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Toxicity, Iron

Clifford S Spanierman, MD, Consulting Staff, Departments of Emergency Medicine and Pediatrics, Lutheran General Hospital of Oak Brook, Advocate Health System

Updated: Mar 26, 2009

Introduction

Background

Iron overdose has been one of the leading causes of death caused by toxicological agents in children younger than 6 years. Iron is used as a pediatric or prenatal vitamin supplement and for treatment of anemia. Iron is particularly tempting to young children because it appears similar to candy. Patients with anemias that require frequent blood transfusions also are at risk for developing chronic iron toxicity.

Iron overload may develop chronically as well, especially in patients requiring multiple transfusions of red blood cells. This condition develops in patients with sickle cell disease, thalassemia, and myelodysplastic syndromes.

Pathophysiology

Iron toxicity can be classified as corrosive or cellular.

• Corrosive toxicity: Iron is an extremely corrosive substance to the GI tract. It acts on the mucosal tissues and can manifest with nausea, vomiting, abdominal pain, hematemesis, and diarrhea; patients may become hypovolemic because of significant fluid and blood loss.
• Cellular toxicity: The absorption of excessive quantities of ingested iron results in systemic iron toxicity. Severe overdose causes impaired oxidative phosphorylation and mitochondrial dysfunction, which can result in cellular death. The liver is one of the organs most affected by iron toxicity, but other organs such as the heart, kidneys, lungs, and the hematologic systems also may be impaired.
• End result of corrosive and cellular toxicity is significant metabolic acidosis due to several factors.
  • Hypoperfusion due to significant volume loss, vasodilatation, and negative inotropic effect of iron will result in lactic acidosis.
  • Inhibition of oxidative phosphorylation will promote anaerobic metabolism.

Individuals demonstrate signs of GI toxicity after ingestion of more than 20 mg/kg. Moderate intoxication occurs when ingestion of elemental iron exceeds 40 mg/kg. Ingestions exceeding 60 mg/kg can cause severe toxicity and may be lethal.

Suggested doses are based on calculation of the amount of elemental iron. Different iron preparations (salts) contain different amounts of elemental iron.

• Fumarate - 33%
• Sulfate - 20%
• Gluconate - 12%

Chronic iron overload may deposit iron into organs such as the liver and heart, which may cause death due to myocardial siderosis.

Frequency

United States

More than 20,000 children accidentally ingested iron in 1995.¹  Iron was the most common cause of childhood mortality due to nonintentional ingestion. The incidence of iron poisoning has decreased dramatically.

Mortality/Morbidity

Iron poisoning may result in mortality or short-term and long-term morbidity.

Sex

Pregnant patients are at increased risk due to availability of prenatal vitamins and iron supplements in addition to the emotional stress that pregnancy can precipitate.

Age

Iron overdose is one of the leading causes of fatality from toxicological agents in children younger than 6 years.

Clinical

History

• Alert patients who present without vomiting most likely did not ingest a toxic dose of iron.
• More that 4 episodes of vomiting suggest significant iron toxicity.
• Iron ingestions with GI symptoms such as vomiting and diarrhea (especially hemorrhagic)
• Hemorrhagic gastroenteritis, even in the absence of ingestion
• Hyperglycemia with metabolic acidosis during or following episodes of abdominal pain and gastroenteritis

Physical

Iron poisoning is often classified into 5 distinct stages. Understanding the course of poisoning is important, especially the second (recovery) stage, which may lure the physician into a false sense of security and result in premature and inappropriate discharge of a patient.

