Iron Toxicity


Article Author:
Ho-Wang Yuen


Article Editor:
Wenxia Becker


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
10/30/2019 1:22:06 PM

Introduction

Iron is found in many over-the-counter (OTC) multivitamins. Iron toxicity from intentional or accidental ingestion is a common poisoning. The acute ingestion of iron is especially hazardous to children. Life-threatening toxicity is associated with pediatric ingestion of potent adult preparations, such as prenatal vitamins. Serious iron ingestion in adults is usually associated with suicide attempts.[1][2]

Accidental ingestions are more common in children less than 6 years. In addition, iron toxicity may also develop after multiple blood transfusions for a chronic disorder like thalassemia, sickle cell, and hematological cancers.

Etiology

Ingestion of less than 20 mg/kg of elemental iron is non-toxic. Ingestion of 20 mg/kg to 60 mg/kg results in moderate symptoms. Ingestion of more than 60 mg/kg can result in severe toxicity and lead to severe morbidity and mortality. The amount of elemental iron ingested is different depending on the formulations of iron salts. The most common iron formulations are 325 mg ferrous sulfate tablets, which contains 20% (or 65 mg) of elemental iron per tablet; 300 mg ferrous gluconate tablets, which contain 12% (or 36 mg) of elemental iron per tablet; and 100 mg ferrous fumarate tablets, which contain 33% (or 33 mg) of elemental iron per tablet. Prenatal vitamins may contain 60 to 90 mg of elemental iron per tablet. Children's vitamins vary from 5 to 19 mg of elemental iron per tablet.[1]

Epidemiology

In 2015, the Annual Report of the American Association of Poison Control Centers (AAPCC) National Poison Data System reported 4072 single exposures to iron or iron salts. Out of these, 3211 cases were unintentional ingestion. Furthermore, 2036 of reported cases occurred in children 5 years old or younger, and 1161 cases were treated in a healthcare facility. There was one death.[3]

Pathophysiology

Iron toxicity is classified as corrosive or cellular. Ingested iron can cause direct caustic injury to the gastrointestinal mucosa, resulting in nausea, vomiting, abdominal pain, and diarrhea. Significant fluid and blood loss can lead to hypovolemia. Hemorrhagic necrosis of gastrointestinal mucosa can lead to hematemesis, perforation, and peritonitis. At the cellular level, iron impairs cellular metabolism in the heart, liver, and central nervous system. Free iron enters cells and concentrates in the mitochondria. This disrupts oxidative phosphorylation, catalyzes lipid peroxidation, forms free radicals, and ultimately leads to cell death.[4]

When cellular injury occurs, metabolic acidosis is common.

Toxicokinetics

Serum iron level peaks at 2 to 4 hours post-ingestion, but serum concentrations of enteric-coated or sustained-release formulations are erratic and warrant serial levels. Approximately 10% of ingested iron is absorbed from the intestine and is subsequently bound to transferrin. Normal serum iron levels range from 50 to 150 micrograms/dL, and total iron-binding capacity (TIBC) ranges from 300 to 400 micrograms/dL. When iron levels rise after significant ingestion, transferrin becomes saturated. Excess iron will circulate in the blood as free iron, which is directly toxic to target organs.[5]

History and Physical

The clinical course of iron toxicity is divided into five stages. The progression from stage to stage may be very rapid, and not every patient goes through every stage.

  1. During the first stage (0.5 to 6 hours), the patient mainly exhibits gastrointestinal (GI) symptoms including abdominal pain, vomiting, diarrhea, hematemesis, and hematochezia.
  2. The second stage (6 to 24 hours) represents an apparent recovery phase, as the patient’s GI symptoms may resolve despite toxic amounts of iron absorption.
  3. The third stage (6 to 72 hours) is characterized by the recurrence of GI symptoms, shock, and metabolic acidosis. Iron-induced coagulopathy, hepatic dysfunction, cardiomyopathy, and renal failure are also observed in this stage.
  4. The fourth stage (12 to 96 hours) is characterized by an elevation of aminotransferase levels and possible progression to hepatic failure.
  5. The fifth stage (2 to 8 weeks) represents the consequences of the healing of the injured GI mucosa including pyloric or proximal bowel scarring and obstruction.

