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Critical Care > MEDICAL TOPICS
Toxicity, Iron
Article Last Updated: Aug 16, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Marcel E Conrad, MD, BS, (Retired) Distinguished Professor of Medicine, University of South Alabama
Marcel E Conrad is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwestern Oncology Group
Editors: Lisa Kirkland, MD, FACP, CNSP, MSHA, Assistant Professor, Department of Internal Medicine, Division of General Internal Medicine, Mayo Clinic; ANW Intensivists, Abbott Northwestern Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Harold L Manning, MD, Associate Professor, Departments of Medicine, Anesthesiology and Physiology, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; Michael R Pinsky, MD, CM, Professor of Critical Care Medicine, Bioengineering, Cardiovascular Diseases and Anesthesiology, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
iron toxicity, iron equilibrium, excess iron, hemochromatosis, iron-overloading disorders, oxygen transport, electron transport
Background
Iron is vital for all living organisms because it is essential for multiple metabolic processes, including oxygen transport, DNA synthesis, and electron transport. Iron equilibrium in the body is carefully regulated to ensure that sufficient iron is absorbed to compensate for body losses of iron. Unlike other nutritional metals, iron is highly conserved, and excess iron in the body can be excreted only by the slow processes of desquamated epithelium and intestinal secretions.
Toxicity attributable to excess iron can occur either acutely after a single large dose of iron or chronically because of excessive accumulation of iron in the body from either diet or blood transfusions, or both. This article addresses acute iron poisoning because chronic iron toxicity is covered in other articles in the journal that focus on hemochromatosis and iron-overloading disorders.
Pathophysiology
Iron is physiologically essential for life but biochemically dangerous. The energy requirements of most living organisms are met by the oxidation of organic substances by molecular oxygen. This is accomplished by 2 kinds of proteins. First, the oxidative reactions are catalyzed by specific redox enzymes. Second, in higher organisms, oxygen-carrying proteins are essential for the transport of oxygen for utilization in cells. Both types of protein require a metal for their biologic activity, and, in vertebrates, iron is used as an essential component of the hemoglobin molecule and for many of the redox enzymes. Although the importance of iron deficiency generally is recognized, the significance of iron excess has been markedly underestimated. Acute iron intoxication occurs in children who consume their mothers' iron tablets. They may develop circulatory collapse, and death may occur when they ingest sufficient iron to exceed the body's iron-binding capacity, that of the metal-binding proteins that make ionic iron available. The deleterious effects of chronic excess iron were believed to be uncommon and restricted to genetic hemochromatosis and a few iron-overloading disorders. Governments added iron to staples such as flour to prevent iron deficiency, without considering that iron-overloading disorders are as commonplace in the US white population as sickle cell trait is in African Americans. Even considering the 8% prevalence of the hemochromatotic gene (HFE) in white populations, excess biological iron may have wider biologic importance. Partially reduced oxygen byproducts from respiration produce a formidable challenge to the maintenance of biologic structure and function. The formation of the most common ions of these species, which are equivalent to internally generated radiation, requires transitional metal catalysts. Iron is the most important of these metals because of its relative prevalence in all biological tissues. Although the oxidative potential of iron in biologic systems has been recognized for more than a century, its significance went unrecognized until the discovery of superoxide dismutase. The importance of reduced oxygen species then became apparent. It was proposed that the oxidant is the hydroxyl radical generated by the Haber-Weiss reaction. Some queried whether the rate constant for this reaction was too slow for biologic significance and suggested the ferryl ion as an alternative etiology for the oxidant effect of these systems (see Image 1). Other transitional metals such as zinc and copper serve important biologic functions and are known to be toxic when present in such high concentrations that they exceed the capacity of proteins to bind them and are then free in ionic form. However, they are less likely than iron to be important as toxic oxidants in healthy people because they are present in significantly lower tissue concentrations than iron, and iron is very slowly excreted from humans once it is absorbed into the body. Recognition of the pathophysiologic significance of oxygen free radicals and transition metal catalysis has not been widely appreciated. While the focus of this article is restricted to acute iron poisoning, chronic accumulation of excess iron causes pantropic organ damage. Multiple organ damage due to excess iron is well established in hereditary hemochromatosis and certain other iron-overloading disorders. In addition, excess body iron is postulated to play an important role in carcinogenesis, coronary artery disease, inflammation, aging, neurodegenerative disease, and stroke. The oxidant potential of iron and other transitional metals is harnessed by metal-binding proteins. Only when metals exceed the availability of metal-binding proteins do they become toxic. For this reason, determining the total iron-binding capacity is useful in patients with acute iron toxicity in order to assess whether or not it is completely saturated with iron.
