Iron;Benefits or threatens (with emphasis on mechanism and treatment of its poisoning)

Abstract

Iron is a necessary biological element and one of the richest in the human body, but it can cause changes in cell function and activity control. Iron is involved in a wide range of oxidation - reduction activities. Whenever iron exceeds the cellular metabolic needs, its excess causes changes in the products of cellular respiration, such as superoxide, hydrogen peroxide and hydroxyl. The formation of these compounds causes cellular toxicity. Lack of control over reactive oxygen species causes damages to DNA, proteins, and lipids. Conversely, superoxide, hydrogen peroxide and hydroxyl are reactive oxygen species, using antioxidants, restoring DNA function, and controlling iron stores lead to natural conditions. Iron poisoning causes clinical manifestations in the gastrointestinal tract, liver, heart, kidneys, and hematopoietic system. When serum iron is elevated, serum iron concentrations, total iron-binding capacity (TIBC) and ferritin will also increase. Supportive care is provided by whole bowel irrigation (WBI), esophagogastroduodenoscopy is required to evaluate mucosal injury and remove undissolved iron tablets. The use of chelator agents such as deferoxamine mesylate, deferasirox, deferiprone, deferitrin are very effective in removing excess iron. Of course, the combined treatment of these chelators plays an important role in increasing iron excretion, and reducing side effects.

Introduction

For a few decades, access to a variety of chemicals has been unexpectedly easy and improved.^1,2 These chemicals may be used incorrectly and in some cases if necessary, they may also cause poisoning accidentally, intentionally or due to repeated use. ³ Some of these agents are heavy and rare metals. These substances are derived from natural sources or industrial waste as a supplement and in some cases for treatment, and this causes a risk to human health.^4,5 According to research and knowledge, iron is biologically necessary for numerous organs of the human body. Adverse effects of iron occur within the cell. This element alters mitochondrial function and prevents oxidative phosphorylation, thus leading to anaerobic metabolism. Iron poisoning is very rare in adults, but most researchers report iron poisoning in children. ⁶

Iron is a white or gray silver metal with the symbol Fe. It is one of the three magnetic elements in nature and is flexible and conductive, also has an actual high tensile power. This capability provides the conditions in which the stretching process can be performed without breaking. Iron has an atomic number of 26, an atomic mass of 55.847, melting point of about 1536°C and a boiling point of about 3000°C. However, the comparison of all the physical properties mentioned in pure iron and steel alloys is different. Natural and stable isotopes of iron include: iron-54, iron-56, iron-57, iron-58. Generally, 24 radioactive isotopes are known, of which iron- 60 is the most stable with a half-life of 2.6 million years and iron-55 with a half-life 2.7 years. Iron-55, iron-59 are used in medical and scientific research, these isotopes are primarily used as tracers in blood studies. In fact, these two radioisotopes are used to study the growth process of red blood cells in the body.^7,8

Iron combines with oxygen in humid air to produce iron oxide, the reason would be that iron is an active metal. Iron oxide is also known as rust. In addition, iron reacts with hot water and steam, which produces hydrogen gas and reacts with many elements and dissolves in most acids. ⁷

The characteristics and role of iron in human health

Physiology and biochemistry

Iron is one of the most copious elements, ⁹ and is an essential biological element for all living creatures.^10,11 It has a lot of biological adaptability, which shows itself as oxidation-reduction reaction, ¹² but due to all the abundance of iron in the earth, it is known as a limiting factor for growth. ⁹ This contradiction is based on the fact that the combination of iron with oxygen produces highly insoluble oxides, which are not readily available for the absorption of living organisms. There are different cellular mechanisms for the transport of metals, including iron, in different organisms. Cells also manage the toxicity of metals through several mechanisms, such as enzymes that neutralize radicals, intracellular metal chelators, and controlling the transport of metals through membranes. ¹³ In humans, iron binds to protein in two ways: 1- heme compounds, 2- non-heme compounds. The body needs iron to synthesize oxygen-carrying proteins, especially hemoglobin and myoglobin, as well as forming heme and other iron-containing enzymes to transfer electrons and reduce the oxidation of iron. ⁹ In general, heme consumes about 15 to 35% and even 40% of the total absorbed iron. Non-heme iron is less absorbed than heme iron. Based on the balance between inhibitors and enhancers and the body iron situation, all non-heme iron that enters the gastrointestinal tract through diet will be absorbed. It should be noted that not all reinforced iron enters the common pool. ¹⁴ Circulating transferrin also transports iron released from enterocytes or reticuloendothelial macrophages to tissues. Transferrin-bound iron is internalized via the transferrin 1 receptor (TfR1). The second transferrin receptor (TfR2), which has less synthetic affinity for iron than the first transferrin receptor (TfR1), has a regulatory action in the liver and erythroid cells. It can be claimed that almost all circulating iron is bound to transferrin under physiological or normal conditions. However, in cases where the body experiences an increased iron load or iron poisoning, the excess iron in the plasma is called non-transferrin bound iron (NTBI). Currently, it has been proven that non-transferrin bound iron is responsible for iron overload in parenchymal cells. Importantly, on the cell surface, transferrin receptor 1 (TfR1) leads to endocytosis and metal uptake, then iron enters the cell and into the mitochondria to be used in heme and other compounds synthesization, excess iron is also stored and cytosolic ferritin is detoxified. The above actions are disrupted in iron overload or iron poisoning.^9,15

