The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition Dr. Lynette Young. This current third edition chapter is a revision and update of the original author’s work.
A 3-year-old girl presents to the emergency department with a chief complaint of bloody stool, abdominal pain, and vomiting. Her mother, who takes iron supplements daily, noticed her daughter had gotten into her medicine cabinet and started to eat her iron tablets. The mother is unsure of how many tablets her daughter consumed. Since the patient was asymptomatic initially, mother did not bring her to the ER until the patient started showing signs of trouble.
Exam: VS T 36.9, P 130, R 23, BP 78/40, weight 14kg (50th percentile). She is lethargic and being carried by her mom. Her skin is cold and central capillary refill is 3 seconds. HEENT exam is normal. Her oral mucosa is sticky. Her neck is nontender. Heart regular rhythm, no murmurs. Lungs are clear. Her abdomen is soft and tender in the upper quadrants, with active bowel sound and no rebound or guarding. Her distal pulses are weak and her distal extremities are cold.
An abdominal Xray shows radiopaque tablets in the stomach and intestine.
Poisoning is one of the most common emergencies in the pediatric population. Specifically, iron is a dangerous, yet common, ingestion that many children often mistake for candy. Patients may start to become symptomatic once the amount of iron ingestion reaches the minimal toxic dose of 20 mg/kg of elemental iron (1). Ingestion of 40 kg/kg may lead to moderate toxicity and ingestion of 60 mg/kg can lead to severe toxicity. Rarely, iron overdose can also occur intravenously; however, management for this is the same as an overdose via oral ingestion and the source of the intravenous iron should be stopped immediately.
Iron comes in different compounded forms such as iron sulfate, iron fumarate, and iron gluconate. Iron toxicity is based on the dose of elemental iron, rather than the dose of its compounded form (2).
We receive our dietary iron primarily from meat and plants. Dietary iron exists in two oxidative forms: ferrous (Fe2+) and ferric (Fe3+). Ferrous iron is a component of hemoglobin while ferric iron cannot bind oxygen and is a component of methemoglobin. Free iron (Fe2+) can form reactive oxygen species and can lead to oxidative stress and DNA damage (3). The low pH environment in our stomach and proximal duodenum helps convert iron into the ferrous state, which allows our duodenum and jejunum to absorb it. There is no specific means of iron excretion in our bodies so an important enzyme to note is hepcidin, which is a liver enzyme that restricts the amount of iron that we absorb in our intestine. If we have a high amount of total iron stores in our body, hepcidin concentrations increase, which leads to a decrease in iron absorption (3). Iron transport involves ferroportin, which transports ferrous iron from our intestinal cells to our blood stream. Similarly, transferrin transports iron to the bone marrow in order to synthesize hemoglobin (3).
The total iron binding capacity (TIBC, also referred to as the transferrin level) is usually 300-500 mcg/dl and normal serum iron levels are 50-150 mcg/dl. The pathophysiology of iron poisoning is primarily direct damage to the gastrointestinal mucosa and hepatic necrosis from the corrosive effects of iron. This damage can lead to hemorrhage, liver damage, fluid loss, third spacing, and consequently, hypovolemia and shock. Another mechanism of toxicity is due to the presence of free iron in the circulation (1). Free iron may affect many organs including the kidneys, brain, lung, and heart; however, it builds up mainly in the liver. Free iron becomes particularly concentrated in the mitochondria, causing oxidative phosphorylation uncoupling as a mechanism leading to cellular toxicity. Lactic acidosis results from tissue hypoperfusion/cellular hypoxia. Free iron may also cause direct damage to the heart leading to decreased myocardial contractility, and consequently, cardiac dysfunction in affected patients. Coagulopathies may occur from effects of iron on clotting factors (4).
There are five clinical stages of iron toxicity. In Stage I (0 to 6 hours), symptoms are largely due to the direct corrosive effect to the gastrointestinal mucosa from free-radical formation. Patients may have symptoms such as abdominal pain, vomiting GI bleeding, diarrhea, fever, and leukocytosis.
Stage II (6 to 24 hours) is called the latent period and involves the cessation of gastrointestinal symptoms of Stage I, although it does not always occur. It does not signify the resolution of iron toxicity. Stage III (12 to 24 hours) is also known as the shock phase and can include symptoms such as metabolic acidosis, circulatory collapse and failure, cyanosis, DIC (disseminated intravascular coagulation), neurologic damage, coma, seizure, shock, and coagulopathy secondary to thrombin inhibition by free iron. In Stage IV (24 to 48 hours), iron-induced hepatotoxicity is the main feature, as the liver absorbs iron readily and is the first organ that iron encountered when it enters the portal system (2). In Stage V (3 to 6 weeks), the consequences of the corrosive effects of iron to the gastrointestinal mucosa may become apparent through scarring and subsequent stenosis and strictures of the pylorus and intestines. Obstruction may occur at the gastric outlet or small intestines (1).
