Iron Toxicity

Fahad Abuguyan

Overview

Iron is essential to the function of hemoglobin, myoglobin, many cytochromes, and many catalytic enzymes, but becomes extremely toxic when levels are elevated after an overdose or from accumulation in disease states. Iron poisoning used to be the leading cause of poisoning death in children.

Key Points

• The acute ingestion of iron is especially hazardous to children
• Serious iron ingestions in adults are usually associated with suicide attempts
• Acute iron poisoning can result in gastrointestinal symptoms, metabolic acidosis, and hepatotoxicity

Pharmacokinetics and Absorption

• Iron is absorbed in the small intestine
• As little as 10% or as much as 95% of the ingested iron is taken into the cell
• In the cell, iron has three fates: storage bound to ferritin, transfer to the serum where it is bound to transferrin, or loss when the intestinal cell is sloughed off
• Under normal conditions only 15% to 35% of the iron-binding capacity of transferrin is used

Normal Laboratory Values

• Normal serum iron concentrations: 50 to 150 μg/dL
• Total iron-binding capacity (TIBC): 300 to 400 μg/dL (crude measure of serum proteins’ ability to bind iron)
• When iron concentrations rise after a significant overdose, transferrin becomes saturated so that excess iron circulates free and unbound in the serum
• Unbound iron is directly toxic to target organs

Mechanism of Toxicity

Iron causes toxicity through several mechanisms, including:

• Cellular reactions with formation of free radicals and oxidative damage
• Metabolic alterations - changes cellular energy and metabolism
• Mitochondrial dysfunction - uncouples oxidative phosphorylation
• Cellular death - ultimate result of the above mechanisms

Risk Assessment

Risk assessment is based on the amount of elemental iron ingested. The total amount of elemental iron ingested can be approximated by multiplying the estimated number of tablets by the fraction of elemental iron contained in the tablet.

Common Iron Preparations

COMPOUND	PERCENTAGE OF ELEMENTAL IRON
IONIC COMPOUNDS
Ferrous sulfate	20%
Ferrous fumarate	33%
Ferrous gluconate	12%
NON-IONIC COMPOUNDS
Carbonyl iron	100%
Iron polysaccharide	46%

Clinical Example

Case: 30 year-old female (wt = 60kg) presents with a history of ingestion of 90 tablets of ferrous sulfate 325 mg tablet

Calculation: Iron equivalents can be determined as below:

(Strength × % elemental Fe/tablet) × # of tablets/weight (kg)
(325 mg × 20% elemental Fe/tablet) × 90 tablets/60 kg = **97.5 mg/kg**

Pathophysiology

Iron has local gastrointestinal effects followed by systemic effects (that do not occur without preceding GI toxicity following iron ingestion).

Local Effects

Corrosive injury to the gastrointestinal mucosa resulting in:

• Vomiting and diarrhea
• Hematemesis and melena
• Fluid losses that may result in hypovolemia

Systemic Effects

Iron acts as a cellular toxin targeting:

• Cardiovascular system and liver (primary targets)
• Central nervous system (secondary effects)
• Metabolic acidosis and coagulopathy

Dose-Response Relationship

Elemental Iron Dose	Clinical Manifestations	Prognosis
<20 mg/kg	Asymptomatic	Benign
20-60 mg/kg	Mild to moderate symptoms	Generally recoverable
60-120 mg/kg	Severe morbidity and mortality	Poor prognosis
>120 mg/kg	Potentially lethal	Life-threatening

Additional Critical Doses:

• 50% mortality dose: 200 to 250 mg/kg in adults
• Lethal dose in children: as small as 130 mg of elemental iron

Clinical Features

The clinical effects of acute iron poisoning occur in five distinct stages, though not every patient goes through every phase.

