Iron Imbalance in Children, Part 2: Identification and Treatment of Iron Poisoning
ABSTRACT: This article, the second of a 2-part series on iron imbalance in pediatric patients, focuses on iron poisoning due to an acute overingestion of elemental iron. It discusses the clinical and diagnostic clues to overdose, the effects of iron poisoning on specific organ systems, the differential diagnosis of iron overdose, and treatment approaches to iron poisoning in children.
Iron is an essential mineral and nutrient of the human body. It is vital for the normal function of bodily processes by which cells generate energy. The body does not make iron; hence, this element is acquired through dietary sources or supplements absorbed through the gastrointestinal (GI) tract. Too much iron—as well as too little iron—compromises body metabolism and physiology. An acute iron overdose directly threatens human health.1
This article focuses on the ingestion of too much iron. Human iron physiology and iron deficiency were described in the previously published part 1 of this series.2
Acute iron poisoning can be lethal, especially in young children. This essential mineral is found in over-the-counter daily multivitamins and also is prescribed as a solo preparation to treat iron deficiency and health conditions that warrant an increased daily iron intake.
Iron poisoning was a leading cause of death in U.S. children from 1983 to 1991, with almost one-third of all toxicologic deaths related to iron-containing products.3 A significant reason for this was the public perception that an iron-containing product was not medicinal and therefore could not be dangerous or cause harm. Many parents and caregivers did not store iron-containing products safely and out of children’s reach.
Today in the United States, pediatric deaths from iron toxicity have virtually disappeared. Data from the American Association of Poison Control Centers (AAPCC) show that the last recorded iron-related fatalities in U.S. children and adults occurred in 2003.4 Instrumental in this success was hallmark regulation enacted in 1997 by the U.S. Food and Drug Administration (FDA), which established two requirements: that readily visible warning labels be placed on pharmaceutical iron products, and that oral iron products containing more than 30 mg of elemental iron per dose be marketed and sold in unit-dose packaging (eg, blister packs, pouches, or other nonreusable containers).5-7 In 2003, the unit-dose packaging requirement was revoked due to legal issues; however, to date manufacturers have voluntarily continued to use unit-dose packaging given the well-documented decrease in pediatric iron poisonings.5-7
Although no U.S. pediatric fatalities have been reported for the past decade, vigilance about of iron exposure and overdose is essential. Children younger than 6 years old still represent the age group with the largest percentage of iron exposures, accounting for almost two-thirds of all exposures in 2008.4,5 The FDA currently mandates that manufacturers of iron-containing dietary supplements sold in solid-form (tablets or caplets but not powders) include a warning box on the package label to increase consumers’ awareness about the dangers of iron overdose.8 Unit-dose packaging, increased public awareness about iron toxicity, and the clinical recognition of toxic ingestions by caregivers and medical personnel all have had a role in decreasing the occurrence of iron exposures in children.
Chronic iron overload can develop over time in patients who require multiple red blood cell transfusions to treat underlying illnesses such as sickle cell disease, thalassemia, and myelodysplastic syndromes.9 Although chronic iron overload also is a diagnosis of medical concern, this article focuses on iron poisoning resulting from a single acute ingestion.
As with any toxic ingestion, iron overdose can occur at any age. Improper dosing of an infant younger than 1 year of age is termed a therapeutic misadventure, indicating that the infant’s caregiver administered a medication incorrectly in either dosage or frequency. Accidental or unintentional poisonings occur in toddlers and young children who can access medications or other toxic substances in an unsupervised environment.
Today, most childhood iron poisonings are accidental and result in minimal to no toxicity. Serious exposures involve prenatal or postpartum iron supplements and solo iron preparations; among younger children, lone iron preparations are the primary source of most lethal ingestions of iron due to these tablets’ small size, red coloring, and candy-like appearance.10,11
A study in Ontario, Canada, found an increased risk for iron poisoning in children younger than 3 years old when there had been a recent birth of a sibling in the household; this risk was highest during the first month postpartum.11 There was heightened risk for iron exposure for the first 6 months after the sibling’s birth, and the risk remained high for 1 year.11
Although it is a rarer occurrence, teenagers and adults may ingest a toxic amount of an iron preparation due to confusion about or misunderstanding of the amount of elemental iron contained in each dose. Different iron salts contain different amounts of elemental iron per tablet; for example, a ferrous sulfate tablet contains 65 mg, while a ferrous fumarate tablet contains 107.25 mg. Intent to cause self-harm also must be considered in cases of iron overdose in adolescents and adults.
