Iron Toxicity

Iron toxicity can be classified as corrosive or cellular. Ingested iron can have an extremely corrosive effect on the gastrointestinal (GI) mucosa, which can manifest as nausea, vomiting, abdominal pain, hematemesis, and diarrhea; patients may become hypovolemic because of significant fluid and blood loss.

Cellular toxicity occurs with the absorption of excessive quantities of ingested iron. Severe overdose causes impaired oxidative phosphorylation and mitochondrial dysfunction, which can result in cellular death. The liver is one of the organs most affected by cellular iron toxicity, but other organs such as the heart, kidneys, lungs, and the hematologic systems also may be impaired. With chronic iron overload, the deposit of iron into the heart may cause death due to myocardial siderosis.

With both corrosive and cellular toxicity, the end result is significant metabolic acidosis, due to several factors. Hypoperfusion due to significant volume loss, vasodilatation, and negative inotropic effect of iron will result in lactic acidosis. Inhibition of oxidative phosphorylation will promote anaerobic metabolism.

Individuals demonstrate signs of GI toxicity after ingestion of more than 20 mg/kg. Moderate intoxication occurs when ingestion of elemental iron exceeds 40 mg/kg. Ingestions exceeding 60 mg/kg can cause severe toxicity and may be lethal.[5]

Suggested iron doses are based on calculation of the amount of elemental iron. Different iron preparations (salts) contain different amounts of elemental iron, as follows:

• Fumarate - 33%
• Sulfate - 20%
• Gluconate - 12%

The 2021 Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System reported 5311 single exposures to iron or iron salts, with 14 major outcomes and 2 deaths. In addition, the AAPCC reported 6029 single exposures to multiple vitamins containing iron, with one major outcome and no deaths. Overall, 79% of cases were in children younger than 6 years.[6]

 

Safekeeping of all medications, not just iron pills, from young children is important. Common medicines and vitamins may be lethal. Also see Vitamin Toxicity. The most effective measure to prevent iron ingestion is to store iron tablets in areas that are inaccessable to children.

For patient education information, see the First Aid and Injuries Center, as well as Iron Poisoning in Children and Poison Proofing Your Home.

Gastrointestinal (GI) manifestations such as vomiting and diarrhea (especially when hemorrhagic) are an important feature of acute iron toxicity. Pediatric patients who are alert and not vomiting most likely did not ingest a toxic dose of iron; in adults, however, abdominal pain and vomiting may be absent. More than four episodes of vomiting suggests significant iron toxicity. Hemorrhagic gastroenteritis, even in the absence of a history of iron ingestion, should raise suspicion for iron toxicity. The absence of GI symptoms would strongly suggest a non-toxic ingestion.

Iron poisoning is often classified into five distinct stages, as follows:

• Stage 1 - Gastrointestinal (GI)
• Stage 2 - Latent
• Stage 3 - Metabolic/cardiovascular
• Stage 4 - Hepatic
• Stage 5 - Delayed

Understanding the course of poisoning is important. In particular, the second stage may lure the physician into a false sense of security and result in premature and inappropriate discharge of a patient.

Stage 1

Features of stage 1 iron toxicity are as follows:

• This stage usually occurs within 6 hours after exposure
• Nausea and diarrhea, often accompanied by abdominal pain, characterize this stage
• When the intoxication is severe, a hemorrhagic component is observed in conjunction with gastroenteritis
• The combination of GI fluid loss and blood loss, with additional third-spacing, may result in hypovolemia or shock
• Fatality occurs in a significant percentage of patients during this stage

Stage 2

Features of stage 2 iron toxicity are as follows:

• GI symptoms resolve, and the patient appears to improve and recover
• This deceptive phase usually occurs 6-12 hours after ingestion and may last as long as 24 hours.
• Metabolic abnormalities during this phase may include hypotension, metabolic acidosis, and coagulopathy
• Some patients skip this phase and progress directly to stage 3

Stage 3

Features of stage 3 iron toxicity are as follows:

• Stage 3 is characterized by metabolic acidosis and cardiovascular symptoms; the acidosis may indicate failure of organs such as the heart and kidneys
• It is hypothesized that high iron concentrations produce venous pooling and third-spacing of fluids
• Central nervous system (CNS) symptoms, usually stupor and coma, are also characteristic of stage 3
• Most deaths occur during this stage
• Stage 3 can start very early (6-8 h), depending on severity of exposure, and can last up to 2 days

Stage 4

Features of stage 4 iron toxicity are as follows:

• Elevated liver enzymes and bilirubin levels are commonly observed with coagulopathy, indicative of liver dysfunction
• Hypoglycemia may accompany liver dysfunction

Stage 5

Stage 5 iron toxicity is characterized by scarring of the healing GI tract; the stomach and/or intestines may be affected, resulting in gastric outlet or intestinal obstruction. This phase usually occurs weeks after a severe poisoning.