Clinical Manifestations by Phase

Phase	Timeframe	Clinical Features	Mechanism of Toxicity
1	Gastrointestinal (≤6 hours)	• Vomiting • Diarrhea • Hematemesis • Hematochezia	Corrosive effect of iron on gastrointestinal mucosa
2	Latent (6-24 hours)	• Resolution of GI symptoms • Tachycardia • Acidosis • Depressed mental status	Ongoing cellular toxicity and organ damage
3	Systemic (12-24 hours)	• Return of GI symptoms • Metabolic acidosis • Leukocytosis • Coagulopathy • Renal failure • Lethargy or coma • Cardiovascular collapse	Iron distributes to tissues with worsening cellular toxicity
4	Hepatic (2-5 days)	• Fulminant liver failure • Coagulopathy	Rapid absorption from portal system with oxidative damage
5	Obstructive (3-6 weeks)	• Pyloric or bowel scarring • Obstruction	Healing of injured gastrointestinal mucosa

Key Clinical Indicators

• No vomiting within 6 hours after ingestion → likely non-toxic dose
• Serum iron levels may fall to normal during phase 3 due to tissue distribution

Diagnosis

History

Critical historical elements include:

• Amount and type of iron preparation ingested
• Time of ingestion
• Presence of vomiting (key prognostic indicator)

Laboratory Evaluation

Essential Laboratory Tests

• Complete Blood Count (CBC) - assess for anemia, leukocytosis
• Renal profile and electrolytes - evaluate renal function
• Liver Function Tests (LFTs) - monitor for hepatic toxicity
• Arterial/Venous Blood Gas - assess for metabolic acidosis
• Serum glucose - hypoglycemia can occur
• Coagulation studies - PT/INR, PTT for coagulopathy
• Serum iron level - definitive diagnostic test

Serum Iron Concentration

• Peak levels occur 4-6 hours following acute iron ingestion
• Levels usually correlate with severity of toxicity initially
• After 8-12 hours iron levels fall due to intracellular shift
• Levels may not clearly correlate with clinical toxicity in later phases

Predicted Toxicity Based on Laboratory Values

Predicted Clinical Effects	Elemental Iron Dose	Serum Iron Concentration
Nontoxic or mild GI symptoms	<20 mg/kg	<300 μg/dL (<54 μmol/L)
Significant GI symptoms ± systemic toxicity	20-60 mg/kg	300-500 μg/dL (54-90 μmol/L)
Moderate to severe systemic toxicity	>60 mg/kg	>500 μg/dL (>90 μmol/L)
Severe systemic toxicity	>60 mg/kg-	>1000 μg/dL (>180 μmol/L)

Important: Because iron is rapidly cleared from serum and deposited in liver, concentrations may be deceptively low if measured many hours after peak absorption.

Blood Gas Analysis

• High anion-gap metabolic acidosis is a useful marker of systemic toxicity
• In the absence of iron levels, serum bicarbonate can serve as a surrogate marker

Management

Supportive Measures

• ABCs - Airway, Breathing, Circulation management
• Early volume restoration is priority due to potential GI fluid losses
• Monitor vital signs closely, especially blood pressure

Decontamination

• Activated charcoal: Not effective for iron (iron is not adsorbed)
• Whole-bowel irrigation: Generally the preferred method for significant iron ingestions
• Hemodialysis and hemoperfusion: Not effective due to iron’s large volume of distribution

Antidote Therapy: Deferoxamine

Deferoxamine is the antidote of choice for serious iron overdose.

Indications for Deferoxamine

• Severe clinical symptoms
• High anion-gap metabolic acidosis
• Serum iron level > 500 μg/dL
• Significant number of pills visible on abdominal radiography

Dosing and Administration

• Continuous IV infusion at 15 mg/kg/hr for up to 24 hours
• Maximum administration rate: 35 mg/kg/hr

Adverse Effects

• Hypotension (most common significant adverse effect)
• Acute respiratory distress syndrome (ARDS)
• Pulmonary toxicity with prolonged therapy

Clinical tip: Monitor urine color - “vin rose” or orange-red discoloration indicates iron-deferoxamine complex formation and therapeutic effect

Disposition Criteria

Low-Risk Patients

The asymptomatic patient who has reliably ingested < 40 mg/kg of elemental iron does not need additional therapy after observation.

Moderate-Risk Patients (≥ 40 mg/kg ingestion)

Serial iron concentrations should be obtained:

• 3-5 hours post-ingestion
• 6-8 hours post-ingestion

Discharge criteria: If peak iron remains < 300 μg/dL, is not rising, and the patient remains asymptomatic during 6 hours of observation, the patient can be discharged home.

Clinical Management Algorithm