Acute Iron Toxicity
Also known as: Ferrous fumarate, ferrous sulfate, ferrous gluconate, carbonyl iron. Sold under many brand names and as a generic dietary supplement. Also found as a component of soil acidifiers, fertilizers, stain removers, oil primer, and many other industrial chemicals.
Related conditions: Acute aluminum toxicity is treated similarly.
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1. Description of the problem
Iron toxicity occurs either after acute overdose, or after repeated ingestion of supra-therapeutic doses. Children aged less than six months are at particular risk due to their inability to mitigate oxidative stress. Acute exposures greater than 40 mg/kg in children, or exposures greater than 20 mg/kg in adults, warrant referral to a healthcare facility.
Although the phases of iron toxicity overlap considerably, it is useful to anticipate the pathologic effects in the following progression.
Phase I: The gastrointestinal (GI) phase begins with nausea, vomiting, diarrhea, and abdominal pain. The most severe poisonings result in hemorrhagic gastritis. This phase may be absent in neonates.
Phase II: The latent phase is characterized by resolution of GI symptoms but prior to development of systemic dysfunction. It is classically described as the period 6 to 24 hours after ingestion; however, considerable inter-subject variability exists. Metabolic acidosis, tachycardia, and central nervous system (CNS) depression may be the only indicators of illness during this phase.
Phase III: The shock phase is the hallmark of serious toxicity. Although classically described as starting 12 to 24 hours post-exposure, shock may occur within hours of massive overdoses. The shock is distributive and cardiogenic, as iron-associated metabolic disruption causes vasodilation and decreased inotropy. Additionally, preceding GI manifestations may produce hypovolemia. These patients are lethargic and may develop seizures or coma.
Phase IV: The hepatotoxic phase presents 2 to 3 days after ingestion as the reticuloendothelial system sequesters iron, leading to organ-specific (as opposed to diffuse) oxidative injury. Iron is mobilized from other sites in the body and returned to the liver via the hepatic portal system. Liver failure in iron toxicity is a dose-related phenomenon and these patients may develop coagulopathy.
Phase V: The gastric outlet obstruction phase rarely occurs. Patients who initially experienced hemorrhagic gastritis may develop pyloric scarring 2 to 8 weeks post-exposure. Gastric mucosal injury is secondary to the direct effects of iron and not necessarily related to the degree of systemic compromise.
Key Management Points
1. Resuscitate and control the airway if necessary.
2. Administer deferoxamine to chelate intravascular iron.
3. Dialyze if unable to renally eliminate complexed iron.
2. Emergency Management
Chronic iron intoxication rarely requires emergency treatment and is typically ameliorated by avoidance of the source, whether dietary or environmental.
Initial management of acute iron overdose should be approached like any other emergency condition. Patients with excessive vomiting who cannot protect their airway should undergo endotracheal intubation. Patients exhibiting evidence of hypovolemia should receive weight-appropriate resuscitative boluses of intravenous fluid. Patients who do not respond to fluid resuscitation should receive vasopressor support. Some patients may require inotropic support as well. No specific vasopressor has demonstrated an outcome advantage.
Management points not to be missed
Activated charcoal does not bind small molecules well and is not indicated in iron overdoses. Whole bowel irrigation (WBI) may be of use in patients in whom an iron bezoar can be identified either with diagnostic imaging or direct visualization during endoscopy. Adult iron tablets are usually radiopaque on abdominal radiographs. Children’s chewable and liquid preparations are not. The pediatric infusion rate for WBI with polyethylene glycol electrolyte lavage solution is 500mL/h or 25mL/kg/h in small children.
We recommend weighing the benefits against the risks of securing the patient’s airway prior to gastric decontamination with WBI, due to the risk of vomiting and aspiration.
3. Diagnosis
Diagnostic approach
The key to making a diagnosis and predicting clinical course is taking a good exposure history. Different iron preparations contain different quantities of elemental iron. The exact product name, probable tablet number (or solution volume) ingested, maximum tablet number ingested, and the estimated time of exposure should be communicated to the regional poison control center (1-800-222-1222) to calculate a weight-based dose estimate.