Metabolism

Absorption

Under normal circumstances, 35 mg/kg and 45 mg/kg of iron are available in female and male adults, respectively. Of this amount, about 60 to 70% is present in hemoglobin. 10% of iron is in the form of cytochromes, myoglobin, and iron-containing enzymes. The rest of the excess iron, 20 to 30%, is stored as ferritin and hemosiderin in hepatocytes and reticuloendothelial macrophages. The part of iron absorbed from the amount consumed is usually small, but depending on the condition and type of iron it can be between 5 and 35%.^9,16 As mentioned, enterocytes absorb iron through the transport of divalent metal transporter 1 (DMT1). This uptake primarily occurs in the duodenum and upper jejunum through the bloodstream. It is then carried to bone marrow to produce red blood cells.^17–19

The absorption and distribution of iron in tissues is done by an important regulator called hepcidin; a peptide with 25 amino acids. Hepcidin plays a balancing role in iron deficiency and iron overload. Hepcidin regulates iron balance by limiting and releasing iron. Thus, with increasing iron absorption, iron deficiency will be solved. Conversely, iron overload reduces iron absorption through hepcidin. It is now accepted that iron uptake is performed by ferroportin. This transporter controls whether or not iron enters the plasma from the mucosal cell. ²⁰ Ferrous iron is oxidized to insoluble ferric iron under usual conditions and physiological pH. The fact that the gastric acidity is lower than the proximal duodenum, and in the intestinal lumen, ferric reductases cause changes on ferric iron, allows the transfer of ferrous iron into the enterocyte membrane. This process increases the solubility of ferric iron. If stomach acidity is reduced, iron absorption will be impaired. ⁹ The mechanism of dietary heme transmission is unknown but its transportation is through the apical membrane, where it is metabolized by the oxygenase in enterocytes and ferrous iron is released. ²¹ The performance of this process is higher than the absorption of mineral iron, it will have an independent way and is not affected by duodenal pH. Accordingly, the process will not be affected by inhibitors such as phytates and polyphenols. As pointed out above, when the iron in the diet; ferric iron, is reduced to ferrous iron by cytochrome b reductase, it will be absorbed by divalent metal transporter (DMT1) through the duodenal membrane. Ferrous Iron passes through the cytoplasm of enterocytes, where ferrous iron is transported by ferroportin (FPN1) and before binding to transferrin in the circulatory system is converted to ferric iron by multicopper ferroxidase hephaestin. ²²

The uptake of ferrous iron in humans by the ferritin protein contrasts with the transport of single iron atoms by the divalent metal transporter (DMT1) as ferrous iron, whether the iron contained in ferritin in the body is converted to single atoms in the stomach or intestine, or is ferritin absorbed as an intact protein-iron complex? Past in vivo or in vitro studies have measured iron uptake through ferritin, contradictory findings related to iron uptake in humans in this field and the challenge of isotopic labeling of iron in ferritin molecules. It has recently been suggested that the iron in ferritin is protected by iron inhibitors through the body of the protein, which allows it to increase iron absorption. Studies show that any residual iron-ferritin compound, whether soluble as intact ferritin, as denatured insoluble ferritin, or as a bare mineral nucleus, its solution during gastric digestion depends on pH. The uptake of released and dissolved iron is done through the divalent metal transporter-1 pathway for non-heme iron. Finally, it can be said that similar sensitivities occur in enhancers and inhibitors of iron absorption.^23,24

Regulation of iron homeostasis

Iron absorption is a necessary factor to regulate iron balance, and since humans do not have a mechanism for active excretion of excess iron, iron balance is solely maintained by absorption. Continuity of balance between absorption, transport, storage and utilization is required in maintaining iron homeostasis. Whenever an imbalance occurs, an increase in iron deposition occurs in the tissue. When reactive oxygen species increase, tissue damage and organ failure can occur.^25,26 The hormone hepcidin is a peptide with 25 amino acids that is the main controller of iron absorption and distribution in tissues. It is mainly synthesized in liver cells, and also in smaller amounts in other cells and tissues, including brain, fat cells, macrophages, and is important for the control of autocrine and paracrine iron. Therefore, it is the most important regulator of systemic iron homeostasis and balances the use and storage of iron with iron access.^20,27 The hepcidin and ferroportin (Fpn) bonds are absorbed throughout the surface of intestinal enterocyte cells, macrophages, hepatocytes, and placenta, all of these cells release iron into the plasma.^27,28 The lack of ferroportin prevents iron from entering the plasma. Consequently, transferrin saturation will occur less because of the reduction of iron in plasma and less iron being carried to the developing erythroblast. In contrast, a decrease in hepcidin leads to an increase in ferroportin cell levels. In other words, hepcidin-ferroportin regulation can regulate plasma iron and iron intake.^9,29

