Iron poisoning

Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children younger than 6 years who have ingested pediatric multivitamin preparations. Iron tablets are available without a prescription and iron is available in many multivitamin-mineral supplements and in supplements that contain only iron, which may be perceived as health supplements with minimal toxic potential ¹. Dietary supplements that contain iron have a statement on the label warning that they should be kept out of the reach of children. When taken in excess, however, iron is far more dangerous than most prescription medications ². As few as 10 ferrous sulfate tablets (total of 600 mg elemental iron) can kill a small child ³. Indeed, iron is one of the leading causes of poisoning-related death in children ⁴.

Using population-based health care records, Juurlink et al ⁵ identified an association between hospital admission for iron poisoning in young children and the birth of a sibling. Children whose mothers had given birth to a sibling were almost twice as likely as children whose mothers had not given birth to a sibling to be admitted for iron poisoning within 6 months of birth (adjusted odds ratio 1.9). The postpartum year was associated with a consistently elevated risk, including an almost 4-fold increase in the risk of iron poisoning during the first postpartum month (adjusted odds ratio 3.6). This provides empirical evidence implicating perinatal iron therapy as a risk factor for childhood iron poisoning. Pregnancy is a major risk factor for iron poisoning in young children, and the period immediately after delivery is associated with the greatest risk. Almost half of all hospital admissions for iron poisoning in young children could be prevented by keeping iron supplements safely out of reach in the year before and after the birth of a sibling ⁵.

In 2017, the American Association of Poison Control Centers reported 4400 single exposures to iron and iron salts: 2181 were in children under the age of 6 years, 142 in children 6 to 12 years old, and 516 in patients 13 to 19 years old; there were eight major outcomes and two deaths. In addition, the American Association of Poison Control Centers reported 9640 single exposures to multiple vitamins with iron, 7926 of them in children younger than 6 years, with one major outcome and no deaths ⁶.

The potential severity of iron poisoning depends on the amount of elemental iron ingested. Calculation of the amount of elemental iron ingested involves the number of tablets ingested and the percentage of elemental iron in the salt that the tablets contain ⁷.

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 ⁸.

Many of the serious acute iron ingestions follow the pattern of iron ingestions in general and occur in children younger than 3 years. Children may show signs of toxicity with ingestions of 10-20 mg/kg of elemental iron ⁹. Serious toxicity is likely with ingestions of more than 60 mg/kg. Iron exerts both local and systemic effects and is corrosive to the gastrointestinal mucosa and can affect the heart, lungs, and liver. Excess free iron is a mitochondrial toxin that leads to derangements in energy metabolism.

Although iron poisoning is a clinical diagnosis, serum iron levels are useful in predicting the clinical course of the patient. In treatment of iron poisoning, consider both bowel decontamination with whole bowel irrigation and chelation using intravenous deferoxamine.

In addition, chronic iron overload may develop in pediatric cancer patients who receive multiple transfusions. At one center, iron overload was diagnosed in 37% of pediatric patients who received 10 or more transfusions. Chelation therapy may be beneficial in these cases ¹⁰.

To prevent iron poisoning, educate parents about the need for childproofing the home and keeping medications out of reach of children.

Iron poisoning causes

Ingestion of less than 20 mg/kg of elemental iron is non-toxic ¹¹. Ingestion of 20 mg/kg to 60 mg/kg results in moderate symptoms. Ingestion of more than 60 mg/kg can result in severe iron 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 ¹².

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 a significant ingestion, transferrin becomes saturated. Excess iron will circulate in the blood as free iron, which is directly toxic to target organs ¹³.

Iron toxicity pathophysiology

The absorption of iron is normally very tightly controlled by the gastrointestinal system. However, in iron overdose, local damage to the gastrointestinal mucosa allows unregulated absorption, which leads to potentially toxic serum iron levels.

Much of the pathophysiology of iron poisoning is a result of metabolic acidosis and its effect on multiple organ systems. Toxicity manifests as local and systemic effects. Typically, iron poisoning is described in 5 sequential phases. No consensus has been reached regarding the number of phases and the times assigned to those phases. Patients may not always demonstrate all of the phases.

Phase 1

Phase 1, initial toxicity, predominantly manifests as gastrointestinal effects. This phase begins during the first 6 hours postingestion and is associated with hemorrhagic vomiting, diarrhea, and abdominal pain. This is predominantly due to direct local corrosive effects of iron on the gastric and intestinal mucosa. Early hypovolemia may result from gastrointestinal bleeding, diarrhea, and third spacing due to inflammation. This can contribute to tissue hypoperfusion and metabolic acidosis.