Acute ingestions greater than 20 mg/kg will probably be symptomatic and exposures greater than 60 mg/kg typically require chelation therapy.
Normal lab values
If iron overdose is suspected, obtain a serum iron level. Iron binding studies are of no utility. However, if the patient is unstable and a clear history of iron exposure is available, the results of the iron level are not necessary to begin chelation therapy. Ideally, a serum iron level should be obtained 2-6 hours after ingestion. Peak serum iron levels greater than 300mcg/dL usually indicate significant ingestions. Levels greater than 500mcg/dL are associated with shock.
Liver failure may occur in patients with serum iron levels greater than 700mcg/dL obtained within 12 hours of ingestion. Serum iron levels should be obtained every 4 to 6 hours until levels have peaked and demonstrate a clear declining trend on at least two consecutive values.
In the undifferentiated pediatric overdose, any child presenting with vomiting, metabolic acidosis, and/or shock should have the diagnosis of iron toxicity considered. A symptomatic iron overdose will have an elevated serum iron concentration.
Differential diagnosis
Unfortunately, the presentation of vomiting is common to many conditions. Only maintaining a high index of suspicion and obtaining a history of iron exposure will lead to the diagnosis.
Confirmatory tests
A symptomatic iron overdose will have an elevated serum iron concentration.
4. Specific Treatment
Deferoxamine is an iron chelator, complexing with free iron in the serum so it can be renally eliminated. Chelation therapy should be considered in any patient with shock or altered mental status, anticipated deterioration (iron level greater than 500mcg/dL, elevated anion gap metabolic acidosis), or evidence of a potentially lethal ingestion (estimated dose greater than 60 mg/kg).
Iron chelated with deferoxamine is excreted in the urine as ferroxamine. Ferroxamine turns the urine a pink, vin-rosé color. Some have suggested that the absence of this color change indicates poor iron chelation; however, urine color change has proven to be an unreliable indicator of chelation effectiveness.
Drugs and dosages
Patients are usually administered a deferoxamine infusion with an initial rate of 5 mg/kg/h. The infusion should be increased as tolerated, up to a goal rate of 15 mg/kg/h, relatively quickly (over 15 minutes). Tolerance of deferoxamine depends on the patient’s ability to avoid a vasodilator response and to renally excrete it. Patients with compromised glomerular filtration rates may not reach goal without experiencing side effects. The most common side effect is hypotension.
In addition to patients with disease-associated renal compromise, children less than 6 months of age may need slower infusion rates due to physiologic immaturity. However, the dose of deferoxamine was established in the 1970s and some toxicologists have administered deferoxamine at dosages substantially in excess of the manufacturer’s guidelines. Older children appear to tolerate the chelator well and titrating to doses as high as 60 mg/kg/h in massive overdoses may not produce adverse effects.
Refractory cases
Both hemodialysis and continuous veno-venous hemofiltration have been used to lower iron levels in severe poisonings. For patients with renal insufficiency or failure, deferoxamine in concert with these modalities can enhance elimination of iron.
Three case reports of exchange transfusion (ET) exist in the literature. The most recent reported case combined ET with subsequent plasmapheresis in an 18-month-old who ingested 442 mg/kg of elemental iron. The ET was performed 9 hours after ingestion and the patient survived.
Iron tablets ingested in large amounts may agglutinate in the stomach. Gastroenterology consultation for endoscopic removal is prudent if WBI does not effectively remove these bezoars from the GI tract. In rare cases, bezoars have been removed surgically via both laparoscopic gastrotomy and open techniques.
5. Disease monitoring, follow-up and disposition
Expected response to treatment
In children older than 6 months, the absence of both vomiting and abdominal pain within 6 hours of ingestion virtually rules out serious intoxication. Therefore, all children with suspected iron overdose should be observed for a minimum of 6 hours. If patient remains asymptomatic during this observation period, the patient may be safely discharged home.