Frequency
United States
Acute iron poisoning is most prevalent in populations where iron tablets are relatively available to young children, and it is the most common fatal poisoning in children aged 12 months to 3 years.
International
The hazard of acute iron poisoning exists in all populations where iron tablets are available.
Mortality/Morbidity
- In children, acute iron poisoning is the single most frequent cause of death due to accidental ingestion, accounting for approximately 33% of all fatalities in this group of disorders.
- Despite this alarming statistic, most children who ingest iron tablets recover without significant obvious sequelae.
- Prompt and appropriate treatment is highly effective in reducing both mortality and morbidity following the ingestion of excess iron.
Race
- No racial predilection is associated with acute iron poisoning.
Sex
- No obvious sex predilection exists for children who ingest iron tablets.
Age
- Preschool-aged children, particularly children aged of 1-3 years, are at highest risk because the children watch their parents ingest the tablets and the tablets resemble a popular candy.
- Adult suicide attempts have been reported, but they are relatively uncommon in comparison to acute iron poisoning in young children.
History
- The most important information is that the patient consumed an excessive number of iron tablets. Obtain an estimate of the number of iron tablets consumed.
- The diagnosis should be considered in any preschool-aged child from a household where iron tablets are available who presents with abdominal pain, diarrhea, and/or vomiting of brown or bloody stomach contents. These symptoms may occur within 30 minutes of ingestion of iron, or they may be delayed for several hours.
- If larger numbers of tablets are swallowed, somnolence, hyperventilation from acidosis, and cardiovascular collapse may occur. If death does not occur within the first 6 hours after ingestion, the patient may transiently improve and appear to be recovering, only to die 6-24 hours later.
- Acute iron poisoning has been divided into 4 phases of illness, described as follows:
- Phase 1: This occurs 6-12 hours following ingestion of iron. It is caused by the direct effect of iron on the gastrointestinal tract and manifests as nausea, vomiting, diarrhea, hematemesis, and hematochezia. Death in the first phase is due to hypovolemic shock from loss of fluid and blood.
- Phase 2: This phase is deceptive and lasts 12-48 hours after iron ingestion. The patient improves and appears to be recovering. However, iron absorption continues in the absence of recovery of the iron by gavage and prevention of absorption by chelation and precipitation of the ingested iron. Inadequate treatment leads to the third phase of iron poisoning, where treatment has less affect and outcome is poor.
- Phase 3: This begins 12-48 hours after ingestion and is caused by the exposure of multiple body organs to excess iron. Death in this phase is caused by widespread cellular dysfunction as a result of mitochondrial damage from intracellular iron. This is most marked in the liver. Transaminase values are increased. Serum prothrombin time is prolonged. Hypoglycemia and metabolic acidosis may occur. The time course of this phase is dependent on the extent of liver damage and may last from days to weeks. Most deaths occur in this phase.
- Phase 4: Occasionally, patients have a fourth phase. This occurs weeks to months after iron poisoning. It is caused by scarring and stenosis of the pylorus of the stomach from the iron exposure. It may require surgical intervention to relieve obstruction.
- Estimation of the number of tablets ingested and the size and weight of the patient are important. Death rarely occurs in patients who ingest less than 60 mg of iron per kilogram of body weight or 1 ferrous sulfate tablet (0.325 g of ferrous sulfate) per kilogram of body weight. Patients who ingest 60 mg/kg should be hospitalized and not merely monitored on an outpatient basis.
- Gastrointestinal symptoms may be observed with doses as low as 20 mg/kg.
- When the number of tablets is uncertain, the pills should be counted after vomiting and gavage, after which a flat plate of the abdomen should be obtained to count the number of tablets remaining in the gut (iron tablets are radiopaque).
- Parenteral administration of 1 g of deferoxamine can be used to help predict outcome. Deferoxamine does not chelate iron bound to transferrin and remains colorless until it binds iron. Colorless urine after injection of deferoxamine suggests the iron dosage has been small, whereas pink urine indicates that sufficient iron was ingested to exceed the iron-binding capacity of circulating transferrin.
Physical
- Usually, abdominal tenderness initially is epigastric and then becomes more diffuse.
- Rigidity of the abdominal muscles is uncommon at presentation, and bowel sounds usually increase during the initial hours after ingestion.
- Frequent loose stools may occur.
- Vomiting of brownish fluid, with or without blood, may be seen.
- Pills may be removed by forced vomiting, gastric lavage, or both.
- Ominous signs include the following:
- Hypotension
- Hyperventilation from metabolic acidosis
- Cardiovascular collapse
- Corrosive injury to the stomach may result in pyloric stenosis and gastric scarring days-to-weeks after the acute event.