• Stage 1 (gastrointestinal)
  • This stage usually occurs within 6 hours after exposure.
  • Nausea and diarrhea, often accompanied by abdominal pain, characterize the gastrointestinal (GI) phase.
  • When the intoxication is severe, a hemorrhagic component is observed in conjunction with gastroenteritis.
  • The combination of fluid and blood loss, with additional third-spacing, may result in hypovolemia or shock.
  • Fatality occurs in a significant percentage of patients during this first phase.
• Stage 2 (latent)
  • This stage is characterized by resolution of GI symptoms.
  • The patient appears to improve and recover.
  • This deceptive phase usually occurs 6-12 hours after ingestion and may last as long as 24 hours.
  • Metabolic abnormalities during this phase may include hypotension, metabolic acidosis, and coagulopathy.
  • Some patients skip this phase and progress directly to stage 3. Usually, the clinician does not recognize subtle signs of toxicity.  
• Stage 3 (metabolic/cardiovascular)
  • Stage 3 is characterized by metabolic acidosis and cardiovascular symptoms.
  • It is hypothesized that high iron concentrations produce venous pooling and third-spacing of fluids.
  • This phase is also characteristic of CNS symptoms, usually stupor and coma.
  • Most patients die during this phase.
  • It can start very early (6-8 h), depending on severity of exposure, and it can last up to 2 days.
  • The acidosis may indicate failure of other organs, such as the heart and kidneys.
• Stage 4 (hepatic)
  • Elevated liver enzymes and bilirubin levels are commonly observed with coagulopathy, indicative of hepatic dysfunction.
  • Hypoglycemia may accompany liver dysfunction.
• Stage 5 (delayed)
  • This stage is characterized by scarring of the healing GI tract. The stomach and/or intestines may be affected, resulting in gastric outlet or intestinal obstruction.
  • This phase usually is experienced weeks after a severe poisoning.

Differential Diagnoses

Other Problems to Be Considered

Sepsis

Workup

Laboratory Studies

• Measure steady-state serum iron levels at least 4 hours postingestion. levels drawn more than 6 hours after ingestion may underestimate toxicity caused by ferritin binding and redistribution of iron.
  • Mild-to-moderate toxicity generally manifests at levels of 350-500 mcg/dL.
  • Hepatotoxicity usually is observed at levels higher than 500 mcg/dL.
  • levels higher than 800 mcg/dL are associated with severe toxicity.
  • Samples drawn too early or too late postingestion may be unreliable.
  • In adults, hyperglycemia, leukocytosis, abdominal pain, and vomiting may be absent.
• Glucose levels
  • Glucose levels exceeding 150 mg/dL are common with severe iron toxicity.
  • Following glucose levels is important because hepatic dysfunction may cause hypoglycemia.
• Complete blood count
  • A white blood cell (WBC) count more than 15,000/mm³ is associated with severe iron poisoning.
  • A CBC is also helpful because anemia from blood loss may develop.
• In addition to serum lactic acid levels (lactate), the arterial blood gas (ABG) measurements are useful in determining the existence and severity of a metabolic acidosis.
• Coagulation studies are essential. Following the prothrombin time may be helpful.
• Perform liver function tests (LFTs). Hepatic dysfunction is common in severe iron poisoning because the liver is the first organ outside of the GI tract to encounter large iron load through the portal blood supply.
• Electrolyte measurements and renal function tests assist in calculation of the anion gap and detection of electrolyte abnormalities and the presence of prerenal azotemia.
• Lipase and amylase levels may document occasional pancreatic injury.
• Obtain a pregnancy test in women of childbearing age.
• Determine type and cross-matching.
• Ferritin levels are helpful for chronic toxicity >1000 mcg/L.
• Iron toxicity is one of the MUDPILES (M-methanol; U-uremia; D-DKA, AKA; P-paraldehyde, phenformin; I-iron, isoniazid; L-lactic [ie, CO, cyanide]; E-ethylene glycol; S-salicylates) that causes an acidosis with an increased anion gap.

Imaging Studies

• A kidneys, ureters, bladder (KUB) film can determine if radiopacities are present; iron tablets are radiopaque for a few hours postingestion. However, the absence of radiopacities does not rule out a significant or lethal ingestion.

Treatment

Prehospital Care

• This section only refers to the acute overdose.
• IV access should be established immediately.
• For patients who are hypovolemic, administer fluid boluses of 20 mL/kg of 0.9 isotonic sodium chloride solution or lactated Ringer (LR) solution.
• Provide oxygen to patients in shock.