A patient may present in or skip any of the five stages. Determination of the iron toxicity stage should be based on symptoms and clinical manifestations and not on time of ingestion.[4]

Evaluation

The diagnosis of iron toxicity is based on the history and clinical presentation. Serum iron levels are used to determine a patient’s potential for toxicity. A serum iron level measured at its peak, 4 to 6 hours after ingestion, is the most useful laboratory test. Sustained-release or enteric-coated preparation may have erratic absorption, and therefore a second level 6 to 8 hours post-ingestion should be checked. Peak serum iron levels below 350 micrograms/dL are associated with minimal toxicity. Levels between 350 to 500 micrograms/dL are associated with moderate toxicity. Levels above 500 micrograms/dL are associated with severe systemic toxicity. Iron is rapidly cleared from the serum and deposited in the liver. Therefore, the iron level drawn after ingestion may be deceptively low if measured after its peak.

Other laboratory tests include electrolytes, kidney function, serum glucose, coagulation studies, complete blood count, and liver function. Plain radiographs may reveal iron in the GI tract, but many iron preparations are not radiopaque. Normal radiographs do not exclude iron ingestion.[6]

X-rays may show the radiopaque iron tablets for 2-6 hours post-ingestion. One may be able to see the pills on the KUB film. However, there is no correlation between radiopacities on x-rays and the severity of poisoning.

Treatment / Management

Patients who remain asymptomatic 4 to 6 hours after ingestion or those who have not ingested a potentially toxic amount do not require any treatment for iron toxicity.

Patients who have GI symptoms that resolve after a short period of time and have normal vital signs require supportive care and an observation period, as it may represent the second stage of iron toxicity.

Patients who are symptomatic or demonstrate signs of hemodynamic instability require aggressive management and admission to an intensive care unit. The following is used for the treatment of iron toxicity:

  1. IV crystalloid infusion is administered to correct hypovolemia and hypoperfusion.
  2. Deferoxamine, a chelating agent that can remove iron from tissues and free iron from plasma, is indicated in patients with systemic toxicity, metabolic acidosis, worsening symptoms, or a serum iron level predictive of moderate or severe toxicity. It is administered as a continuous infusion at 15 mg/kg/hr for up to 24 hours with a maximum dose of 35 mg/kg/hr if there is no rate-related hypotension. The maximum daily dose is 6 g. Clinical recovery guides the termination of deferoxamine therapy but the duration of therapy is typically 24 hours. Consultation with a toxicologist is highly recommended.
  3. Whole-bowel irrigation with polyethylene glycol solution may clear the GI tract of iron pills before absorption and should be administered at 250 to 500 mL/h in children and 1.5 to 2 L/h in adults via nasogastric tube.
  4. Coagulopathy can be corrected with vitamin K (5 to 10 mg subcutaneously) and fresh frozen plasma (10 to 25 mL/kg in adults; 10 mL/kg in children).
  5. Gastric lavage with a large-bore orogastric tube is only indicated if abdominal x-ray demonstrates a large number of visible pills in the stomach. For most cases, the risks of gastric lavage outweigh the benefits.
  6. Activated charcoal binds iron poorly and is not effective.

Patients with GI symptoms or evidence of dehydration should be admitted. Patients receiving deferoxamine treatment should be admitted as well. Intensive care unit admission is indicated for patients presenting with coma, shock, metabolic acidosis, or iron levels over 1000 mg/dL. Psychiatric referral is indicated for patients with an intentional overdose. Patients can be safely discharged if they are asymptomatic after a 6 to 12-hour observation period and have a negative radiograph, or if they have mild GI symptoms that resolve without metabolic acidosis and serum iron level under 350 mg/dL after a 6 to 12 hour observation period.[7][4][2][8]

Patients with iron bezoars may require surgery. In severe cases, hemodialysis can also be effective.

Differential Diagnosis

Other diseases or conditions that can present similarly to iron toxicity include sepsis; acetaminophen toxicity; other toxic ingestions that cause anion gap metabolic acidosis including salicylate, cyanide, methanol, and ethylene glycol toxicity; mushroom ingestion; heavy metal toxicity; theophylline toxicity; and GI bleed from other causes.

Complications

  • Liver necrosis
  • Cardiogenic shock
  • Myocardial dysfunction
  • Coma
  • Seizures
  • Coagulopathy
  • Esophagitis
  • Anemia
  • ARDS
  • Stricture formation of the intestine
  • Gastric perforation

Enhancing Healthcare Team Outcomes

Iron poisoning is commonly seen in the emergency room. The key reason why children overdose on iron tablets is because they appear as chocolate candy. In adults, the cause may be suicide or chronic blood transfusions. Iron toxicity has significant morbidity and mortality.