Children’s chewable vitamins with iron are less likely than adult iron preparations to cause serious toxicity. Children’s chewable multivitamin supplements with iron have such a small amount of elemental iron per tablet (15 mg/tablet) that toxicity is rare. From 1983 to 1998, the AAPCC reported no fatalities in 195,780 exposures from chewable children’s vitamins with iron. However, within this same 15-year period, 60 deaths were reported among 147,079 ingestions of adult elemental iron preparations.12
Medicinal iron salt preparations, either over-the-counter or prescribed, have concentrations of elemental iron per unit measurement ranging from 12% to 33%. Different formulations can complicate the correct dosing of a particular iron supplement. A children’s chewable multivitamin with iron standardly contains 15 mg/tablet. However, a multivitamin caplet for teenaged girls contains 18 mg/caplet, whereas the comparable caplet for teenaged boys contains 9 mg/caplet. This difference of 9 mg/caplet between the sexes in adolescent dosages is due to the greater daily iron requirement for menstruating girls.
Knowledge of the number of tablets ingested and the corresponding percent of elemental iron in the salt preparation aids in determining the amount of elemental iron ingested.5,6 The amount of elemental iron ingested gives clues to potential toxicity. Toxic effects can start to occur at ingestions from 10 to 20 mg/kg of elemental iron. Ingestions of more than 50 mg/kg of elemental iron cause significant toxicity. A helpful clinical tool to quickly assess a patient’s potential ingestion severity after acute ingestion of an iron preparation, based on mg/kg of elemental iron, is as follows5,6:
• < 20 mg/kg ingested: no toxicity to mild toxicity
• 20-60 mg/kg ingested: mild to moderate toxicity
• > 60 mg/kg ingested: serious toxicity to potential lethality.
Acute iron poisoning produces negative multisystem responses within the human body. Neurologic, cardiovascular, GI, and metabolic systems are harmed due to iron’s caustic effects on GI mucosa and to the presence of circulating free unbound iron (Table 1).13 Free iron is a powerful vasodilator, increasing capillary and intravascular permeability. The caustic nature of iron weakens the intestinal protective barrier, and a large load of iron enters the circulation. Circulatory failure through direct action on peripheral blood vessels ensues.9
Iron’s corrosive action on the GI mucosa causes abdominal pain, vomiting, and diarrhea. Intestinal necrosis, perforation, and peritonitis follow. Hypovolemia occurs due to GI fluid and blood losses. Free iron also impacts cellular function as a mitochondrial poison. Disruption of oxidative phosphorylation leads to increased anaerobic metabolism, lactic acidosis, and, ultimately, shock.9
The clinical progression of iron poisoning is outlined into 5 stages (Table 2).10 However, variation in the medical literature exists as to the number of stages (usually 4 or 5 total) and the time intervals associated with each stage. In addition, not all patients will follow the stages in sequence.
Stage 1, the GI stage, generally occurs within 6 hours postingestion but can begin as early as 20 minutes postingestion. Patients may be febrile.9 Abdominal pain, nausea, emesis, and diarrhea occur. GI hemorrhage ensues due to iron’s direct caustic insult, presenting as hematemesis and hematochezia. Dehydration and hypovolemia occur from fluid and blood losses. Third-spacing of fluid into the interstitial space from ongoing tissue inflammation occurs. Tissue hypoperfusion and metabolic acidosis ensue. Severe toxicity can cause encephalopathy, shock, and coma within the first 6 hours after ingestion.9 In this clinical setting, the mortality rate is 10%.10
Stage 2, the latent or “honeymoon” phase, begins 6 to 12 hours and up to 48 hours after ingestion, and it may last 24 hours. It is characterized by remission of GI symptoms as result of the focus on aggressive fluid resuscitation to treat the chief symptoms of stage 1.5,14 Laboratory test results reflect the progression of toxicity, revealing metabolic acidosis, coagulopathy, and hepatic dysfunction. Patients may not experience a latent phase at all and may progress directly from stage 1 to stage 3.5,15
Stage 3, the metabolic/cardiovascular stage, occurs 12 to 48 hours postingestion but can start earlier at 6 to 8 hours postingestion in cases of serious toxicity. Stage 1’s GI symptoms return after some resolution in stage 2. Stage 3 is characterized by systemic toxicity with hemodynamic instability, coagulopathy, and metabolic acidosis. Disseminated intravascular coagulation can present due to free iron’s ability to inhibit thrombin and the coagulation cascade.16 Mitochondrial damage and hepatocellular injury occur. Signs of cardiac and renal failure follow, with evidence of central nervous system involvement such as encephalopathy. Shock (hypovolemic, distributive, and/or cardiogenic) and coma ensue. Morbidity and mortality is high.5
In stage 4, the hepatic stage, 2 to 5 days postingestion, multiorgan failure progresses. Insult to hepatic tissue is significant due to the free iron circulating through the portal system with concurrent avid absorption by the mononuclear phagocyte system.5 Evidence of hepatic dysfunction is indicated by elevated liver transaminases and bilirubin levels. Coagulopathy and hypoglycemia further reflect iron-induced hepatotoxicity.
