Iron Toxicity

Article Author:
Ho-Wang Yuen
Article Editor:
William Gossman
Updated:
10/27/2018 12:31:56 PM
PubMed Link:
Iron Toxicity

Introduction

Iron is found in many over-the-counter (OTC) multivitamins. Iron toxicity from an intentional or accidental ingestion is a common poisoning. The acute ingestion of iron is especially hazardous to children. Life-threatening toxicity is associated with pediatric ingestion of potent adult preparation, such as prenatal vitamins. Serious iron ingestion in adults usually is associated with suicide attempts.

Etiology

Ingestion of less than 20 mg/kg of elemental iron is non-toxic. Ingestion of 20 mg/kg to 60 mg/kg results in moderate symptoms. Ingestion of more than 60 mg/kg can result in severe 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 ferrous sulfate, which contains 20% elemental iron; ferrous gluconate, 12% elemental iron; and ferrous fumarate, 33% elemental iron. 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.

Epidemiology

In 2015, the Annual Report of the American Association of Poison Control Centers (AAPCC) National Poison Data System reported 4072 single exposures to iron or iron salts. Out of these, 3211 cases were unintentional ingestion. Furthermore, 2036 of reported cases occurred in children 5 years old or younger, and 1161 cases were treated in a healthcare facility there was one death.

Pathophysiology

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, primarily of the heart, liver, and central nervous system. Free iron enters cells and concentrates in mitochondria, disrupting oxidative phosphorylation, catalyze lipid peroxidation and free radical formation, resulting in cell death.

Toxicokinetics

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 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 blood as free iron, which is directly toxic to target organs.

History and Physical

The clinical course of iron toxicity is divided into five stages, and not every patient goes through every stage. During stage 1 (0.5 to 6 hours), the patient mainly exhibits gastrointestinal (GI) symptoms including abdominal pain, vomiting, diarrhea, hematemesis, and hematochezia. The second stage (6 to 24 hours) represents an apparent recovery phase, as the patient’s GI symptoms may resolve despite toxic amounts of iron absorption. The third stage (6 to 72 hours) is characterized by the recurrence of GI symptoms, shock, and metabolic acidosis. Iron-induced coagulopathy, hepatic dysfunction, cardiomyopathy, and renal failure are also observed in this stage. The fourth stage (2 to 5 days) is characterized by elevation of aminotransferase levels and possible progression to hepatic failure. The fifth stage (4 to 6 weeks) represents the consequences of the healing of the injured GI mucosa including pyloric or proximal bowel scarring and obstruction. A patient may present in or skip any of the five stages.

Evaluation

The diagnosis of iron toxicity is based on the history and clinical presentation. Serum iron levels are used to determine a patient’s potential for toxicity. A serum iron level measured at its peak, 3 to 5 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.

Other laboratory evaluation includes electrolytes, kidney function, serum glucose, coagulation studies, complete blood count, and liver function. Plain radiographs may reveal iron in the GI tract, but many iron preparations are not radiopaque. Normal radiographs do not exclude iron ingestion.

Treatment / Management

Patients who remain asymptomatic four 6 hours after ingestion or have not ingested a potentially toxic amount do not require any treatment for iron toxicity.

Patients who have GI symptoms which resolve after a short period and 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:

  1. IV crystalloid infusion is administered to correct hypovolemia and hypoperfusion.
  2. Gastric lavage is indicated when ingestion occurred within 60 minutes of presentation.
  3. Activated charcoal binds iron poorly and is not effective.
  4. Whole-bowel irrigation with polyethylene glycol solution may clear the GI tract of iron pills before absorption and should be administered at 250 to 500 mL/h in children and 2 L/h in adults via nasogastric tube.
  5. 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).
  6. 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 5 mg/kg/hr for up to 24 hours and is titrated up to 15 mg/kg/hr if there is no rate-related hypotension. Maximum daily dose is 6 g. Clinical recovery guides the termination of deferoxamine therapy.

Patients with GI 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 presented 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 with a negative radiograph, with no or minimal symptoms after 6-hour observation, or with mild GI symptoms that resolve without metabolic acidosis and serum iron level under 350 mg/dL.

Differential Diagnosis

Other diseases or conditions that can present similarly to iron toxicity include sepsis, acetaminophen toxicity, other toxic ingestions that can cause anion gap acidosis including salicylate, cyanide, methanol, and ethylene glycol, mushroom ingestion, heavy metals toxicity, theophylline toxicity, and GI bleed from other causes.