Different factors such as plasma iron levels, anemia, hypoxia, cytokines such as interleukin 6, BMPs and TGF-β, Other regulatory molecules, including TFR2(BMP type II receptor) and SMAD7 participate in regulation of plasma hepcidin. If hepcidin expression is disturbed, iron disorders can occur. ²⁸ There are two states of hepcidin expression; 1- Overexpression and 2- Underexpression of hepcidin. Mutations in four genes lead to impaired hepcidin expression: transferring receptor 2 (TFR2), hemochromatosis (HFE), hemochromatosis type 2 (HFE2), hepcidin antimicrobial peptide (HAMP). The most important gene is HAMP, the gene that encodes hepcidin. The role of genes TFR2, HFE, HFE2 in regulation of hepcidin is uncertain. Decreased regulation of hepcidin synthesis leads to increased iron release; the main cause of non-HFE hemochromatosis, classic HFE hemochromatosis and thalassemia syndromes. Also, anemia and hypoxia both reduce hepcidin levels. Under these conditions, liver cells are overloaded with iron, because it is believed that iron bound to transferrin in the bloodstream exceeds ferroportin-mediated excretion. Hepcidin deficiency increases ferroportin-mediated iron secretion, thereby increasing the uptake of iron in enterocytes and, perhaps more importantly, the excretion of recycled iron into plasma transferrin by macrophages and into cell storage by hepatocytes. Conversely, in response to overexpressed hepcidin, chronic diseases and anemia occur. Also, in chronic diseases, the production of cytokines happens. In this case, iron is stored by key cells: enterocytes, macrophages, and liver cells. Under these conditions, i.e., increased hepcidin synthesis, the hepatocyte responds to increased transferrin iron saturation or increased iron stores in hepatocytes by inducing hepcidin synthesis. This reaction is still unknown, so the physiological response to iron overload is normally hepcidin-mediated decrease in iron uptake (enterocytes), recycling (macrophages), and storing (liver cells).^28,30

Storage

After intracellular exchanges between ferritin and hemosiderin, Iron exchange takes place between plasma and iron storage cells, which is called iron storage. Therefore, the concentrations of ferritin and hemosiderin reveal the body's iron stores. The iron stored in the liver, spleen and bone marrow is insoluble. In iron deficiency, iron storage will be less than 100 mg and serum ferritin will be less than 12 ng/ml. The level of stored iron controls the absorption of iron. It is noteworthy that in iron deficiency, the ratio of ferritin iron to hemosiderin iron enhances. After treatments such as phlebotomy, stored iron is restored by hemosiderin decreases. The important point will be that; in iron overload, the ratio of ferritin to hemosiderin iron decreases and the rate of iron conversion between ferritin and hemosiderin decreases as the iron supply increases. In iron overload, the iron storage will be more than 4 g and serum ferritin will be more than 250 ng/mL. ³¹

Excretion

In theory, the body's iron level is defined by the balance between absorption and excretion. The biological status of iron is determined by the amount of iron absorbed and is prominently regulated by hepcidin. Unlike iron absorption, iron excretion is based on the base amount, regardless of iron deficiency or excess iron. Specialists believe that excretion happens in the process of intestinal epithelium turnover, blood loss, dead skin exfoliation, and in women following menstruation and childbirth. It is essential to note that; one of the main ways of iron excretion is through the circulation of the intestinal epithelium, also in mammals, the intestinal epithelium will change in less than a week. In addition, renal iron excretion is negligible, and the hepatobiliary system plays a minimal role in iron excretion.^32,33

Mechanisms of iron poisoning

Iron is a transition metal that participates in reduction- oxidation reactions, and therefore plays a major role in biology. On the other hand, it can be a potentially dangerous metal, and applies its effects through a combination of constituent (translation) and induction (transcription) mechanisms. ³⁴ As mentioned, iron has access to extensive series of reduction- oxidation potentials and can contribute in a lot of electron transmission reactions with a normal reduction- oxidation. Whenever iron exceeds the cellular metabolic needs, a low molecular weight reservoir may be formed, called a mobile iron reservoir, which changes natural cellular respiration products such as superoxide anion (O₂^-) and hydrogen peroxide (H₂O₂). Highly harmful hydroxyl radicals (• OH) are bridged by the Fenton reaction (first reaction) or Fe²⁺ catalysis in the Haber-Weiss reaction (second reaction), or by free ions or oxygen to the Fe²⁺/Fe³⁺ complex. Fe³⁺ can be reduced by O²⁻ (third reaction) or by ascorbate to produce more radicals.

${\mathbf{F}\mathbf{e}}^{2+}+{\mathbf{H}}_2{\mathbf{O}}_2\to {\mathbf{F}\mathbf{e}}^{3+}+{\mathbf{H}\mathbf{O}}^{-}+•\mathbf{O}\mathbf{H}$

(1)

${\mathbf{O}}_2^{-}+{\mathbf{H}}_2{\mathbf{O}}_2\to {\mathbf{O}}_2+{\mathbf{H}\mathbf{O}}^{-}+•\mathbf{O}\mathbf{H}$

(2)

${\mathbf{F}\mathbf{e}}^{3+}+{\mathbf{O}}_2^{-}\to {\mathbf{F}\mathbf{e}}^{2+}+{\mathbf{O}}_2$

(3)