Complications of iron toxicity include the following:

• Hepatic necrosis
• Myocardial dysfunction
• Cardiogenic shock
• CNS depression
• Coma
• Convulsions
• Anemia
• Coagulopathy
• Sepsis ( Yersinia infection)
• Acute respiratory distress syndrome (ARDS)
• GI perforation
• Intestinal stricture formation
• Esophagitis ^[7]

The workup for iron toxicity includes the following studies:

• Serum  iron
• Glucose
• Complete blood count (CBC)
• Serum lactate
• Arterial blood gas (ABG) - To assess for metabolic acidosis
• Serum electrolytes - For anion gap calculation
• Kidney function tests
• Liver function tests (LFTs)
• Coagulation studies
• Lipase and amylase levels - Occasional patients experience pancreatic injury
• Pregnancy test in women of childbearing age
• Blood type and cross-matching
• Ferritin levels - Helpful for diagnosing chronic toxicity; levels may exceed 1000 mcg/L

For serum iron measurement, samples should be drawn at least 4 hours postingestion, to allow levels to reach steady state; however, levels drawn more than 6 hours after ingestion may underestimate toxicity because of ferritin binding and redistribution of iron. With extended-release products, consider a level at 8 hours. The significance of results is as follows:

• In adults, levels may not correlate well with the clinical presentation
• Mild-to-moderate toxicity generally manifests at levels of 350-500 mcg/dL
• Persistently symptomatic patients with serum iron levels higher than 350 mcg/dL should be admitted
• Hepatotoxicity usually is observed at levels higher than 500 mcg/dL
• Levels higher than 800 mcg/dL are associated with severe toxicity
• Patients with serum iron levels higher than 1000 mcg/dL should be in a facility that can provide age-appropriate intensive care

Glucose levels exceeding 150 mg/dL are common with severe iron toxicity. Monitoring glucose levels is important because hepatic dysfunction may cause hypoglycemia.

On the CBC, a white blood cell (WBC) count of more than 15,000/mm3 is associated with severe iron poisoning. A CBC is also helpful because anemia from blood loss may develop.

LFTs are indicated because hepatic dysfunction is common in severe iron poisoning. The liver is the first organ outside of the GI tract to receive a large iron load, which enters through the portal blood supply.

Electrolyte measurements and kidney function tests assist in calculation of the anion gap (see the Anion Gap calculator) and detection of electrolyte abnormalities and the presence of prerenal azotemia. Iron toxicity is one of the causes of acidosis with an increased anion gap, as noted in the mnemonic MUDPILES:

• Methanol
• Uremia
• Diabetic ketoacidosis, alcoholic ketoacidosis
• Paraldehyde
• Iron, isoniazid
• Lactic (eg, from carbon monoxide, cyanide)
• Ethylene glycol
• Salicylates

Iron tablets remain radiopaque for a few hours postingestion, and may be visible on a kidneys, ureters, bladder (KUB) film. However, the absence of radiopacities does not rule out a significant or even potentially lethal ingestion.

Magnetic resonance imaging (MRI) has become widely accepted as the primary method for noninvasively quantifying liver iron concentration.[8] Annual measurements of liver iron concentration by MRI has been recommended for all patients receiving long-term chronic transfusion therapy, along with MRI measurement of cardiac iron in patients at high risk of cardiac iron deposition.[8, 9]  

MRI measurement of liver iron has also been suggested as a surrogate marker for total body iron in dialysis patients, who routinely receive parenteral iron in conjunction with erythropoiesis-stimulating agents for treatment of anemia. However, while these findings challenge the current reliance on transferrin saturation and serum ferritin levels as markers of iron load, the clinical relevance of MRI for this patient population remains to be determined.[10]

In patients with acute iron overdose, intravenous access should be established immediately. Patients who are hypovolemic should receive fluid boluses of 20 mL/kg of normal saline or lactated Ringer (LR) solution. Provide oxygen to patients in shock. 

Assume that symptomatic patients are hypovolemic. Administer vigorous volume therapy with isotonic crystalloids (eg, normal saline, LR solution) in 20 mL/kg boluses to attain and maintain hemodynamic stability. Give supplemental oxygen.