Emergency Department Care

• Assume that symptomatic patients are hypovolemic. Administer vigorous isotonic crystalloid therapy (eg, 0.9 isotonic sodium chloride solution, LR solution) in 20 mL/kg boluses to attain and maintain hemodynamic stability.
• Gastric lavage with a large-bore orogastric tube or administration of ipecac syrup may remove iron from the stomach. However, ipecac is not used routinely for iron removal because it can mask clinical signs of iron toxicity (vomiting). Due to local caustic effect of iron, poisoned patients routinely are vomiting on their own performing self-decontamination even without ipecac.
• Ideally, these treatments should be performed 1-2 hours postingestion or even later if evidence of iron products in the stomach are observed on a radiograph. Each modality has its disadvantages.
  • Iron has a gelatinous texture and may be difficult to remove by lavage. Bezoar formation may occur.
  • Ipecac is not routinely indicated. Significant ingestions of iron may cause hypotension and unstable vital signs, and ipecac may endanger the patient's airway as an aspiration risk. The only exception to the rule might be the patient who presents very early and with a very large amount of ingested iron where ipecac can expedite evacuation. Prolonged vomiting (more than one hour) should be attributed to iron toxicity rather than to the effects of ipecac.
• Perform whole-bowel irrigation in patients with a radiopacity on KUB until the radiopacity clears. Activated charcoal does not bind iron but should be utilized if co-ingestants are suspected.
• Oxygen should be supplemented.

Consultations

• Consultation with a toxicologist is recommended.
• Obtain a gastroenterology consultation for patients who have large iron bezoars.

Medication

The goals of pharmacotherapy are to reduce iron levels, prevent complications, and reduce morbidity.

Chelating agents

Chelation is the mainstay of therapy. It is indicated for serum iron levels >350 mcg/dL with evidence of toxicity or >500 mcg/dL regardless of signs or symptoms.

Deferoxamine (Desferal)

DOC for iron intoxication. 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. Readily chelates iron from ferritin and hemosiderin but not transferrin. Most effective when administered continuously by infusion. May be administered by IM injection or slow IV infusion. Does not effectively chelate other trace metals of nutritional importance. Provided in vials containing 500 mg of lyophilized sterile drug. Add 2 mL of sterile water to each vial for injection, bringing the concentration to 250 mg/mL. For IV use, may be diluted in 0.9% sterile saline, 5% dextrose solution, or Ringer solution. IM is preferred route of administration, except in hypotension and cardiovascular collapse when the IV route should be considered.

Dosing

Adult

1000-2000 mg IM, followed by 500 mg q4h for 2 doses; not to exceed 6000 mg/24 h
Alternatively, 1000 mg IV may be administered at initial rate of 5 mg/kg/h and not to exceed 15 mg/kg/h to avoid hypotension; followed by 500 mg q4h for 2 doses; administer additional IV infusion slowly over 24 h; not to exceed 6000 mg/24 h to reduce the hypotensive effects of deferoxamine

Pediatric

<3 years: Not established
>3 years: Start at 5 mg/kg/h and titrate up to 15 mg/kg/h IV, not to exceed 6 g/d (acute) or 12 g/d (chronic)

Interactions

None reported

Contraindications

Documented hypersensitivity; patients who do not have acute iron poisoning; severe renal disease and anuria (consider dose reduction after the loading dose in these circumstances)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Tachycardia, hypotension, and shock may occur in patients receiving chronic therapy and could add to the cardiovascular collapse caused by iron toxicity; GI adverse effects of the drug include abdominal discomfort, nausea, vomiting, and diarrhea, which may add to symptoms of acute iron toxicity; flushing and fever are reported

GI decontaminants

Because adsorption to activated charcoal is minimal, whole bowel irrigation is the GI decontamination method of choice.

Polyethylene glycol bowel prep (GoLYTELY, Colyte)

Laxative with strong electrolytic and osmotic effects that has cathartic actions in the GI tract.

Dosing

Adult

1000-2000 mL PO or NG tube, until rectal effluent is clear

Pediatric

25 mL/kg/h (not to exceed 500 mL) PO or NG tube, until rectal effluent is clear

Interactions

Reduces effectiveness and absorption of oral medications

Contraindications

Documented hypersensitivity; colitis, megacolon, bowel perforation, gastric retention, or GI obstruction

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in ulcerative colitis and hot loop polypectomy

Follow-up

Further Inpatient Care

• Treat patients who are symptomatic with deferoxamine, regardless of iron level.
• Admit patients who have been hemodynamically unstable to an intensive care unit.
• Whole-bowel irrigation may be of benefit.
• Other modalities that may be essential include mechanical ventilation and blood product transfusions.
• Aggressive hydration aids in eliminating chelated iron by maintaining an appropriate urine output.
• Exchange transfusion has been reported to be successful in management of a case of severe iron poisoning.²

Further Outpatient Care

• Asymptomatic patients observed for 6 hours with serum iron levels less than 300-350 mcg/dL may be discharged.

Transfer

• Transfer patients if intensive care facilities or deferoxamine is not available locally.