Two specific iron-binding proteins, extracellular transferrin (Tf) and intracellular ferritin (Ft), provide toxic effects of the combination of iron and oxygen. Fe preserved as Fe³⁺, unless their motion can effectively catalyze the making of free radicals. Iron is stored inside the cell, where it can cause the most damage.^35,36 Inside the cell, iron concentrations are detected by iron-regulatory proteins 1 and 2(IRP1 and IRP2). On the mRNAs, iron-regulating proteins bind to iron regulatory element (IRE) sequences when iron is low in the cytoplasm. The IRE/IRP-regulated mRNAs comprise ferritin, transferrin receptor, one isoform of DMT-1, and ferroportin. The important point is that as the extracellular iron concentration is normal, the IRP/IRE system protects cell iron homeostasis. The protection is achieved by modifying the uptake, storing and release of the proteins involved. This adjustment is made concerning the concentration of iron in cytoplasm. ²⁶ Systemic regulation of iron results in constant maintenance of iron-transferrin in plasma and extracellular fluids. ²⁶ These proceedings occur by setting the main actions in plasma: Recycling old red blood cells and releasing iron from macrophages, use of iron stores from liver cells, adsorption of dietary iron from duodenal enterocytes, in addition, during pregnancy, iron is transferred from mother to fetus through the placenta. Finally, iron is released from all of the above tissues, transmitted via ferroportin and regulated by hepcidin. Iron as well as other conditions such as anemia and hypoxia also regulate hepcidin. This process between ferroportin and hepcidin regulates the systemic iron concentration, and is followed by tissue distribution.^27,37

The work of a group of researchers in this field has shown that a hormone called hepcidin, a significant factor in the systemic regulation of iron homeostasis, is produced in the liver, and contains 25 amino acids and is a component of antimicrobial peptides. It binds to ferroportin and passes through the membrane and directs iron out of the cell. Ferroportin is expressed in the basolateral membrane of enterocytes and the plasma membrane of macrophages, in fact, the places where iron is released from cells into the plasma. On the other hand, hepcidin binds with ferroportin, internalizes and destroys ferroprotein in lysosomes, and accordingly, hepcidin activity reduces the absorption of iron in the diet and decreases the release of recycled iron from macrophage storage. In humans, lack of hepcidin gene due to mutation leads to juvenile hemochromatosis (JH), a disease that causes iron to deposit in large amounts in vital organs.^29,38 Hepcidin production occurs in reaction to numerous physiological stimuli. When the expression of hepcidin occurs, the iron load increases, thus limiting the absorption of iron from the diet. In contrast, in anemia and hypoxia, hepcidin will be suppressed, creating the conditions for the accessibility of iron to red blood cells. In this way, systemic iron balance will be achieved. ³⁸ Detoxification of excess iron is achieved by trapping and storing iron in ferritin molecules. This is accomplished by closely controlling ferritin synthesis. Proteins are now known to be involved in the transport of iron in and out of cells. In fact, the interface of cytosolic iron levels with iron-regulating proteins controls the uptake and storage of cellular iron, and under normal circumstances, prevents toxic cytosolic iron concentrations. However, in some cases, this protective mechanism is not sufficient. Physiological failure of iron absorption leads to intoxication. ³⁴

In hemochromatosis and other conditions caused by iron overload, the plasma iron binding to ferritin increases, which significantly increases free plasma iron. Such iron can reach very high concentrations in pathological conditions without non-transferrin bound iron (NTBI),^39,40 and is rapidly cleared from the plasma by liver and other organs. As a result, progressive accumulation of iron occurs in these tissues and can cause toxicity.^41,42 It is assumed that, iron without binding to transferrin is not toxic in plasma, but a labile component of iron without binding to transferrin enters the cell, which has potentially toxic and harmful properties. Researchers have recently identified labile plasma iron (LPI) as a component of iron without binding to transferrin that has reduction-oxidation activity, and the ability to enter organs and iron overload in tissue. In addition, intracellular labile iron can degrade ferritin. ⁴⁰ When the capacity of labile iron is catalyzed, it produces reactive oxygen radicals, which cause cytotoxicity and damage to cell macromolecules to a large extent. Reactive oxygen species (ROS) are harmful, but during normal metabolism are also formed in organs such as mitochondria and peroxisomes. There are numerous reactive oxygen species (ROS), including superoxide anion, hydroxyl radicals, alkoxyl radicals, peroxyl radicals, hypochlorous acid, and proxy nitrite. Extensive cellular damage occurs as a result of the activity of these radicals if they are not controlled. Lack of control over radicals causes them to attack DNA, proteins, and lipids. According to studies, the main pathways of damage caused by reactive oxygen species are peroxidation of cell membranes and organelle lipids. It is noteworthy that the hydroxyl radical attacks biomolecules and has a specific reactivity, however, some lipid-derived hydroperoxide radicals play an important role in intensifying lipid peroxidation activity.^41,43

In normal conditions the body will defend itself against the unlimited accumulation of reactive oxygen species (ROS) and its adverse effects in numerous ways. These include numerous enzymes that break down ROS, antioxidants, repair functions (e.g., DNA repair), and iron storage mechanisms. Also, the results of several articles suggested the fact that ferritin plays a supportive role against damage caused by free oxygen radicals. This procedure is performed by iron-regulating proteins (IRPs) that regulate the intracellular iron metabolism, such as hepcidin. In this way, the body’s iron homeostasis will be regulated. In addition, intracellular storage of iron in ferritin and.^41,43,44

Due to the formation of reactive oxygen species and lipid peroxide, and on the other hand, the production of hydrogen peroxide in the Fenton reaction, as well as ferroptosis, which causes the loss of the lipid repair enzyme glutathione peroxidase 4(GPX4) and the subsequent accumulation of lipid-based reactive oxygen species, especially lipid hydroperoxides, cell death Iron-dependent occurs, because ferroptosis does not require caspases, ATP depletion or mitochondrial ROS production, Bax/Bak (mitochondrial outer membrane permeability mediators) and intracellular Ca²⁺ increase. Therefore, with these descriptions, iron poisoning has a fundamental and basic role in the physiopathology of severe injuries in cardiomyocytes, hepatocytes, microglia, etc., and it causes diseases such as heart failure, liver failure, kidneys failure, and several different types of neurodegenerative diseases.^45–47