Convulsions, shock, and coma may complicate this phase if the circulatory blood volume is sufficiently compromised. In these cases, the patient progresses directly to phase 3, possibly within several hours.

Phase 2

Phase 2 is known as the latent phase and typically occurs 4-12 hours postingestion. It is usually associated with an improvement in symptoms, especially when supportive care is provided during phase 1. During this time, iron is absorbed by various tissues, and systemic acidosis increases. Clinically, the patient may appear to improve, especially to nonmedical personnel, because the vomiting that occurs in phase 1 subsides. However, laboratory analysis demonstrates progressive metabolic acidosis and, potentially, the beginning of other end-organ dysfunction (ie, elevation of transaminase levels).

Phase 3

Phase 3 typically begins within 12-24 hours postingestion, although it may occur within a few hours following a massive ingestion. Following absorption, ferrous iron is converted to ferric iron, and an unbuffered hydrogen ion is liberated. Iron is concentrated intracellularly in mitochondria and disrupts oxidative phosphorylation, resulting in free radical formation and lipid peroxidation. This exacerbates metabolic acidosis and contributes to cell death and tissue injury at the organ level.

Phase 3 consists of marked systemic toxicity caused by this mitochondrial damage and hepatocellular injury. GI fluid losses lead to hypovolemic shock and acidosis. Cardiovascular symptoms include decreased heart rate, decreased myocardial activity, decreased cardiac output, and increased pulmonary vascular resistance. The decrease in cardiac output may be related to a decrease in myocardial contractility exacerbated by the acidosis and hypovolemia. Free radicals from the iron absorption may induce damage and play a role in the impaired cardiac function.

The systemic iron poisoning in phase 3 is associated with a positive anion gap metabolic acidosis. The following explanations for the acidosis have been proposed:

• Conversion of free plasma iron to ferric hydroxide is accompanied by a rise in hydrogen ion concentration.
• Free radical damage to mitochondrial membranes prevents normal cellular respiration and electron transport, with the subsequent development of lactic acidosis.
• Hypovolemia and hypoperfusion contribute to acidosis.
• Cardiogenic shock contributes to hypoperfusion.

A coagulopathy is observed and may be due to 2 different mechanisms. Free iron may exhibit a direct inhibitory effect on the formation of thrombin and thrombin’s effect on fibrinogen in vitro. This may result in a coagulopathy. Later, reduced levels of clotting factors may be secondary to hepatic failure.

Phase 4

Phase 4 may occur 2-3 days postingestion. Iron is absorbed by Kupffer cells and hepatocytes, exceeding the storage capacity of ferritin and causing oxidative damage. Pathologic changes include cloudy swelling, periportal hepatic necrosis, and elevated transaminase levels. This may result in hepatic failure.

Phase 5

Phase 5 occurs 2-6 weeks postingestion and is characterized by late scarring of the gastrointestinal tract, which causes pyloric obstruction or hepatic cirrhosis.

Iron poisoning prevention

Most iron ingestions are accidental. As for any medication, preventive measures include keeping the bottles of iron supplements, with childproof tops, inaccessible to children. Changing the appearance of prenatal vitamins to make them look less like candy has been considered ¹⁴. This would be ideal.

In 1997, the US Food and Drug Administration (FDA) issued a regulation requiring unit-dose packaging for iron-containing products with 30 mg or more of iron per dosage unit. Because of the time and effort to open unit-dose packages, the FDA believes this packaging limits unintentional access to children. This requirement is in addition to existing Consumer Product Safety Commission regulations that require child-resistant packaging for most iron-containing products. In 2003, this requirement was rescinded because of a lawsuit in which the National Health Alliance charged that the FDA had no jurisdiction over the packaging of dietary supplements.

Iron poisoning symptoms

As with pediatric poisonings in general, pediatric iron poisonings are typically unintentional. Children may ingest the iron prescribed to mothers as prenatal vitamins or postpartum supplements. Other iron exposures include ingestion of iron-fortified children’s vitamins, although these tend to be less toxic. Parents may not immediately be aware of the ingestion or the specific amount of the iron tablets ingested.

As stated in iron toxicity pathophysiology, iron toxicity is typically described in 5 sequential phases. Universal agreement does not exist as to the number of phases or the times assigned to those phases. Patients may not always demonstrate each of the phases.

If possible, determining the number of pills ingested, how much iron was in each pill, and the of iron in the supplement is important.