Stage 5, the delayed stage, occurs 2 to 6 weeks postingestion and is characterized by scarring of the healing GI tract. Abdominal pain and clinical indicators of GI obstruction occur as a result of strictures and fistulas formed from intestinal mucosal scar formation. Any site along the GI tract can develop these scars. The gastric outlet (pyloric stricture) most often is affected because of the high concentration of iron tablets that tend to collect in this location.5,17
With significant ingestions, rapid medical intervention is required to prevent morbidity and mortality. Understanding the clinical course of iron poisoning is important, especially for the second (latent) stage. In stage 2, the GI symptoms of stage 1 appear to remit. Medical personnel can be falsely reassured, leading to differing treatment approaches and possibly the too-early discharge of a patient from a medical facility.9 Lack of symptoms within the first 6 hours after ingestion markedly decreases the risk of significant toxicity.5
Iron Poisoning Diagnosis
Other conditions can have clinical presentations that are similar to acute iron poisoning. A complete medical history (including past and present illnesses, past hospitalizations and surgeries, travel history, family history, medication history, recent ingestions, environmental exposures, allergies to medications or foods, and immunization status), in conjunction with a thorough physical examination, can offer clues to other possible causes of a patient’s clinical presentation.
Among the differential diagnoses for iron poisoning are diabetic ketoacidosis and gastroenteritis. Other ingestions, poisonings, and toxicities must be ruled out, including acetaminophen, colchicine, mercuric chloride, organophosphates, salicylates, and theophylline, along with amatoxin, disulfiram-like toxins, and hallucinogens associated with mushroom ingestion.18
Blood and urine samples are needed for laboratory evaluation. A serum iron level drawn 4 to 6 hours postingestion is vital, since peak toxicity occurs during this period.19 Results obtained 6 hours postingestion are not as reliable due to hepatic clearance of free iron.9
Pediatric serum iron reference ranges are 100 to 250 µg/dL in newborns, 40 to 100 µg/dL in older infants, and 50 to 120 µg/dL in children. For comparison, normal serum iron levels range from 50 to 170 µg/dL in adult women and from 65 to 176 µg/dL in adult men.19 Serum iron levels 4 hours postingestion correspond to a degree of toxicity as follows5,20: less than 300 µg/dL, asymptomatic with no to mild toxicity (300 µg/dL denotes the upper limit of the body’s total iron-binding capacity21); 300 to 500 µg/dL, moderate toxicity; 500 µg/dL and greater, severe toxicity; and 800 µg/dL or greater, very severe toxicity.
While serum iron is the most important and useful diagnostic laboratory test, additional but not routinely indicated laboratory studies are arterial blood gases; plasma salicylate and acetaminophen levels (if concern of a coingestant exists); a complete blood count; electrolytes (assessing for metabolic acidosis with an increased anion gap), glucose, blood urea nitrogen, and creatinine levels; alanine aminotransferase and aspartate aminotransferase levels; bilirubin level; and coagulation studies (especially prothrombin time).5
These laboratory studies require repeating as the potential for organ failure progresses during the stages of iron poisoning. Blood typing and cross-matching for clearance of blood products, and a pregnancy test in female patients of childbearing age, should be obtained.
A pediatric patient with a suspected iron overdose must be assessed immediately in an emergency department or other hospital medical facility. Stabilization of the patient is critical, including completing the ABCDE (airway, breathing, circulation, disability, exposure) assessment.22 Close attention is required to establish fluid balance and cardiovascular stability. The identification of possible other toxic exposures and/or coingestants such as acetaminophen or salicylate directly impacts the patients’ treatment course and must be addressed with patients or their parents and caregivers. Immediate critical steps are placing access lines for fluid administration and obtaining blood and urine samples for laboratory studies.
The focus of initial emergent care is decreasing the continued bodily absorption of iron via the GI tract. Options for GI decontamination include gastric lavage and/or the administration of activated charcoal. Gastric lavage should be attempted in patients who have ingested 40 to 60 mg/kg of greater of elemental iron, patients who have ingested an unknown amount of iron, or patients who present with overt symptoms.6 Because activated charcoal does not bind iron, this method should be considered only if coingestants are a concern.