Clinical manifestation

Iron poisoning is related to the amount of iron absorbed. Iron poisoning can even have serious consequences, and result in death. ⁴⁸ Manifestations of oral iron poisoning include a number of symptoms that appear in the advanced stages. Early symptoms or the first stage that occurs in the first 6 h include vomiting, diarrhea, abdominal pain, gastrointestinal bleeding, and these patients may develop hypovolemia due to fluid and blood loss.^48,49 In fact, these symptoms are due to direct damage to the mucosa or part of the symptoms of corrosion. But there is another toxicity, known as cytotoxicity, which occurs by absorbing large amounts of iron. Impaired oxidative phosphorylation and mitochondrial dysfunction, two major disorders in iron overload, which can cause cell death. The liver, heart, kidneys and hematological systems are exposed to iron cytotoxicity. ⁴⁸

Early symptoms include shock or metabolic acidosis with a positive anion gap. Stage II occurs within 12 to 24 h after ingestion and may involve a transient relief from gastrointestinal symptoms. Nevertheless, hypoperfusion and metabolic acidosis are possible. Stage three takes place within 24–48 h after ingestion. It is noteworthy that recurrent vomiting and gastrointestinal bleeding occur which lead to shock and metabolic acidosis. As a result, patients suffer from hypovolemia and cardiogenic shock due to direct poisoning of the myocardium. ⁵⁰ The fourth stage, which is associated with hepatotoxicity, happens 48 h after oral iron intake in surviving patients. Finally, the fifth stage, which occurs 2 to 4 weeks after oral administration, is accompanied by pyloric stenosis and intestinal obstruction. ⁴⁸

In general, cardiovascular dysfunction, mental condition (status) changes, gastrointestinal bleeding, liver and kidney failure will occur in iron poisoning ⁴⁸ (44). The clinical stages of iron poisoning are summarized in Table 1. ⁵⁰

Table 1.

Different clinical stages of iron poisoning.

Stage	Symptoms	Time of use
1	Vomiting, diarrhea, gastrointestinal bleeding	0–6 h
2	Transient relief of GI tract symptoms	12–24 h
3	Return of gastrointestinal symptoms, metabolic acidosis, shock, acute respiratory syndrome	24–48 h
4	Hepatotoxicity, leads to recovery	Over 48 h
5	Vomiting, obstruction of gastric outlet	2–4 weeks

Diagnostic evaluation

Laboratory evaluation

The main reason for doing laboratory tests is to find out the clinical complications caused by iron poisoning (such as metabolic acidosis, liver damage, blood coagulation, and anemia). Laboratory evaluation for iron poisoning should be performed for any patient with symptoms of systemic toxicity, consumption of unspecified amounts of iron, and/or consumption of more than 40 mg/kg of iron (30 mg/kg of iron in children). ⁵¹

Serum iron concentration

A common method of evaluating poisoning severity is to measure serum iron concentration, although its interpretation will be complex. There are few studies on the kinetics of iron in acute overdose. Plasma concentrations are likely to peak within 4 h and then decrease quickly; hence, using a single concentration, especially in the first few hours after ingestion, is hard as a way to assess the severity of intoxication Even serum iron testing, with its slow release formulation, is less commonly used. Only free iron is toxic in circulation, but it is not useful for the patient to measure the total iron binding capacity because this mistake may increase after over-consumption. Based on limited data, it is suggested that if the initial serum iron concentration is 5000 micrograms per liter (90 micromoles per liter) or more, deferoxamine treatment is indicated and the patient with clinical characteristics is considered important for iron poisoning. ⁵² When the amount of serum iron levels is between 300 and 500 micrograms per deciliter, asymptomatic or mild symptomatic, it does not pose a serious risk to the patients if they are brought to medical centers in suitable time. Serum iron levels of 500 to 1000 micrograms per deciliter are moderate to severe poisoning. Patients with a level greater than 1000 micrograms per deciliter usually have severe toxicity and a high risk of death. ⁵⁰

Determining the need for patient admission and chelation therapy based on iron serum concentration is questionable. The contradictory point can be made as follows; there are patients who have a high serum iron concentration of 500 micrograms per deciliter or more but have no systemic symptoms and should not be treated with deferoxamine. On the contrary, there are patients who have cardiovascular instability but the iron concentration is less than 500 micrograms per deciliter. Therefore, it is not possible to rely on the concentration of serum iron and solve the patient's problems. ⁵³

Total iron binding capacity

Total iron binding capacity cannot be used to manage patients with iron overdose. ⁵⁰ Serum iron-binding capacity measures the amount of iron in the blood that needs to bind to transferrin. In theory, there is no free iron when the total binding capacity of serum iron is greater than the concentration of serum iron, or when the concentration of serum iron exceeds the binding capacity of transferrin, unbonded or “free” iron unbounded or “free” iron has systemic toxic effects. This hypothesis has not been confirmed clinically. However, the laboratory methods (such as magnesium carbonate or iron absorption resin, etc.) used to measure the total binding capacity of serum iron in patients with excessive iron intake are incorrect. Therefore, it is not yet clear whether proper TIBC measurements can help medical decisions about chelators. In addition, to prevent errors in measuring iron and TIBC in the presence of deferoxamine, it is necessary to take a 4-h interval between the last use of deferoxamine and assess these two tests. ⁵⁴

