6, TNF-a, IL-1 and CRP (Bianchi, 2018), all of which are etiological in anemia.
Michael’s comment: Living in a rural Mexican village, I was able to witness firsthand how the administration of Testosterone Androgel could correct severe anemia in female, elderly patients. The effect of testosterone was shown to be immediate (begin working within hours), as evidenced by increased circulation, body temperature, improved cognition, energy and mental acuity. Correction of underlying inflammatory states through use of testosterone and extensive dietary and supplemental interventions led to the normalization of hematological parameters (serum iron, RBC, hemoglobin, MCV) without the use of iron or high iron foods.
Ascorbate, Whole Food Ascorbate: It is known that Vitamin C can therapeutically improve hematological parameters. For example, meta analysis research demonstrates that in kidney dialysis patients with anemia, Vitamin C therapy increases both hemoglobin as well as transferrin saturation parameters (Deved, et al, 2009).
There is ongoing debate that ascorbic acid and whole food vitamin C are not the same. While it is known that Vitamin C attenuates hematological parameters, there appears to be clinical evidence to suggest that ascorbic acid may adversely lower ceruloplasmin values, whereas whole food vitamin C may do the opposite. This may be significant because ceruloplasmin (the primary copper transporting protein in plasma) is also a ferroxidase; it converts harmful Fe2+ into Fe3+. More research is needed in this area.
Michael’s Comment: Raw, unprocessed vegetable juice was among the foundational dietary interventions used in Mexican patients with severe anemia. Concentrated vegetable juice is highly bioavailable, and will contain not only whole food vitamin C, but also minerals, such as copper, B-vitamins, and whole food antioxidants.
Copper & Ceruloplasmin: Copper is necessary to maintain iron homeostasis, whereas ceruloplasmin, copper’s primary transport protein is a ferroxidase, and is etiological in the conversion of Fe2+ into Fe3+. Deficiency of ceruloplasmin has been shown to cause iron accumulation in the liver and in other organs (Harris, et al; 1995). Copper deficiency can cause iron deficiency states, and can also produce low MCV similar to iron-deficient anemia. Remarkably, copper has a high affinity for hepcidin and the increased binding of copper to hepcidin enhances its anti-microbial effects (Maisetta, et al; 2010). Is this one reason why ceruloplasmin and copper levels tend to rise during the acute phase? More research is needed.
Genetics & Iron
Numerous genetic polymorphisms can affect iron activity in the body. These polymorphisms can alter how iron is stored, used and affected during inflammation. Some of these include:
- HFE (light chain ferritin): Associated with hemochromatosis
- HMOX (heme oxygenase): Acts both with pro and anti-inflammatory properties
- TRFC (transferrin receptor): Is the receptor for the transferrin protein. Polymorphisms are associated with diabetes
- HAMP (hepcidin): Polymorphisms are associated with a form of hemochromatosis
The Metabolic Healing Nutrigenomics report helps individuals and healthcare practitioners identify and address genetic polymorphisms. Based on your raw data from 23andme or AncestryDNA, our reports analyze hundreds of genes, including several iron-related.