- Hemorrhagic gastritis, liver damage, and hepatic damage may ensue and be found at autopsy.
Causes
- The presence of large quantities of iron within the gastrointestinal lumen produces gastroenteritis with pain, hemorrhage, and scarring.
- Iron in body organs in excess of the capability of iron-binding proteins to prevent the availability of ionic iron produces free-radical formation with tissue destruction.
- Because the major cause of acute iron poisoning is the availability of iron tablets in the household, the prevalence of this poisoning can be diminished by storing the tablets in inaccessible locations, using tamper-proof containment on tablet containers, and using tablets containing less than 20 mg of iron for iron prophylaxis in pregnancy.
Other Problems to be Considered
Catastrophic etiologies of an acute abdomen
Gastroenteritis, ie, bacterial, viral, or toxic etiologies
Lab Studies
- Because deferoxamine interferes with total iron-binding capacity measurement, a blood specimen should be obtained for measurement of serum iron and total iron-binding capacity before initiating treatment with deferoxamine. If the serum iron concentration exceeds the total iron-binding capacity, the patient should be hospitalized and treated with deferoxamine. Serum iron values greater than 500 mcg/mL are associated with shock and/or coma in one third of patients.
- A complete blood count and comprehensive metabolic profile should be obtained. Leukocytosis usually is observed with significant ingestion of iron. Acid-base measurements are needed for the assessment of possible elevated anion-gap metabolic acidosis. Anemia may occur from blood loss in the gastrointestinal tract. Serum creatinine values are needed to monitor deferoxamine (Desferal) toxicity.
- Vomitus should be tested for the presence or absence of hemoglobin. If any question exists about whether iron toxicity is the cause the patient's condition, vomitus should be tested for iron concentration in much the same way serum iron concentration is measured. Iron values in vomitus of less than 3.5 mg/L usually are associated with rapid recovery. However, this finding should not be used as a substitute for induced-vomiting and lavage.
- After vomiting has been induced and the stomach lavaged with either 10% sodium phosphate solution or 1% sodium bicarbonate solution, a flat plate of the abdomen should be obtained to quantify the number of remaining iron tablets that were not recovered by vomiting and lavage.
Procedures
- Gastric lavage with a large-bore tube should be performed to remove iron tablets from the gut and to chelate the iron to render it nonabsorbable (10% sodium phosphate or 1% sodium bicarbonate solution).
Histologic Findings
Necrotizing gastritis and enteritis occur in all patients with severe iron poisoning. Mucosal surfaces are hemorrhagic, with gross destruction of the villi and sloughing of the epithelium. Hepatic parenchymal cell damage occurs with hemorrhagic necrosis of the periportal and peripheral parts of the hepatic lobules.
Ultimately, mild-to-moderate fatty infiltration of the periportal tissue occurs that persists for several days. Hyperplasia of the Kupffer cells occurs, with phagocytosis of cellular debris. Ultrastructural studies show swelling and contraction of the mitochondria in hepatocytes, with an accumulation of granules in the mitochondrial intracristal lumen.
Other organs also show damage, with cloudy swelling, edema, and hemorrhage in the heart, lungs, kidneys, and brain. The myocardium develops functional impairment, which probably plays an important role in the clinically observed circulatory failure.
Medical Care
- Establish vascular access and obtain baseline laboratory studies. Treat cardiovascular collapse and metabolic acidosis if present.
- Induce vomiting if the patient's level of consciousness is not depressed.
- This can be done mechanically by stroking the posterior pharynx.
- Syrup of ipecac orally (15 mL in children aged 6 mo to 12 y, 30 mL in older children and adults) induces vomiting in 15-30 minutes.
- Apomorphine (6 mg for adults and 0.06 mg/kg for children) administered subcutaneously induces vomiting in 3-5 minutes.
- Perform gastric lavage using a large-bore tube and solutions of either sodium bicarbonate (1%) or sodium phosphate (10%).
- A large-bore tube is desirable to try to remove any tablets that were not vomited.
- In the past, oral administration of deferoxamine was advocated to chelate iron, but this is unnecessary if adequate lavage is accomplished with either sodium bicarbonate or sodium phosphate solutions.
- Administer deferoxamine.
- It can be injected intramuscularly (IM) in a dose of 50 mg/kg, with a maximum initial dose of 1000 mg. In patients weighing more than 12 kg, one can administer 1000 mg IM, followed by 500 mg IM 4 and 8 hours later.