A patient who has ingested less than 20 mg/kg of elemental iron and is asymptomatic or has been symptom-free for more than 6 hours, does not require treatment and can be discharged home (2). A serum iron level should be obtained on arrival to the emergency department if the patient is symptomatic or has ingested more than 60 mg/kg of elemental iron. A serum iron level should be drawn 4 to 6 hours post-ingestion if the patient is asymptomatic and has ingested 20 to 60 mg/kg or an unknown amount of elemental iron. With a serum iron level of less than 350 mcg/dl, the patient usually remains asymptomatic. There is potentially moderate toxicity with an iron level between 350 to 500 mcg/dl and patients often progress to mild Stage I symptoms. Serum iron levels greater than 500 mcg/dl fall in the severe toxicity range and these patients have a significant risk of progression to Stage III (4). If the iron tablet is enteric-coated or a sustained-released tablet, the absorption may be delayed necessitating a second level drawn 6 to 8 hours after ingestion. The serum iron level may not be reliable if deferoxamine has been given. TIBC is not a reliable lab test for toxicity levels. Other laboratory tests that are recommended are serum electrolytes, BUN, creatinine, serum glucose, blood gas, CBC, and liver function tests. This is because iron toxicity can cause metabolic acidosis, hyperglycemia, increased liver enzymes, hyperbilirubinemia, and leukocytosis. An abdominal X-ray can show radiopaque iron tablets; however, if negative, this can be deceiving because some iron compounds and preparations do not appear opaque on plain radiographs (4).
A toxicologist should be consulted in the management of serious iron overdose cases. Severe overdose includes administration of deferoxamine, gastrointestinal decontamination, and supportive therapy. Deferoxamine chelates ferric iron and works by removing iron from tissues and blood. It is indicated in the following situations: if serum iron levels are greater than 500 mcg/dL, or if serum iron levels are greater than 300 mcg/dL associated with acidosis, hyperglycemia, or leukocytosis, if the patient has severe gastrointestinal symptoms, or if more than 100 mg/kg of iron was consumed (1). If serum iron levels are still unknown, a dose of deferoxamine can be given as a test. The iron-deferoxamine complex (ferrioxamine) is water-soluble and is excreted in the urine as a red/pink color (vin rose), the test is positive, meaning the patient consumed a clinically significant amount of iron (1). Initially, deferoxamine is administered IV at of 5 to 15 mg/kg/hr, with 15 mg/kg/hr being the safe maximum dose, although faster administration rates have been reported (2). The maximum daily dosage is 360 mg/kg up to 6 g total per day. Rapid infusion of deferoxamine may cause hypotension. The dosage of deferoxamine can be tapered down, depending on the patient’s response (5).
Whole bowel irrigation (WBI) is recommended only when life-threatening ingestion is present. The preferred liquid for WBI is polyethylene glycol and it should be performed via a nasogastric tube until the patient expels clear rectal fluids. Children 9 months to 6 years of age should receive 500 mL/hr, children 6 to 12 years of age should receive 1000 mL/hr, and children 13 years and older should receive 2000 mL/hr (2).
Activated charcoal does not bind to iron and, therefore is not an effective iron overdose treatment. However, it can be given in suspected cases of polysubstance ingestion (1). Gastric lavage is not usually recommended as there is a lack of evidence of its clinical benefit (4).
Hypovolemia and possible shock secondary to bleeding should be anticipated and addressed. IV crystalloid infusions are generally used to treat this. Dopamine and norepinephrine can be used if the hypotension persists. Coagulopathy may be treated with a subcutaneous administration of 5 to 10 mg of vitamin K or 10 mL/kg of fresh frozen plasma. Admission to the ICU is indicated for patients with metabolic acidosis, iron levels above 1000 mg/dL, and those in a coma or in shock (4).
With the creation of child-safe packaging, iron poisoning has become far less common. Mortality is low in iron poisoning patients if they do not have shock or coma. Patients may be discharged home from the emergency department after 6 to 12 hours of observation if they are asymptomatic and have a negative abdominal X-ray and a serum iron level of less than 350 mg/dL after the observation period (4). A psychiatric evaluation via a behavioral health specialist is needed if intentional ingestion is suspected.
Questions
1. True or False: Charcoal is effective in binding iron and should be given in significant iron ingestions.
2. Deferoxamine chelates the:
a. Ferrous ion (Fe2+).
b. Ferric ion (Fe3+).
3. The two basic mechanisms of iron toxicity include:
a. Direct corrosive effect on the gastrointestinal mucosa.
b. Formation of a toxic metabolite.
c. Binding to the protein transferrin.
d. Toxic effect of the free ion.
4. Gastrointestinal symptoms may improve in which clinical (latent) stage of iron poisoning?
a. Stage I
b. Stage II
c. Stage III
d. Stage IV
e. Stage V
5. True or False: Total iron binding capacity (TIBC) is a reliable predictor of toxicity in iron poisoning?
6. The whole bowel irrigation rate in children 9 months to 6 years of age is?
a. 500 mL/hr.
b. 250 mL/hr.
c. 750 ml\L/hr.
d. 1000 mL/hr.
References
1. Lowe GK. Chapter 20. Emergency Medicine. In: Brown LJ, Coller RJ, Miller LT (eds). Pediatrics, second edition. Wolters Kluwer, Philadelphia, 2019. pp:459-482.
2. Chang T P, Rangan C. Iron Poisoning. Pediatric Emergency Care. 2011;27(10):978-985. doi: 10.1097/PEC.0b013e3182302604.
3. Ems T, St. Lucia K, Huecker MR. Biochemistry, Iron Absorption. [Updated 2023 Apr 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448204/
4. Yuen HW, Becker W. Iron Toxicity. [Updated 2022 Jun 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www-ncbi-nlm-nih-gov.eres.library.manoa.hawaii.edu/books/NBK459224/
5. Renny MH, O’Donnell KA, Calello DP. Chapter 102. Toxicologic Emergencies. In Shaw KN, Barchur RG, Chaimberlain JM, et al. (eds). Fleisher & Ludwig’s Textbook of Pediatric Emergency Medicine. Eighth edition. Wolters Kluwer, Philadelphia, 2021. pp:1029-1083.
Answers to questions
1.False, 2.b, 3.a&d, 4.b, 5.False, 6.a