Iron toxicity is determined by the amount of elemental iron (Fe) ingested. Examples of Fe formulations and the amount of elemental Fe contained in each formulation are listed in the table below (adapted from 1).
|Contents||Elemental Fe (%)|
Calculating amount of elemental Fe ingested
Multiply the total Fe content in each tablet by the percentage of elemental Fe for the product formulation. For example, the elemental iron equivalent calculation for 80 tablets of Ferrous Sulfate is: 325 mg Fe/tablet x 20% elemental Fe/tablet = 65 mg elemental Fe/tablet. The total elemental Fe ingested is: (65 mg/tab x 80 tablets) /50 kg = 104 mg/kg. Notable levels for elemental Fe include:
- >20 mg/kg Gastrointestinal symptoms start
- ≥40 mg/kg Current level recommended for ED referral after ingestion2
Pharmacology and Toxicology
Humans do not synthesize or secrete Fe. Total body Fe is regulated via absorption from the gastrointestinal tract. Absorption occurs in the duodenum, where Fe is stored as ferritin in the intestinal cells. It is then disposed of via epithelial cell shedding or, depending on the body’s need, can be released to transferrin, a serum Fe-binding protein. In Fe overdoses, the corrosive effects of Fe on the GI tract mucosa permit passive absorption of Fe. Once transferrin is saturated, “free” Fe is available to cause toxicity. Iron causes toxicity thru several mechanisms, including3:
- Engages in redox reactions with the formation of free radicals and oxidative damage
- Alters cellular energy and metabolism
- Uncouples oxidative phosphorylation
- Ultimately results in cellular death
Iron Toxicity: Presentation
Classically, five stages of iron toxicity are described (adapted from 4):
|Stage||Timing post-ingestion||Symptoms of Iron Toxicity|
|1||0.5-6 hours||Local toxicity: Nausea, vomiting, diarrhea; abdominal pain, gastrointestinal bleeding|
|2||6-24 hours||Latent toxicity: Resolution of local toxicity with ongoing cellular toxicity, hypovolemia, poor tissue perfusion (metabolic acidosis, ↑ lactate levels)|
|3||12-24 hours||Shock, acidosis, coagulopathy, coma, multisystem organ failure|
|4||2-3 days||Hepatic failure (periportal)|
|5||3-6 weeks||Sequelae: Gastric outlet obstruction, small bowel obstruction|
The lack of vomiting early after an ingestion (during stage I) has important clinical significance. If no vomiting has occurred within 6 hours after ingestion, then the patient likely did not ingest a toxic dose. This patient can be medically cleared.2
For most preparations, a peak Fe level occurs 2–6 hours post-ingestion. The peak level predicts severity of iron toxicity and guides management decisions (see table below). After 6 hours, Fe distributes out of the intravascular compartment, and levels are less useful for predicting toxicity.1 Additional lab tests to consider obtaining include:
- Basic metabolic panel
- Complete blood count (CBC)
- Coagulation tests (PT/INR/PTT)
- Liver function tests (LFT)
Total iron binding capacity (TIBC), glucose, and WBC counts are unreliable in predicting iron toxicity.4 The radiopacity of Fe varies with the preparation, time since ingestion, and amount of ingestion. If pill fragments are visualized on the KUB, then administration of whole bowel irrigation (WBI) may limit further absorption of Fe. However, a normal KUB does not exclude ingestion.
|Serum Iron Level (mcg/dL)||Clinical Symptoms of Iron Toxicity|
|<300||Lacks significant clinical effect|
|300-499||Mild – moderate: nausea, vomiting, diarrhea; mild systemic symptoms; serious toxicity unlikely|
|500-1000||Moderate – Severe systemic toxicity|
|>1000||Significant morbidity and mortality|
The treatment of Fe overdose starts with attention to supportive care and adequate fluid resuscitation.
- Isotonic fluids: Numerous reasons account for hypovolemia and poor perfusion. Start fluid resuscitation with isotonic fluid boluses to restore hypovolemia.
- Activated charcoal (or other oral complexing agents): This is INEFFECTIVE at binding Fe to limit absorption.2,5
- Whole bowel irrigation: This may be considered when Fe tablets are visualized on the KUB film. However, no controlled studies support the efficacy of WBI and so individual risks and benefits should be considered. WBI is achieved by administration of polyethylene glycol (PEG) solution via NG tube at recommended rates of 500 mL/hr in children and 1.5 – 2 L/hr in adolescents and adults.6
- Gastric lavage: Generally NOT recommended7
Antidote: Deferoxamine (DFO)
DFO is a chelator with high affinity and specificity for Fe. After chelation with Fe, it forms a stable compound ferrioxamine that is excreted in the urine. Indications for use in acute Fe toxicity are not well defined, or based on controlled studies, and are expert consensus derived. General indications for intravenous DFO administration include ANY of the following:
- Fe level > 500 mcg/dl
- Presence of metabolic acidosis
- Toxic appearance
Unfortunately, no study has determined the optimal dosing regimen, maximum dose, or length of administration. As such, consultation with a toxicologist for dosing administration and duration is recommended. Side effects from DFO:
- Acute, rate related side effects of DFO include urticaria and hypotension. Thus adequate fluid resuscitation prior to initiation of DFO is important.
- A late side effect is Yersinia sepsis. DFO is a siderophore that fosters the growth of Yersinia, accounting for sepsis.
- ARDS has been noted with prolonged DFO infusions > 24 hours.
Outdated Practice Regarding Deferoxamine
Ferrioxamine is a brick-orange color (AKA vin rose). Two antiquated recommendations guiding the administration of DFO relate to visualizing vin rose in the urine. The first is to administer a DFO challenge (IM shot); if vin rose is present in urine, then continue with further DFO treatment. The second is to continue DFO until vin rose in the urine clears. Both practices have been abandoned secondary to lack of reliability.1,4