- In patients suspected of significant ingestion of iron tablets with a potential for coma or shock, intravenous administration of deferoxamine probably is preferable. A slow intravenous injection of 20 mg/kg over 1-2 minutes, followed by an infusion of 60 mg/kg over 6-8 hours, may be given (10-15 mg/kg/h).
- Obtain a flat plate of the abdomen to quantify the number of tablets remaining in the intestinal tract.
- Fluid and electrolyte replacement may be necessary to treat hypotension and metabolic acidosis.
- Transfusion of red blood cells may be required to replace blood loss resulting from gastrointestinal hemorrhage.
Surgical Care
Pyloric stenosis may occur in patients 6 days to 6 weeks following ingestion. This may require surgical intervention to prevent intestinal obstruction.
Consultations
Because acute iron poisoning is a condition usually observed in young children, consult a pediatrician to aid in the management of the fluid and electrolyte imbalance.
Deferoxamine mesylate (Desferal) is the mainstay of therapy in the treatment of acute iron poisoning. It is an iron chelator that is available for either IM or IV administration. It should be used in concert with methods to prevent absorption of ingested iron, including stimulation of vomiting and lavage of the stomach with solutions that chelate iron to make it less absorbable (1% sodium bicarbonate or 10% sodium phosphate).
Patients may require treatment for hypotension, metabolic acidosis, and intestinal hemorrhage.
Drug Category: Iron chelating agents
These agents chelate and facilitate the elimination of iron via urine and bile.
| Drug Name | Deferoxamine mesylate (Desferal) |
|---|
| Description | Freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. Excreted in urine and bile and gives urine a red discoloration. It readily chelates iron from ferritin and hemosiderin but not from transferrin. Most effective when provided to the circulation continuously by infusion, but it may be administered IM or by slow IV infusion. Does not effectively chelate other trace metals of nutritional importance. Deferoxamine is provided in vials containing 500 mg of lyophilized sterile drug. Two mL of sterile water should be added to each vial for injection, bringing the concentration to 250 mg/mL. For IV use, this may be diluted in 0.9% sterile saline, 5% dextrose solution, or Ringer solution. The preferred route of administration is IM, except in hypotension and cardiovascular collapse, in which case the IV route should be considered. |
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| Adult Dose | 1000 mg IM, followed by 500 mg 4 and 8 h later; depending on response, 500 mg may be administered q4-12h IM; not to exceed 6000 mg/24h
Alternatively, 1000 mg IV may be given at a rate not to exceed 15 mg/kg/h; followed by a dose of 500 mg q4h for 2 doses; give additional IV infusion slowly over 24 h, not to exceed 6000 mg/24 h |
|---|
| Pediatric Dose | <3 years: Not established
>3 years: 50 mg/kg IM initially, not to exceed 1000 mg/dose; administer half that dose IM 4 and 8 h later; similar IM doses can be administered at 4 h intervals over next 24 h if clinical findings warrant additional therapy
Alternatively, 20 mg/kg IV initially over 1-2 min followed by an infusion of 60 mg/kg over 6-8 h; rapid injection can cause hypotension; additional therapy, if clinically indicated, can be given as IM therapy in most circumstances |
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| Contraindications | Documented hypersensitivity; absence of acute iron poisoning; severe renal disease and anuria (dose reduction after the loading dose should be considered in these circumstances) |
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| Interactions | None reported |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Tachycardia, hypotension, and shock may occur in long-term therapy and could add to cardiovascular collapse due to iron toxicity; adverse GI effects include abdominal discomfort, nausea, vomiting, and diarrhea, which may add to the symptoms of acute iron toxicity; flushing and fever also are reported |
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| Drug Name | Deferasirox (Exjade) |
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| Description | Tab for oral susp. Oral iron chelation agent demonstrated to reduce liver iron concentration in adults and children who receive repeated RBC transfusions. Binds iron with high affinity in a 2:1 ratio. Approved to treat chronic iron overload due to multiple blood transfusions. Treatment initiation recommended with evidence of chronic iron overload (ie, transfusion of about 100 mL/kg packed RBCs [about 20 U for 40-kg person] and serum ferritin level consistently >1000 mcg/L). |
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| Adult Dose | Initial: 20 mg/kg PO qd on empty stomach 30 min ac
Maintenance: Adjust dose by 5- to 10-mg/kg/d increments q3-6mo according to serum ferritin level trends; not to exceed 30 mg/kg/d
Note: Dissolve tab completely in water, orange juice, or apple juice, then immediately drink susp; resuspend any remaining residue in small volume of liquid and swallow |
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| Pediatric Dose | <2 years: Not established
>2 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Data limited; not to be taken with aluminum-containing antacids |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Common adverse effects include diarrhea, nausea, abdominal pain, headache, pyrexia, cough, and rash; may increase serum creatinine and hepatic enzyme levels; decrease dose with persistent elevation of serum creatinine level; may cause auditory and visual disturbances; slight decreases in serum copper and zinc levels may occur; dissolve tab completely in water, orange juice, or apple juice and drink resulting susp immediately (do not swallow tab whole, do not chew or crush); measure serum ferritin levels monthly and adjust dose every 3-6 mo based on serum ferritin trends |
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Further Outpatient Care
- Patients should be seen at a follow-up visit and monitored for evidence of intestinal obstruction due to pyloric stenosis and/or other intestinal strictures.