For both of these approaches, standard treatment guidelines must be followed, paying close attention to neurologic awareness and airway protection. Ingestion time is important, because successful decontamination with gastric lavage typically occurs within 1 hour postingestion, and within 2 hours postingestion with activated charcoal.23
The ideal method of GI decontamination for iron overdose is catharsis using whole bowel irrigation (WBI). WBI is initiated as part of an inpatient care plan and may require ongoing care in the intensive care unit. This method speeds the transit time of undissolved iron tablets through the GI tract and hence reduces the available mucosal absorption.5 Polyethylene glycol-electrolyte solutions are administered by way of a nasogastric or gastric feeding tube. Approximate WBI goal rates are 500 mL/h for children aged 9 months to 6 years, 1,000 mL/h for children aged 6 to 12 years, and 2,000 mL/h for children aged 13 years and older.5,24 An abdominal radiograph can further determine the presence of radiopaque iron tablets and/or concretions in the stomach or small intestine.9 Ideally, irrigation is continued until the rectal effluent is clear of tablets and tablet fragments. The absence of radiopaque findings on abdominal radiographs does not rule out iron poisoning, however.
Iron Poisoning Treatment
Aggressive supportive care with a focus on vital sign monitoring and intravenous (IV) fluid resuscitation is a core aspect of treatment.6 Chelation is a critical adjunct therapy for patients with significant iron poisoning. Iron chelation with deferoxamine (DFO) is indicated for patients with serum iron levels greater than 350 µg/dL with clinical evidence of toxicity, for patients with iron levels greater than 500 µg/dL regardless of the presence or absence of clinical toxic effects,5,6 and for patients with an estimated ingested dose of of elemental iron greater than 60 mg/kg. Additional indicators for chelation therapy are patients with significant clinical manifestations of iron toxicity (eg, altered mental status, shock, persistent GI symptoms), metabolic acidosis,5 or inability to clear iron tablets from the GI tract despite initial decontamination efforts.6 Hepatotoxicity is a major concern with high serum iron levels. Hepatic dysfunction is common, because the liver is the first organ outside the digestive tract to encounter a large iron load from the portal blood supply.
DFO is an avid iron chelator of ferric iron (Fe3+) and is freely soluble in water; in theory, 100 mg of DFO can bind 8.5 to 9.5 mg of free ferric iron.25 Chelation occurs with Fe3+ and iron from intracellular and mitochondrial stores. However, DFO does not chelate iron bound to other organic molecules, such as the iron in hemoglobin, myoglobin, transferrin, ferritin, or other iron-carrying proteins (eg, cytochromes).5,14 This chelating agent can be administered intramuscularly (IM) or as a continuous IV infusion. IM administration is preferred if the patient does not show signs of shock.25
IV DFO is used for patients with significant cardiovascular compromise and usually is dispensed in an intensive care setting. Although adverse effects of IV DFO are rare, too-rapid IV administration can cause rate-related hypotension from histamine release5,21; thus, close monitoring of blood pressure during IV infusion is important. Acute respiratory distress syndrome and sepsis have been reported in pediatric patients who received prolonged high-dose IV DFO therapy (for more than 36 hours).25 Consultation with a poison control center and a clinical toxicologist are strongly recommended with its use.
DFO binds Fe3+ in the serum, forming a water-soluble compound called ferrioxamine.5 Once this binding occurs, the ferrioxamine is excreted in the urine and as bile in the stool. Effective chelation changes the urine color to an orange-red or a “vin rose” or “rose wine” hue.5DFO must be used cautiously in patients with renal impairment, since adequate urine output must be maintained to enhance clearance of the ferrioxamine. DFO therapy (IV or IM) should be continued until the urine returns to a normal color or until the serum iron level returns to less than 100 µg/dL.9
DFO dosage and mode of administration vary with acute or chronic iron overload as well as with the size and age of the patient (Table 3).26 An oral tablet formulation of DFO is available and is used to treat chronic iron overload, such as that due to transfusional hemosiderosis, but at present is not used to treat acute iron toxicity.6,27,28
Toxicologists and pharmacologists can provide key insight, especially for patients with a concern for coingestion, complicated past or present medical histories, or an atypical clinical presentation. Specialist expertise in toxicology, critical care, and gastroenterology is vital to the care of pediatric patients with iron poisoning. Intentional and unknowing misuse of iron preparations requires intervention by social work and mental health teams. Once the patient is home, outpatient continuity of care is critical, especially given the potential risk for gastric outlet or intestinal obstruction 2 to 6 weeks postingestion.
Early identification of iron overdose should prompt a diagnostic investigation and therapeutic assessment. Education and awareness about the importance of daily dietary iron, the case-specific role of iron supplementation, and the potentially fatal consequences of too much iron will help further reduce of the number of pediatric iron overdoses in the United States. n
Germaine L. Defendi, MD, MS, is an associate clinical professor of pediatrics at Olive View–UCLA Medical Center in Sylmar, California.
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