Different formulations of iron contain varying amounts of elemental iron, as follows:

• Ferrous sulfate – 20% elemental iron
• Ferrous gluconate- 12% elemental iron
• Ferrous fumarate – 33% elemental iron
• Ferrous lactate – 19% elemental iron
• Ferrous chloride – 28% elemental iron

The following is a formula used to calculate the amount of ingested iron for a 10-kg child who consumed 10 tablets of 320 mg ferrous gluconate (12% elemental iron per tablet):

• 10 tablets × 38.4 mg elemental iron per tablet = 384 mg/10 kg = 38.4 mg/kg

Carbonyl iron and iron polysaccharide complex are nonionic forms of iron that have less toxicity than ferrous salts.

Attempt to determine the time of ingestion. This is important in determining observation periods and timing of serum levels.

Few, if any, physical examination findings are specific to iron toxicity. 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 ⁸.

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

Overall findings tend to vary by stage (phase), as follows:

• Phase 1. During the first stage (0.5 to 6 hours postingestion), the patient mainly exhibits gastrointestinal symptoms including abdominal pain, vomiting, diarrhea, hematemesis, and hematochezia. This stage is associated with hemorrhagic vomiting, diarrhea, and abdominal pain due to mucosal injury. The hemorrhagic gastrointestinal symptoms are due to the direct effects of iron on the gastrointestinal mucosa. A patient is unlikely to develop significant systemic toxicity without first having gastrointestinal symptoms. In severe cases, the gastrointestinal losses of blood and fluid may be massive and lead to shock and coma.
• Phase 2. The second stage (6 to 24 hours postingestion) represents an apparent recovery phase, as the patient’s gastrointestinal symptoms may resolve despite toxic amounts of iron absorption, especially when supportive care has been provided during phase 1. This period of apparent recovery may be confusing. In mild cases, this recovery may represent true recovery. However, in serious ingestions, it may represent only a temporary respite or may not occur at all; the patient may progress directly to phase 3. The etiology of phase 2 is unclear, but it may represent the time it takes for iron to distribute throughout the body and for systemic injury to occur. The only findings on examination may be lethargy, mild tachycardia, or tachypnea.
• Phase 3. The third stage (6 to 72 hours postingestion) is characterized by the recurrence of gastrointestinal symptoms, shock, and metabolic acidosis. Iron-induced coagulopathy, shock, seizures, and altered mental status due to mitochondrial damage and hepatocellular injury. Cardiomyopathy, and renal failure are also observed in this stage.
• Phase 4. The fourth stage (12 to 96 hours postingestion) is characterized by elevation of aminotransferase levels and possible progression to hepatic failure.
• Phase 5. The fifth stage (2 to 8 weeks postingestion) represents the consequences of the healing of the injured gastrointestinal mucosa including pyloric or proximal bowel scarring and obstruction and hepatic cirrhosis. However, these complications are rare, even in severe cases.

Iron poisoning diagnosis

Iron toxicity diagnosis is based on the history and clinical presentation and any studies are simply adjuncts. Toxic effects of iron may occur at doses of 10-20 mg/kg of elemental iron. Serum iron levels are used to determine a patient’s potential for toxicity.

Little is known about the absorption rate of iron in an overdose, the timing of peak serum iron levels, or the rate at which serum levels fall from their peak levels. Serum iron levels generally correlate with clinical severity and are as follows:

• Mild – Less than 300 µg/dL
• Moderate – 300-500 µg/dL
• Severe – More than 500 µg/dL

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.

Difficulties involved with interpretation of serum iron levels include the following:

• The ideal serum iron level is a peak level at 2-6 hours postingestion, and the time from ingestion is often unknown.
• Deferoxamine interferes with standard assays and leads to falsely decreased iron levels.
• Serum iron levels may not be available in a timely fashion. Serum levels obtained more than 8-12 hours postingestion may not be useful because iron redistributes into the tissues and the serum level does not reflect the total body burden of iron.

Total iron-binding capacity (TIBC) has traditionally been used to determine toxicity. Previously, a patient with a serum iron level greater than the total iron-binding capacity was thought to be at risk for developing systemic toxicity. However, determining the total iron-binding capacity in the presence of large amounts of iron or deferoxamine may yield a falsely elevated number. Hence, a total iron-binding capacity above the iron level does not indicate sufficient binding capacity, and this test is not useful in determining the likelihood of toxicity ¹⁵.

Because iron levels are not always readily available, the predictive value of other laboratory test results has been explored. Previously, a white blood cell count greater than 15,000/µL and a serum glucose level greater than 150 mg/dL were said to correlate with iron levels greater than 300 µg/dL. However, more recent studies do not support the predictive value of these ancillary tests, and they are not useful in the setting of iron poisoning.

Deferoxamine challenge test

The deferoxamine challenge test consists of administering a single dose of deferoxamine that binds available free iron and is excreted in the urine as the ferrioxamine complex (deferoxamine and iron). This complex changes the urine to a reddish (vin rosé) color, indicating the need for chelation. However, the urine does not change color reliably, even when elevated serum iron levels are present.