Alternative diagnosis
Patients in shock who are not acidotic or do not have elevated serum iron levels should have other etiologies considered.
Follow-up
Admitted patients who survive to discharge often make a full recovery. Gastric and intestinal stricture formation and persistence of hepatic dysfunction acquired during the period of acute intoxication are potential risks. Prior to discharge from the hospital, patients and their parents should be educated about the possibility of gastric scarring and obstruction. No specific gastroenterology follow-up is necessary in asymptomatic patients.
Pathophysiology
In the body, iron typically exists in its reduced ferrous state (Fe2+). However, excessive iron in vivo overwhelms the body’s natural capacity to reduce oxidants. Iron in its oxidative ferric state (Fe3+) increases overall oxidative stress on the body. Specifically, ferric iron damages mitochondrial membranes, disrupts oxidative phosphorylation, and liberates hydrogen ions. This reduces ATP production and creates a cellular metabolic acidosis.
Iron is the primary catalyst in Fenton chemistry, accelerating peroxide’s ability to generate hydroxyl free radicals and hydroxyl anions. Ferric iron and these free radicals initiate the lipid peroxidation cascade, causing extensive damage to phospholipid membranes. This cellular insult is responsible for the clinical manifestations of iron toxicity.
Epidemiology
Iron overdose is one of the most common pediatric causes of pharmaceutical-induced toxicity because of its widespread availability. In children less than 5 years of age, ingestion of vitamins is the fifth most common reason for parents to call poison control centers (excluding inert foreign body exposures). In the 1980s, iron toxicity accounted for 30% of pediatric poisoning deaths. However, the introduction to unit-dose packaging has reduced both the incidence of pediatric iron toxicity and mortality. Almost all deaths from iron overdose are in children less than 3 years of age.
Prognosis
Although pediatric iron intoxications are common, deaths are now rare. Most fatalities occur in children less than 3 years of age following massive ingestions of adult preparations.
What's the evidence?
Bronstein, AC, Spyker, DA, Cantilena, LR. “2009 Annual Report of American Association of Poison Control Centers’ National Poison Data System (NPDS): 27
Annual Report”. Clin Toxicol. vol. 48. 2010. pp. 979-1178. (National data reporting incidence of iron ingestion.)
Carlsson, M, Cortes, D, Jepsen, S, Kanstrup, T. “Severe iron intoxication treated with exchange transfusion”. Arch Dis Child. vol. 93. 2008. pp. 321-2. (Good overview of use of exchange transfusion in severe cases.)
Fine, J. “Iron poisoning”. Curr Probl Pediatr. vol. 30. 2000. pp. 71-90. (Good review)
Haider, F, De Carli, C, Dhanai, S, Sweeney, B. “Emergency laparoscopic-assisted gastrotomy for the treatment of an iron bezoar”. J Laparoendosc Adv Surg Tech. vol. 19. 2009. pp. S141-3. (Management techniques for bezoar.)
Howland, MA. “Antidotes in depth: deferoxamine”. Goldfrank’s Toxicologic Emergencies. 2006. pp. 604-8.
Manoguerra, AS, Erdman, AR, Booze, LL, Christianson, G, Wax, PM. “Iron ingestion: An evidence-based consensus guideline for out-of-hospital management”. Clin Toxicol. vol. 43. 2005. pp. 553-70. (Guideline for management out of hospital)
Milne, C, Petros, A. “The use of haemofiltration for severe iron overdose”. Arch Dis Child. vol. 95. 2010. pp. 482-3.
Perrone, J. Iron. Goldfrank’s Toxicologic Emergencies. 2006. pp. 596-603.
Robertson, A, Tenenbein, M. “Hepatotoxicity in acute iron poisoning”. Human Exp Toxicol. vol. 24. 2005. pp. 559-62.
Valentine, K, Mastropietro, C, Sarnaik, A. “Infantile iron poisoning: Challenges in diagnosis and management”. Pediatr Crit Care Med. vol. 10. 2009. pp. e31-3.
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