Other tests accessible

Hyperglycemia and leukocytosis are known to play a part in stress in children and adults, but this role cannot be attributed to iron poisoning. Because the serum iron concentration less than 500 micrograms per deciliter with signs and symptoms of iron poisoning is considered insignificant. Gastrointestinal symptoms and a positive abdominal radiograph are not expected to differentiate the severity of iron intake. ⁵⁵

Radiographic evaluation

Patients who may be consuming more than 30 mg/kg of iron or have significant symptoms should have an X-ray of the abdomen. In abdominal radiographs, if undissolved iron tablets are visible, further procedures such as whole bowel irrigation should be performed. Complete whole bowel irrigation should be continued until the abdominal films are cleared of undissolved tablets. If iron tablets are not observed on the abdominal radiograph, it does not mean that the iron tablets are not significantly present. ⁵¹ With industry support and processing software, imaging techniques have become the standard care for patients. Computed tomography (CT) and MRI can be used to diagnose iron overload. CT scan shows a view with increased homogeneity in the liver parenchyma. CT scan for detecting iron overload has low sensitivity (63%) and high specificity (96%). ⁵⁶ Magnetic resonance imaging (MRI) evaluation has become increasingly important for the determination of tissue iron in the treatment of iron overload, because it is non-invasive and relatively widespread, and provides a diagnostic method for the dysfunction of asymptomatic organs. Magnetic resonance imaging is the best non-invasive method for measuring iron levels in the liver to confirm the diagnosis, determine the severity and monitor the treatment with sensitivity, specificity and positive and negative predictive value. These techniques have the ability to be replicated in the evaluation of internal organs and have been approved.^56,57

Deferoxamine challenge test

When deferoxamine is given intravenously, it will bind to Fe³⁺ to form ferrioxamine, which is excreted in the urine. The color of urine containing ferrioxamine can change to brick orange or “vine-rose”. The deferoxamine challenge test involves administering an intramuscular dose of deferoxamine and then waiting to see if the patient’s urine is “vine- rose” or not? However, various reports differ in patients with serum iron concentrations greater than 500 micrograms per deciliter. In some cases, there is a discoloration of the urine and in others, there is no discoloration of the urine. Therefore, deferoxamine challenge testing is no longer recommended. ⁵⁸

Treatment

The treatment of patients with iron poisoning begins with supportive measures. Detoxification with a whole bowel irrigation can be helpful. Treatment with iron chelators increases iron excretion in patients who have been severely poisoned.

Supportive care

All patients with iron poisoning or iron overdose of more than 60 mg/kg or gastrointestinal symptoms should have vital signs, gastrointestinal bleeding, dehydration, acidosis, arterial blood gas, electrolytes, and preferably hospitalization in intensive care unit is required. ⁵⁹ Clinical manifestations in individuals, even if the corrosive dose is the same, can range from mild gastrointestinal disorders to hypovolemic shock, metabolic acidosis, and liver failure. The important point is that; treatment should be started at the earliest opportunity in all cases. Actions to follow include; vital signs stabilization, reducing the absorption of iron compounds, cleaning the stomach and intestines, which depends on the amount of medicine and the time of ingestion. Induction of vomiting is performed with ipecac-induced emesis or gastric lavage, in some cases esophagogastroduodenoscopy is required to remove iron tablets and assess mucosal damage. ⁶⁰

Limit absorption

Large volume lavage through the nasogastric tube should be performed in all cases. Whole bowel irrigation with Peglec powder is very effective. Abdominal imaging of the pills in the pylorus or throughout the gastrointestinal tract can be helpful. In case an abdominal X-ray is not possible, it is better to do a whole bowel irrigation to clean the bowel quickly and effectively. Peglec powder is safe for children and does not change fluids and electrolytes. ⁵⁹ If the iron tablets accumulate and tend to compress, and the sticky compound of the tablets close the passage of the lavage tube, activated charcoal will not be effective because the metabolic ions of iron will not be absorbed. ⁶¹ For patients who have consumed large amounts of iron, and since there is no other way to detoxify the gastrointestinal tract, a whole bowel irrigation is recommended. The constant release of coated intestinal tablets is another sign of a whole bowel irrigation function. In particular, abdominal X-rays show iron tablets in the pylorus or throughout the gastrointestinal tract radiopaque. Although whole bowel irrigation, especially in children, causes the drug to be absorbed from the gastrointestinal tract, and the contents of the bowel to be emptied, there is no conclusive evidence and it is not agreed upon by the American Academy of Toxicology. However, most clinical toxicologists suggest that it will be the safest method of detoxification in the gastrointestinal tract and this method is useful.^61,62

Deferoxamine

Deferoxamine, under the brand name Desferal, is a special chelator for patients with acute or chronic iron overdose, introduced for use in the 1960s [Figure 1(a)]. Deferoxamine has a high affinity for iron, so in the presence of ferric iron (Fe³⁺), it is converted to the ferrioxamine complex, and is excreted in the urine to as a reddish brown color by kidneys. Deferoxamine chelates free iron and iron transferred between transferrin and ferritin, however this does not work for iron in transferrin, hemoglobin, hemosiderin or ferritin. In addition to binding to excess systemic iron, deferoxamine may work by other mechanisms. There is abundant research and evidence that deferoxamine reaches to free iron in the cytoplasm and mitochondria and reduces intracellular iron toxicity, so taking 100 mg deferoxamine chelates 8.5 mg ferric iron, although this amount will not be high, but will have important clinical advantages. ⁶³

Figure 1.