This test is not reliable and does not alleviate the need for monitoring serum iron levels. Therefore, one should not rely on the deferoxamine challenge test.

Iron poisoning treatment

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.

The first step in treating a case of acute iron toxicity is to provide appropriate supportive care, with particular attention to fluid balance and cardiovascular stabilization. Initial treatment should also address the issue of preventing further absorption of iron by the gastrointestinal tract.

Patients who have gastrointestinal 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.
   • Deferoxamine is the iron-chelating agent of choice ¹⁶. Deferoxamine binds absorbed iron, and the iron-deferoxamine complex is excreted in the urine. Deferoxamine does not bind iron in hemoglobin, myoglobin, or other iron-carrying proteins. Base the indications for using deferoxamine on both clinical and laboratory parameters. Indications for treatment include shock, altered mental status, persistent gastrointestinal symptoms, metabolic acidosis, pills visible on radiographs, serum iron level greater than 500 µg/dL, or estimated dose greater than 60 mg/kg of elemental iron. Initiate chelation if a serum iron level is not available and symptoms are present.

      

   • Deferoxamine may be administered intramuscularly or intravenously. The intramuscular route is not recommended because it is painful and less iron is excreted compared with the intravenous route. Intravenously, deferoxamine is given as a continuous infusion. The standard dose is 15 mg/kg/h, with an initial dose administered for 6 hours ¹⁷.
   • No clear end point of therapy is noted; however, indications for cessation include significant resolution of shock and acidosis. Infusion of deferoxamine for 6-12 hours has been suggested for moderate toxicity. For severe toxicity, administer deferoxamine for 24 hours. Because these end points are arbitrary, observe the patient for the recurrence of toxicity 2-3 hours after the deferoxamine has been stopped.

      

   • Adverse effects from deferoxamine are unusual. Pulmonary toxicity (ie, acute respiratory distress syndrome [ARDS], tachypnea) has been described, especially if patients are treated with deferoxamine for more than 24 hours. Rate-related hypotension can occur. Therefore, monitor the patient while titrating the infusion rate upward to a final rate of 15 mg/kg/h ¹⁸.
3. Whole-bowel irrigation with polyethylene glycol solution may clear the gastrointestinal 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 gastrointestinal 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 gastrointestinal symptoms that resolve without metabolic acidosis and serum iron level under 350 mg/dL after a 6 to 12 hour observation period ¹⁹.

Ipecac-induced emesis is not recommended. This is especially true in iron ingestion, as gastrointestinal distress is an early finding in iron poisoning and is present in all potentially serious ingestions, and ipecac-induced vomiting may cloud the clinical picture. In any event, ipecac is rapidly becoming unavailable ²⁰.

Gastric lavage is not recommended because iron tablets are relatively large and become sticky in gastric fluid, making lavage unlikely to be of benefit.

Whole bowel irrigation has been used to speed the passage of undissolved iron tablets through the gastrointestinal tract, although there is no convincing evidence from clinical studies that it improves the outcome ²¹. A polyethylene glycol electrolyte solution (eg, GoLYTELY) may be administered orally or nasogastrically at a rate of 250-500 mL/h for toddlers and preschoolers and 2 L/h for adolescents. Continue irrigation until the repeat radiographic findings are negative or rectal effluent is clear.

If retained iron tablets are evident after gastrointestinal decontamination, consider endoscopy or surgery for their removal. Failure to remove the iron can result not only in continued iron absorption and exacerbation of systemic symptoms but also in gastric perforation and severe hemorrhage.

Iron poisoning prognosis

Most iron exposures result in minimal toxicity. However, concentrated iron supplement overdoses can result in serious complications and death.

If a patient does not develop symptoms of iron toxicity within 6 hours of ingestion, iron toxicity is unlikely to develop. Expect clinical toxicity following an ingestion of 20 mg/kg of elemental iron. Expect systemic toxicity with an ingestion of 60 mg/kg. Ingestion of more than 250 mg/kg of elemental iron is potentially lethal.

Complications of iron toxicity include the following:

• Infectious -Yersinia enterocolitica septicemia
• Pulmonary – Acute respiratory distress syndrome (ARDS)
• Gastrointestinal – Fulminant hepatic failure, hepatic cirrhosis, pyloric or duodenal stenosis

Susceptibility to Yersinia enterocolitica infection or sepsis is heightened in these patients because Yersinia requires iron as a growth factor. Deferoxamine acts to solubilize iron and aid in intracellular entry for Yersinia. Suspect Yersinia infection in patients who develop abdominal pain, fever, and diarrhea following resolution of iron toxicity.

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