eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology
Toxicity, Iron
Updated: Jun 24, 2009
Introduction
Background
Iron poisoning is a common toxicologic emergency in young children. Contributing factors include the availability of iron tablets and their candylike appearance. Ferrous sulfate tablets (20% elemental iron) are routinely administered to postpartum women, many of whom have toddlers in the family. The potential severity of iron poisoning is based on the amount of elemental iron ingested. The amount of elemental iron ingested must be calculated based on the number of tablets ingested and the percentage of elemental iron in the salt.
Children may show signs of toxicity with ingestions of 10-20 mg/kg of elemental iron. Serious toxicity is likely with ingestions of more than 60 mg/kg. Iron exerts both local and systemic effects and is corrosive to the GI 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 administration of deferoxamine.
Pathophysiology
The absorption of iron is normally very tightly controlled by the GI system. However, in overdose, local damage to the GI mucosa allows unregulated absorption, which leads to potentially toxic serum 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 GI 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 GI 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 GI tract, which causes pyloric obstruction or hepatic cirrhosis.
The oxidative potential of iron was first proposed by Fenton in 1894. The importance of reduced oxygen species in biological reactions became apparent with the discovery of superoxide dismutase by McCord and Fridovich in 1969. The potential role of metal ion catalysis was reported the following year. Subsequently, a plethora of evidence has accumulated linking chronic excess body iron to cardiovascular disease, carcinogenesis, aging, stroke, Alzheimer disease, and Parkinson disease. The organ damage that occurs in the hereditary iron overloading disorders is well documented and can be averted and improved by decreasing the excess iron. Acute iron overload likewise produces tissue and organ damage due to the presence of free ionic iron.
Frequency
United States
In 2007, 49,440 vitamin preparation exposures (some of which contain iron) in children younger than 5 years were reported to the American Association of Poison Control Centers (AAPCC).1 In 2007, no pediatric deaths due to iron poisoning were reported. This reflects the trend that iron-related fatalities are becoming less common.
Mortality/Morbidity
Most exposures result in minimal toxicity. However, concentrated iron supplement overdoses can result in serious sequelae and death.
Age
Most exposures involve children younger than 6 years who have ingested pediatric multivitamin preparations. Many of the serious acute ingestions follow the pattern of ingestions in general and occur in children younger than 3 years.
Clinical
History
Most pediatric poisonings are unintentional. Specifically, in relation to iron toxicity, children may ingest the iron administered to mothers as prenatal vitamins or as postpartum supplements. Other iron exposures include ingestion of iron-fortified children's vitamins, although these tend to be less toxic. A recent study examined the effects of iron supplements in breastfed infants.2 Parents may not immediately be aware of the ingestion or the specific amount of the iron tablets ingested.
- If possible, determining the number of pills ingested, how much iron was in each pill, and the formulation 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 ten 320-mg tablets of ferrous gluconate (12% elemental iron per tablet):
10 tablets X 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.
Physical
As stated in 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.
Few, if any, physical examination findings are specific to iron toxicity.
- Phase 1 usually occurs within the first 6 hours postingestion. This phase is associated with hemorrhagic vomiting, diarrhea, and abdominal pain due to mucosal injury. The hemorrhagic GI symptoms are due to the direct effects of iron on the GI mucosa. A patient is unlikely to develop significant systemic toxicity without first having GI symptoms. In severe cases, the GI losses of blood and fluid may be massive and lead to shock and coma.
- Phase 2 usually occurs 6-12 hours postingestion and may be associated with an improvement in symptoms, 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 begins after 12-24 hours postingestion and consists of multisystem damage. This may include marked metabolic acidosis, coagulopathy, shock, seizures, and altered mental status due to mitochondrial damage and hepatocellular injury.
- Phase 4 occurs 2-3 days postingestion and is characterized by hepatic injury.
- Phase 5 occurs 2-6 weeks postingestion and is characterized by late scarring of the GI tract, which causes pyloric obstruction or hepatic cirrhosis. However, these complications are rare, even in severe cases.
Causes
- As with any ingestion, the risk of ingestion increases as the availability of the medication increases.
- Childproof containers for multivitamins and prenatal vitamins may be of some assistance in decreasing exposure. In addition, some consideration has been given to changing the appearance of prenatal vitamins to make them look less like candy.
- One study found an association between iron poisoning in young children and recent birth of a sibling.3
More on Toxicity, Iron |
 Overview: Toxicity, Iron |
| Differential Diagnoses & Workup: Toxicity, Iron |
| Treatment & Medication: Toxicity, Iron |
| Follow-up: Toxicity, Iron |
| Multimedia: Toxicity, Iron |
| References |
| Next Page » |
References
Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). Dec 2008;46(10):927-1057. [Medline].
[Best Evidence] Ziegler EE, Nelson SE, Jeter JM. Iron supplementation of breastfed infants from an early age. Am J Clin Nutr. Feb 2009;89(2):525-32. [Medline].
Juurlink DN, Tenenbein M, Koren G, Redelmeier DA. Iron poisoning in young children: association with the birth of a sibling. CMAJ. Jun 10 2003;168(12):1539-42. [Medline].
[Guideline] Manoguerra AS, Erdman AR, Booze LL, et al. Iron ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2005;43(6):553-70. [Medline].
Bryant SM, Leikin JB. Iron. Critical Care Toxicology. 2005;687-693.
Desferal (deferoxamine mesylate) [package insert]. East hanover, NJ: Novartis Pharmaceuticals Corporation; 2007. [Full Text].
Eldridge DL, Holstege CP. Utilizing the laboratory in the poisoned patient. Clin Lab Med. Mar 2006;26(1):13-30, vii. [Medline].
Engle JP, Polin KS, Stile IL. Acute iron intoxication: treatment controversies. Drug Intell Clin Pharm. Feb 1987;21(2):153-9. [Medline].
Fine JS. Iron poisoning. Curr Probl Pediatr. Mar 2000;30(3):71-90. [Medline].
Jacobs J, Greene H, Gendel BR. Acute iron intoxication. N Engl J Med. Nov 18 1965;273(21):1124-7. [Medline].
Madiwale T, Liebelt E. Iron: not a benign therapeutic drug. Curr Opin Pediatr. Apr 2006;18(2):174-9. [Medline].
McGuigan MA. Acute iron poisoning. Pediatr Ann. Jan 1996;25(1):33-8. [Medline].
Perrone J. Iron. Goldfrank's Toxicologic Emergencies. 2006;629-637.
Siff JE, Meldon SW, Tomassoni AJ. Usefulness of the total iron binding capacity in the evaluation and treatment of acute iron overdose. Ann Emerg Med. Jan 1999;33(1):73-6. [Medline].
Tenenbein M. Position statement: whole bowel irrigation. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol. 1997;35(7):753-62. [Medline].
Tenenbein M. Whole bowel irrigation in iron poisoning. J Pediatr. Jul 1987;111(1):142-5. [Medline].
Further Reading
Keywords
iron toxicity, iron poisoning, ferrous sulfate tablets, ferrous sulfate, ferrous gluconate, ferrous fumarate, ferrous lactate, ferrous chloride, metabolic acidosis, hemorrhagic vomiting, diarrhea, abdominal pain, hepatic failure, pyloric obstruction, hepatic cirrhosis, multivitamin ingestion, treatment, diagnosis