The management of patients with iron toxicity is usually done with an interprofessional team that includes the emergency department physician, poison control specialist, internist, intensivist, nurse practitioner, pharmacist, and a hematologist. The acute toxicity requires reversal of the hypotension and hypovolemia. The use of the chelating agent, deferoxamine may be used in severe cases of metabolic acidosis. Patients with hemodynamic instability should be admitted to the ICU. The nurses should be fully aware of the potential toxicity of iron and closely monitor the patient. The nephrologist should be consulted in case dialysis is required.

The key is to prevent iron toxicity. The pharmacist should educate parents on keeping all iron tablets in locked cabinets and away from the reach of children. Those patients who undergo multiple transfusions should be followed by the hematology nurse and regular blood work should be done to ensure that iron toxicity is not present.

Prior to discharge, a mental health nurse should see the patient if there is suspicion of an intentional overdose. Finally, it is important to educate patients that empirical consumption of iron without any medical indications is not recommended. [7][4][2][8]

Only through a team approach can the morbidity of iron be reduced. [Level V]


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Iron Toxicity - Questions

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A 17-year-old male is brought into the emergency department 6 hours after intentional ingestion of an unknown amount of iron pills in a suicide attempt. The patient states he had several episodes of vomiting prior to arrival, but his symptoms have improved. He continues to have suicidal ideation. His vital signs are stable. Which of the following would be the appropriate management?



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Which of the following is the most efficient method for removing iron from the body?



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Which of the following is a typical outcome of acute iron poisoning?



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What is believed to be responsible for the tissue and organ damage that occurs from an excessive oral dose of iron?



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A 14-month-old child, weighing 10 kg, swallowed 14 tablets of an iron supplement 2 hours ago. Each tablet contains 65 mg of elemental iron. Upon physical exam, level of consciousness is normal, blood pressure is 80/50 mm Hg, and the abdomen is diffusely tender. The patient has an episode of nonbloody emesis and vomits four iron tablets. Abdominal x-ray shows 10 tablets in the stomach. How much deferoxamine should be administered?



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What drug is used to treat acute iron toxicity?



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Which of the following patients are at highest risk of excess iron?



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Which of the following is used in the treatment of iron overdose?



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If a child has ingested an entire bottle of multivitamins, which of the following is most important to know?



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A young child is brought to the emergency department after taking a full bottle of iron tablets. He is lethargic but his vitals signs are stable. His oxygenation is 100% on room air. What is the ideal treatment for this child?



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Which of the following is part of the treatment for iron toxicity?



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A 14-year-old girl was brought to the emergency department after she swallowed 20 tablets of 325 mg ferrous sulfate as a suicide attempt ten hours prior to arrival at the emergency department. The patient weights 50 kg. The patient initially experienced abdominal and vomiting, which have spontaneously resolved. She is currently asymptomatic and her vital signs are stable. What is the most appropriate step?



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Which of the following can be a consequence of an iron overdose?



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Which stage of iron toxicity is associated with liver failure?



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Iron Toxicity - References

References

Sane MR,Malukani K,Kulkarni R,Varun A, Fatal Iron Toxicity in an Adult: Clinical Profile and Review. Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine. 2018 Nov     [PubMed]
Mowry JB,Spyker DA,Brooks DE,Zimmerman A,Schauben JL, 2015 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 33rd Annual Report. Clinical toxicology (Philadelphia, Pa.). 2016 Dec     [PubMed]
Baranwal AK,Singhi SC, Acute iron poisoning: management guidelines. Indian pediatrics. 2003 Jun     [PubMed]
Singhi SC,Baranwal AK,M J, Acute iron poisoning: clinical picture, intensive care needs and outcome. Indian pediatrics. 2003 Dec     [PubMed]
Lacouture PG,Wason S,Temple AR,Wallace DK,Lovejoy FH Jr, Emergency assessment of severity in iron overdose by clinical and laboratory methods. The Journal of pediatrics. 1981 Jul     [PubMed]
Tenenbein M,Kowalski S,Sienko A,Bowden DH,Adamson IY, Pulmonary toxic effects of continuous desferrioxamine administration in acute iron poisoning. Lancet (London, England). 1992 Mar 21     [PubMed]
Bergeron RJ,Wiegand J,Brittenham GM, HBED: A potential alternative to deferoxamine for iron-chelating therapy. Blood. 1998 Feb 15     [PubMed]
Madiwale T,Liebelt E, Iron: not a benign therapeutic drug. Current opinion in pediatrics. 2006 Apr     [PubMed]

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