Deterrence/Prevention

• Safekeeping of all medications, not just iron pills, from young children is important.

Complications

Complications of iron toxicity include the following:

• Hepatic necrosis
• Myocardial dysfunction
• Cardiogenic shock
• CNS depression
• Coma
• Convulsion
• Anemia
• Coagulopathy
• Sepsis (Yersinia infection)
• Adult respiratory distress syndrome (ARDS)
• Gastrointestinal perforation
• Intestinal stricture formation

Prognosis

• Persistently symptomatic patients with serum iron levels higher than 350 mcg/dL should be admitted.
• Patients with serum iron levels higher than 1000 mcg/dL should be in a facility that can provide age-appropriate intensive care.

Patient Education

• Common medicines and vitamins may be lethal. Also see Toxicity, Vitamin.
• All medicines should be kept out of reach of children.
• 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.

Miscellaneous

Medicolegal Pitfalls

• Using serum iron levels instead of clinical evidence (eg, vomiting, hypovolemia, acidosis) to guide treatment of the patient is a pitfall.
• Discharging a patient who is in stage 2 may lead to serious morbidity. Patients in stage 2 may appear well but still have the potential of cardiovascular collapse.
• Obtaining a normal or low iron level more than 6 hours after an ingestion may be misleading. Redistribution of iron in tissues is the reason that the level is low. Toxicity is still possible. Treat the patient, not the numbers.

Special Concerns

• Pregnancy: The lethal potential of severe intoxication without treatment of deferoxamine far outweighs the risk to the fetus.

References

1. Morse SB, Hardwick WE Jr, King WD. Fatal iron intoxication in an infant. South Med J. Oct 1997;90(10):1043-7. [Medline].

2. Carlsson M, Cortes D, Jepson S, Kansstrup T. Severe iron intoxication treated with exchange transfusion. Arch Dis Child. April 2008;93(4):321-2. [Medline].

3. Alymara V, Bourantas D, Chaidos A. Effectiveness and safety of combined iron-chelation therapy with deferoxamine and deferiprone. Hematol J. 2004;5(6):475-9. [Medline].

4. Bosse GM. Conservative management of patients with moderately elevated serum iron levels. J Toxicol Clin Toxicol. 1995;33(2):135-40. [Medline].

5. Cheney K, Gumbiner C, Benson B, Tenenbein M. Survival after a severe iron poisoning treated with intermittent infusions of deferoxamine. J Toxicol Clin Toxicol. 1995;33(1):61-6. [Medline].

6. Goldberg sl. Novel treatment options for transfusional iron overload in patients with myleodysplatic syndromes. Leuk Res. Dec 2007;31:s16-22. [Medline].

7. Hershko CM, Link GM, Konijn AM. Iron chelation therapy. Curr Hematol Rep. Mar 2005;4(2):110-6. [Medline].

8. McGuigan MA. Acute iron poisoning. Pediatr Ann. Jan 1996;25(1):33-8. [Medline].

9. Mills KC, Curry SC. Acute iron poisoning. Emerg Med Clin North Am. May 1994;12(2):397-413. [Medline].

10. Palatnick W, Tenenbein M. Leukocytosis, hyperglycemia, vomiting, and positive X-rays are not indicators of severity of iron overdose in adults. Am J Emerg Med. Sep 1996;14(5):454-5. [Medline].

11. Tenenbein M. Benefits of parenteral deferoxamine for acute iron poisoning. J Toxicol Clin Toxicol. 1996;34(5):485-9. [Medline].

Keywords

iron, iron poisoning, iron overdose, iron toxicity, Fe, vitamins, symptoms, treatment, causes, iron supplements, corrosive iron toxicity, cellular iron toxicity, iron ingestion, high iron levels, prenatal vitamins, elemental iron, chronic iron toxicity

Contributor Information and Disclosures

Author

Clifford S Spanierman, MD, Consulting Staff, Departments of Emergency Medicine and Pediatrics, Lutheran General Hospital of Oak Brook, Advocate Health System
Disclosure: Nothing to disclose.

Medical Editor

David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School
David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

John G Benitez, MD, MPH, FACMT, FACPM, FAAEM, Associate Professor, Department of Medicine, Clinical Pharmacology Division, Vanderbilt University; Managing Director, Tennessee Poison Center
John G Benitez, MD, MPH, FACMT, FACPM, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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