Gastric lavage with a large-bore orogastric tube may remove iron from the stomach. Ideally, lavage should be performed 1-2 hours postingestion, although later use may be appropriate if evidence of iron products in the stomach is observed on a radiograph. However, iron has a gelatinous texture and may be difficult to remove by lavage. Whole-bowel irrigation may be used in patients with a radiopacity on kidneys, ureters, bladder (KUB) plain radiographs, until the radiopacity clears.

In the past, ipecac had been used for gastric decontamination in patients with iron poisoning. The American Academy of Clinical Toxicology advises that the routine administration of ipecac in the emergency department should definitely be avoided. Some reports suggest that ipecac may offer possible benefits in rare situations involving iron poisoning; this may be a moot point, however, since the availability of ipecac is rapidly diminishing.[11] In any case, iron toxicity itself typically causes vomiting, because of its caustic effect on the gastrointestinal mucosa, so iron-poisoned patients routinely perform self-decontamination even without ipecac.

Activated charcoal does not bind iron. However, it should be utilized if co-ingestants are suspected.

Deferoxamine (Desferal) can be used to chelate iron.[12]  Patients who are symptomatic should receive deferoxamine regardless of their iron level. In acute or chronic iron toxicity, chelation therapy with deferoxamine is indicated for patients with serum iron levels >350 mcg/dL who have evidence of toxicity, or levels of > 500 mcg/dL regardless of signs or symptoms (see Medication). In patients with significant clinical manifestations of toxicity, chelation therapy should not be delayed while one awaits serum iron levels.

In acute iron poisoning, intramuscular (IM) administration of deferoxamine is indicated for patients who are not in shock; intravenous (IV) administration should be reserved for patients in a state of cardiovascular collapse or shock. However, note that rapid IV administration of deferoxamine may itself result in hypotension and shock. For chronic iron overload, administration can be subcutaneous, IV, or IM. Aggressive hydration aids in eliminating chelated iron by maintaining an appropriate urine output.

Asymptomatic patients observed for 6 hours with serum iron levels less than 300-350 mcg/dL may be discharged.

Features of further inpatient care are as follows:

• Supportive care with IV fluids and oxygen(as needed) is strongly recommended.

• Conservative management may be adequate in severe intoxication.[13]

• Persistently symptomatic patients with serum iron levels higher than 350 mcg/dL should be admitted.

• Patients who have been hemodynamically unstable, and those with serum iron levels higher than 1000 mcg/dL, should be admitted to a facility that can provide age-appropriate intensive care.

• Other modalities that may be essential include mechanical ventilation and blood product transfusions.

• Exchange transfusion has been reported to be successful in management of a case of severe iron poisoning.[14]

• Hemodialysis has been used in severe intoxications.[15]

• Iron bezoars may be removed laparoscopically or endoscopically.[16, 17]

• Patient with liver failure may require referral for liver transplantantion.

Consultation with a toxicologist is recommended. Obtain a gastroenterology consultation for patients who have large iron bezoars. Transfer patients if intensive care or deferoxamine is not available locally.

The goals of pharmacotherapy are to reduce iron levels, prevent complications, and reduce morbidity. Deferoxamine (Desferal) is used for chelation of iron in both acute and chronic toxicity.

The oral chelating agent deferasirox (Exjade) is approved by the US Food and Drug Administration (FDA) for the treatment of chronic iron overload due to blood transfusions in patients 2 year of age and older; it is also approved for treatment of chronic iron overload resulting from non–transfusion-dependent thalassemia.

Deferoxamine (Desferal)

DOC for iron intoxication. Freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. Excreted in urine and bile and gives urine a red discoloration. Readily chelates iron from ferritin and hemosiderin but not transferrin. Most effective when administered continuously by infusion. May be administered by IM injection or slow IV infusion. Does not effectively chelate other trace metals of nutritional importance. Provided in vials containing 500 mg of lyophilized sterile drug. Add 2 mL of sterile water to each vial for injection, bringing the concentration to 250 mg/mL. For IV use, may be diluted in 0.9% sterile saline, 5% dextrose solution, or Ringer solution. IV administration route is prefered, with the usual dose 15 mg/kg/hour. Histamine may be released, resulting in hypotension that is treatable by fluid resuscitation. The duration of therapy usually is 24 hours, and should be guided by a medical toxicologist.

Polyethylene glycol bowel prep (GoLYTELY, Colyte)

Laxative with strong electrolytic and osmotic effects that has cathartic actions in the GI tract.