Iron Toxicity

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Practice Essentials

Iron overdose has been one of the leading causes of poisoning deaths in children younger than 6 years. Iron is used in pediatric or prenatal vitamin and mineral supplements and for treatment of anemia. Iron tablets are particularly tempting to young children because they look like candy. Iron overdose in adults is typically a suicide attempt.[14]

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 hematologic malignancies such as myelodysplastic syndromes.[1, 16, 17]

For full discussion of iron toxicity in children, see Pediatric Iron Toxicity.

 

Pathophysiology

Iron toxicity can be classified as corrosive or cellular. Ingested iron can have an extremely corrosive effect on the gastrointestinal (GI) mucosa, which can manifest as nausea, vomiting, abdominal pain, hematemesis, and diarrhea; patients may become hypovolemic because of significant fluid and blood loss.

Cellular toxicity occurs with the absorption of excessive quantities of ingested iron. 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 cellular iron toxicity, but other organs such as the heart, kidneys, lungs, and the hematologic systems also may be impaired. With chronic iron overload, the deposit of iron into the heart may cause death due to myocardial siderosis.

With both corrosive and cellular toxicity, the end result 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.[2]

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

Epidemiology

United States

The 2017 Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System reported 4400 single exposures to iron or iron salts, with eight major outcome and two deaths. In addition, the AAPCC reported 9640 single exposures to multiple vitamins containing iron, with one major outcome and no deaths. Overall, 82% of cases were in children younger than 6 years.[3]

Patient Education

Safekeeping of all medications, not just iron pills, from young children is important. Common medicines and vitamins may be lethal. Also see Vitamin Toxicity.

For patient education information, see the First Aid and Injuries Center, as well as Iron Poisoning in Children and Poison Proofing Your Home.

History

Gastrointestinal (GI) manifestations such as vomiting and diarrhea (especially when hemorrhagic) are an important feature of acute iron toxicity. Pediatric patients who are alert and not vomiting most likely did not ingest a toxic dose of iron; in adults, however, abdominal pain and vomiting may be absent. More than four episodes of vomiting suggests significant iron toxicity. Hemorrhagic gastroenteritis, even in the absence of a history of iron ingestion, should raise suspicion for iron toxicity.

Physical Examination

Iron poisoning is often classified into five distinct stages, as follows:

Understanding the course of poisoning is important. In particular, the second stage may lure the physician into a false sense of security and result in premature and inappropriate discharge of a patient.

Stage 1

Features of stage 1 iron toxicity are as follows:

Stage 2

Features of stage 2 iron toxicity are as follows:

Stage 3

Features of stage 3 iron toxicity are as follows:

Stage 4

Features of stage 4 iron toxicity are as follows:

Stage 5

Features of stage 5 iron toxicity are as follows:

Complications

Complications of iron toxicity include the following:

Laboratory Studies

The workup for iron toxicity includes the following studies:

For serum iron measurement, samples should be drawn at least 4 hours postingestion, to allow levels to reach steady state; however, levels drawn more than 6 hours after ingestion may underestimate toxicity because of ferritin binding and redistribution of iron. The significance of results is as follows:

Glucose levels exceeding 150 mg/dL are common with severe iron toxicity. Following glucose levels is important because hepatic dysfunction may cause hypoglycemia.

On the CBC, a white blood cell (WBC) count of more than 15,000/mm3 is associated with severe iron poisoning. A CBC is also helpful because anemia from blood loss may develop.

LFTs are indicated because hepatic dysfunction is common in severe iron poisoning. The liver is the first organ outside of the GI tract to receive a large iron load, which enters through the portal blood supply.

Electrolyte measurements and renal function tests assist in calculation of the anion gap (see the Anion Gap calculator) and detection of electrolyte abnormalities and the presence of prerenal azotemia. Iron toxicity is one of the causes of acidosis with an increased anion gap, as noted in the mnemonic MUDPILES (M-methanol; U-uremia; D-diabetic ketoacidosis, alcoholic ketoacidosis; P-paraldehyde, phenformin; I-iron, isoniazid; L-lactic [ie, carbon monoxide, cyanide]; E-ethylene glycol; S-salicylates).

Imaging Studies

Iron tablets remain radiopaque for a few hours postingestion, and may be visible on a kidneys, ureters, bladder (KUB) film. However, the absence of radiopacities does not rule out a significant or even potentially lethal ingestion. 

In dialysis patients, who routinely receive parenteral iron conjunction with erythropoiesis-stimulating agents for treatment of anemia, recent evidence suggests that measurement of liver iron content with magnetic resonance imaging (MRI) may be a valuable surrogate marker for total body iron. However, while these findings challenge the current reliance on transferrin saturation and serum ferritin levels as markers of iron load, the clinical relevance of MRI for this patient population remains to be determined.[15]

Prehospital Care

In patients with acute iron overdose, intravenous access should be established immediately. Patients who are hypovolemic should receive fluid boluses of 20 mL/kg of normal saline or lactated Ringer (LR) solution. Provide oxygen to patients in shock.