Chemical formula of deferoxamine mesylate (a), deferasirox (b) and deferiprone (c).

For patients with iron overload in acute and chronic conditions, deferoxamine is a specific iron chelator. It is recommended in severe poisoning (e.g., metabolic acidosis, shock) or serum iron concentrations greater than 500 micrograms per deciliter, which is an acute condition. The standard dose for infusion is 15 mg/kg/h, but to prevent hypotension that occurs following rapid infusion, specialists recommend starting infusion at lower doses. ⁶⁴ Deferoxamine is administered early in the intoxication period, while most iron is available in the serum for a short time to prevent side effects from long-term infusion. Due to the very high serum iron concentration, the infusion rate of deferoxamine is increased to at least 15 mg/kg/h to 40 mg/kg/h if the patient can tolerate it. ⁶⁵ Side effects of deferoxamine include hypotension, which occurs during the initial use of deferoxamine. This effect appears to be associated with rapid injection and may be due to histamine secretion. It is generally preventable by preparing fluids. This is preferred to slow the rate of deferoxamine injection, which should be kept low at all times. Acute lung injury and acute respiratory distress syndrome (ARDS) are common side effects after deferoxamine treatment in acute iron overdose. This pulmonary toxicity has been shown in animal studies following the use of high-dose deferoxamine, even with high oxygen concentrations (fraction of inspired oxygen of 70 to 80%). The researchers say this effect occurs through a free radical oxygen mechanism.^63–66

Deferasirox (Exjade) [Figure 1(b)] is another drug that is a sufficiently effective and tolerable chelator. It is a triple iron chelator, and requires two molecules to form a stable complex with each iron atom (Fe³⁺). The active molecule has high lipophilic properties and binds to proteins up to 99%. Main properties of deferasirox are:

1. It has a high affinity for ferric iron (Fe³⁺), and this affinity is 14 times more than copper [Cu²⁺] and 21 times more than zinc [Zn²⁺].

2. Oral bioavailability

3. Very valuable and capable

4. It has the ability to be effective in different doses.

5. It has a long half-life of about 8 to 16 h, so it is used in a single dose [Some sources cite a half-life of 11 to 19 h]

6. It is well tolerated.

Due to its long half-life, it will be taken once a day, with a standard dose of 20 to 30 mg/kg/day (but the appropriate single dose is 2.5 to 80 mg/kg/day). The tablets are mixed with water, orange juice or apple juice to form a good suspension. It is easy to use, especially for children, and any remaining will be swallowed with a small amount of water. Accordingly, deferasirox is taken 30 min before meals on an empty stomach.^67,68

Deferiprone

Deferiprone, a bidentate chelator that binds to iron in a 3:1 ratio [Figure 1(c)] has been used around the world for many years. It binds to iron about 6 times more than deferoxamine. Because it is excreted in tissues and enters the bloodstream rapidly, higher levels of serum iron have been evaluated in laboratory animals receiving deferiprone. Its half-life is about 1.5 to 2.5 h; less than deferasirox, so 75 to 100 mg/kg per day is consumed in three divided doses. If the patient has neutropenia, agranulocytosis (very rare) and arthropathy, the drug should be discontinued. Studies have not reported gastrointestinal and hepatotoxicity, especially hepatic fibrosis. The effect of deferiprone on reducing hepatic iron concentration varies, but it is thought to be comparable to deferoxamine. Its main ability is to enter the cardiac myocytes and take out iron of these cells, thereby improving myocardial function and reducing mortality due to iron deposition in the myocytes of the heart. As mentioned, the use of oral deferiprone is relatively safe and effective. When deferoxamine is not found in a medical center, it may be a viable alternative to save the lives of patients with acute iron poisoning.^69,70

Deferitrin

Deferitrin is an active tridentate oral iron chelator [Figure 2(a)]. In animal studies it has been shown that it is an oral iron chelator that excretes it well, its disadvantage is renal toxicity, so it has been tried with molecular chemical changes in numerical derivatives in 2, 3, 6, 7, 8, 9 and 10 in order to modify and limit its toxicity, this has been realized in animal studies. The dose was the same at all levels, ranging from 3 to 15 mg/kg. The half-life of the drug is 2 to 4 h, therefore, with this amount, the daily dose is not enough. Hypoglycemic coma is not thought to be related to deferitrin in patients with prediabetes. No laboratory abnormalities or electrocardiogram changes occurred.^70,71

Figure 2.

The chemical formula of deferitrin (a), pyridoxal isonicotinoyl hydrazone (PIH) (b) and HBED (c).