Transfer
- Patients should be referred to an emergency department capable of dealing with acutely ill patients.
- Because of the importance of prompt therapy in reducing mortality and morbidity, patients should not be transferred long distances before initial treatment is begun.
Deterrence/Prevention
- Iron tablets should be dispensed in containers that are inaccessible to children. This is best done by putting each tablet in an individual plastic container. Tamper-proof bottle tops are a second-best option.
- Unless iron deficiency anemia is established, pregnant mothers should be given tablets containing less than 20 mg of elemental iron per tablet for prophylaxis.
- Adults receiving iron tablets should be informed to keep them in areas inaccessible to children.
- Adults receiving iron tablets should be advised to not take their medication in the presence of small children so that the children do not mimic their parents' actions.
- Tablets containing therapeutic doses of iron (>20 mg/tab) should be sold only by prescription.
- In households with children, therapeutic iron tablets should be safely discarded and should not be kept in the medicine cabinet after they are no longer needed.
Complications
- Hypotension and shock occur in patients who ingest and absorb sufficient iron such that the serum iron concentration significantly exceeds the capability for transferrin to bind iron and prevent free-radical formation.
- Gastrointestinal bleeding may occur from necrotizing gastritis and enteritis. This may require transfusion of packed red blood cells to prevent hypotension and shock.
- Disseminated intravascular coagulation (DIC) can occur in severe iron poisoning. DIC manifests as thrombocytopenia, hypofibrinogenemia, and a prolonged prothrombin time and activated partial thromboplastin time, with intravascular deposition of fibrinogen and platelets.
- After recovery from acute iron poisoning, the patient may develop pyloric stenosis and intestinal strictures leading to intestinal obstruction.
Prognosis
- Prior to the availability of deferoxamine, the mortality rate of acute iron poisoning was approximately 45%. With appropriate treatment as outlined in Treatment and with the use of deferoxamine, the mortality rate has been reduced to approximately 1%. Mortality usually is associated with a delay in diagnosis or a delay in treatment.
Patient Education
- The hazard of iron tablets is not widely recognized. Patients given iron tablets should be informed of the importance of securing the medication in a safe place, inaccessible to young children.
- Medication should not be taken in the presence of young children because they may mimic what they observe.
- Pharmacies should dispense iron tablets in tamper-proof containers.
- For excellent patient education resources, visit eMedicine's Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Iron Poisoning and Poison Proofing Your Home.
Medical/Legal Pitfalls
- Missed or delayed diagnosis or treatment
| Media file 1:
The oxidative potential of iron was first proposed by Fenton in 1894. The importance of reduced oxygen species in biological reactions became apparent with the discovery of superoxide dismutase by McCord and Fridovich in 1969. The potential role of metal ion catalysis was reported the following year. Subsequently, a plethora of evidence has accumulated linking chronic excess body iron to cardiovascular disease, carcinogenesis, aging, stroke, Alzheimer disease, and Parkinson disease. The organ damage that occurs in the hereditary iron overloading disorders is well documented and can be averted and improved by decreasing the excess iron. Acute iron overload likewise produces tissue and organ damage due to the presence of free ionic iron. |
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Media type: Image
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- Hardman JG, Limbird LE, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY:. McGraw-Hill;1995:1324, 1668-9.
- Klein-Schwartz W, Oderda GM, Gorman RL, et al. Assessment of management guidelines. Acute iron ingestion. Clin Pediatr (Phila). Jun 1990;29(6):316-21. [Medline].
- Litovitz T, Manoguerra A. Comparison of pediatric poisoning hazards: an analysis of 3.8 million exposure incidents. A report from the American Association of Poison Control Centers. Pediatrics. Jun 1992;89(6 Pt 1):999-1006. [Medline].
- McGuigan MA. Acute iron poisoning. Pediatr Ann. Jan 1996;25(1):33-8. [Medline].
Toxicity, Iron excerpt Article Last Updated: Aug 16, 2006
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