Emergency Department Care

Assume that symptomatic patients are hypovolemic. Administer vigorous volume therapy with isotonic crystalloids (eg, normal saline, LR solution) in 20 mL/kg boluses to attain and maintain hemodynamic stability. Give supplemental oxygen.

Gastric lavage with a large-bore orogastric tube may remove iron from the stomach. Ideally, lavage should be performed 1-2 hours postingestion, although later use may be appropriate if evidence of iron products in the stomach is observed on a radiograph. However, iron has a gelatinous texture and may be difficult to remove by lavage. Whole-bowel irrigation may be used in patients with a radiopacity on kidneys, ureters, bladder (KUB) plain radiographs, until the radiopacity clears.

Ipecac has been used for gastric decontamination in patients with iron poisoning. Ipecac might be considered when it can be administered within 60 minutes of iron ingestion, in an alert patient who has ingested a very large amount of iron. Ipecac is not used routinely for iron removal because it can mask clinical signs of iron toxicity (vomiting). Significant iron overdose may cause hypotension and unstable vital signs, in which case ipecac is contraindicated, as it may endanger the patient's airway as an aspiration risk.

The American Academy of Clinical Toxicology advises that the routine administration of ipecac in the emergency department should definitely be avoided. Some reports suggest that ipecac may offer possible benefits in rare situations involving iron poisoning; this may be a moot point, however, since the availability of ipecac is rapidly diminishing.[4] In any case, iron toxicity itself typically causes vomiting, because of its caustic effect on the gastrointestinal mucosa, so iron-poisoned patients routinely perform self-decontamination even without ipecac.

Activated charcoal does not bind iron. However, it should be utilized if co-ingestants are suspected.

Deferoxamine (Desferal) can be used to chelate iron.[5]  Patients who are symptomatic should receive deferoxamine regardless of their iron level. In acute or chronic iron toxicity, chelation therapy with deferoxamine is indicated for patients with serum iron levels >350 mcg/dL who have evidence of toxicity, or levels of >500 mcg/dL regardless of signs or symptoms (see Medication). In patients with significant clinical manifestations of toxicity, chelation therapy should not be delayed while one awaits serum iron levels.

In acute iron poisoning, intramuscular (IM) administration is indicated for patients who are not in shock; intravenous (IV) administration should be reserved for patients in a state of cardiovascular collapse or shock. However, note that rapid IV administration of deferoxamine may itself result in hypotension and shock. For chronic iron overload, administration can be subcutaneous, IV, or IM. Aggressive hydration aids in eliminating chelated iron by maintaining an appropriate urine output.

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

Features of further inpatient care are as follows:

 

Medical Care

 

 

 

Consultations

Consultation with a toxicologist is recommended. Obtain a gastroenterology consultation for patients who have large iron bezoars. Transfer patients if intensive care or deferoxamine is not available locally.

Medication Summary

The goals of pharmacotherapy are to reduce iron levels, prevent complications, and reduce morbidity. Deferoxamine (Desferal) is used for chelation of iron in both acute and chronic toxicity.

The oral chelating agent deferasirox (Exjade) is approved by the US Food and Drug Administration (FDA) for the treatment of chronic iron overload due to blood transfusions in patients 2 year of age and older; it is also approved for treatment of chronic iron overload resulting from non–transfusion-dependent thalassemia.

Deferoxamine (Desferal)

Clinical Context:  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.

Class Summary

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.

Polyethylene glycol bowel prep (GoLYTELY, Colyte)

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

Class Summary

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

What is iron toxicity?What is the pathophysiology of iron toxicity?What is the prevalence of iron toxicity in the US?Which clinical history findings are characteristic of iron toxicity?What are the stages of iron toxicity?What are the clinical features of stage 1 iron toxicity?What are the clinical features of stage 2 iron toxicity?What are the clinical features of stage 3 iron toxicity?What are the clinical features of stage 4 iron toxicity?What are the clinical features of stage 5 iron toxicity?What are the differential diagnoses for Iron Toxicity?Which lab tests are performed in the workup of iron toxicity?What is the role of serum iron measurement in the diagnosis of iron toxicity?What is the role of lab testing in the diagnosis of iron toxicity?What is the role of imaging studies in the diagnosis of iron toxicity?What is included in prehospital care for iron toxicity?How is iron toxicity treated in the emergency department (ED)?Which specialist consultations are beneficial to patients with iron toxicity?What is the role of medications for the treatment of iron toxicity?Which medications in the drug class GI decontaminants are used in the treatment of Iron Toxicity?Which medications in the drug class Chelating agents are used in the treatment of Iron Toxicity?

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.

Specialty Editors

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

Disclosure: Nothing to disclose.

John G Benitez, MD, MPH, Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

Disclosure: Nothing to disclose.

Chief Editor

Michael A Miller, MD, Clinical Professor of Emergency Medicine, Medical Toxicologist, Department of Emergency Medicine, Texas A&M Health Sciences Center; CHRISTUS Spohn Emergency Medicine Residency Program

Disclosure: Nothing to disclose.

Additional Contributors

David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

Disclosure: Nothing to disclose.

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