Pyridoxal isonicotinoyl hydrazone

Pyridoxal isonicotinoyl hydrazone is a tridentate iron chelator identified in 1979 [Figure 2(b)]. When given orally to mice with iron overload, pyridoxal isonicotinoyl hydrazone analogues are more effective than deferoxamine in removing liver iron (2.6 to 2.8 times), but deferoxamine works better in removing iron from cardiac myocytes. Pyridoxal isonicotinoyl hydrazone has a synergistic effect with deferoxamine, and could be used in combination chelating therapy in future. Further studies and research are required to assess the potency of this drug. ⁷¹

N, N-bis (2-hydroxybenzyl) ethylenediamine-N, N-diacetic acid

N, N-bis (2-hydroxybenzyl) Ethylenediamine-N, N-diacetic acid is a synthetic hexadentate ligand [Figure 2(c)]. Like deferoxamine, it also has a high affinity and selectivity, and forms a 1:1 complex with iron. Studies on this compound, especially monosodium salts, confirm the efficiency and safety in acute iron poisoning. To treat acute iron poisoning, NaHBED is orally bound to iron in the gastrointestinal tract, inactivating it and preventing its absorption. Intravenously, NaHBED binds to excess circulating iron in the systemic circulation and inactivates it, without causing hypotension, unlike deferoxamine inducing hypotension by rapid intravenous injection. In the treatment of chronic iron overload, NaHBED is required by subcutaneous or intravenous injection every other day or possibly once or twice a week. This injectable program may be preferred for long-term subcutaneous deferoxamine injections or in large doses of tablets several times a day. Other scientific work has been done to replace deferoxamine with binary and ternary ligands for chronic iron chelation. It is free from the risk of tissue damage by iron and because it is a synthetic product, it will not have problems with local reactions to fermentation in products that have not been removed in purification. Finally, for patients with deferoxamine allergy, HBED is a different member of the chelator family and is doubtful to elicit a similar response. ⁷²

Combination therapy

In a situation where a very heavy load of iron is imposed on people, chelation intensification is needed. On the other hand, we will face limited use of chelators. Therefore, combination therapy will have a greater ability to excrete iron and reduce side effects. In addition, due to the difference in iron distribution in individuals and a quantitative study of iron levels and synergistic properties, the combined use of chelators is recommended.

Desferrioxamine and deferiprone

Desferrioxamine and deferiprone are the most widely studied compounds. In various studies, different doses have been used, all of which have been used to reduce serum ferritin, and this combination has had a significant effect on the clearance of heart iron. The hypothesis is based on the fact that deferiprone releases iron in plasma after entering the cardiac myocytes, and iron is then excreted by binding to deferiprone.^73,74

Deferoxamine and deferasirox

Studies show that concomitant use of deferoxamine and deferasirox can increase potency without increasing side effects. This combination therapy is used in patients who need rapid reduction of iron overload or due to intoxication or high iron load, it is not possible to maintain negative iron stability with other chelators. Concomitant use of deferoxamine and deferasirox has a beneficial and progressive effect in reducing plasma non-transferable iron levels and unstable plasma iron levels. Concomitant use of deferoxamine and deferasirox rapidly reduces systemic and myocardial iron, as measured by hepatic and myocardial iron concentrations, and provides admirable control of plasma-sensitive toxic species without increasing toxicity. Due to the greater convenience of deferoxamine and deferasirox, adherence to this combination therapy may be improved, but future clinical trials will still be needed for overall evaluation. ⁷⁵

Deferasirox and deferiprone

According to existing studies, deferasirox and deferiprone chelators are very well tolerated, are effective in reducing iron load, no side effects have been recorded, and at the same time improve adaptation and quality of life. ⁷⁶ Using these compounds to clear the heart and liver of iron is more effective than monotherapy. Deferasirox and deferiprone have the ability to enter the cell and chelate iron inside the cell, in addition to their synergistic effects. Patient’s serum ferritin level decreased after 1 year of treatment, in addition, MRI of the heart and liver confirms its effectiveness in overcoming toxicity. ⁷⁷

Adjuvant therapy

Hemofiltration can be a lifesaver in poisoning, but its use in iron poisoning is unclear. However, some specialists use hemofiltration to remove serum iron as soon as possible. The results indicate that iron levels are significantly reduced (hemofiltration clears maximal chelated iron) and patients recover rapidly. ⁷⁸ Extracorporeal methods such as hemodialysis will be less useful in removing iron, because iron is lost in the bloodstream and must be done after eating and before iron is transferred to the cells. In severe iron poisoning, other extracorporeal methods like exchange transfusion or continuous intravenous-venous hemofiltration show better results. Despite the administration of deferoxamine, these methods are useful in the case of persistent clinical deterioration and serum iron concentrations. Ultrafiltration is a more appropriate method for the removal of serum iron and the improvement of clinical symptoms is evidence of this method. ⁷⁹ Exchange transfusion was proposed as a helpful treatment for iron poisoning in the 1950s. Exchange transfusions are performed in 2 h and 3 h, in both methods, 20 mL of blood is exchanged. This cycle is repeated until the correct volume of blood is replaced. Exchange transfusions should be performed early, before iron is transported into the cells, probably within 12 h of ingestion. Plasmapheresis is useful when drugs are strongly bound to proteins and distributed in small volumes, however no controlled studies have reported on the efficacy of plasmapheresis in specific poisoning. ⁸⁰

Conclusion

Iron poisoning is one of the clinical important cases in the emergency and poisoning departments. Understanding the mechanism of this poisoning and the adverse effects on the main and vital organs is necessary for all the health professional team, so that clinical measures can be taken to prevent complications. Successful treatment requires knowing the conditions of poisoning and providing helpful measures, teaching the effective and appropriate use of traditional and new chelating drugs based on the latest guidelines, and evaluating the patient’s condition and remaining complications. These actions lead to the reduction of sequelae and deaths. Undoubtedly, this will be realized with a scientific and team approach.