What are the mechanisms by which iron overdose leads to morbidity and mortality?

Mechanisms of Iron Overdose Mortality

Iron overdose kills primarily through cardiovascular collapse, metabolic acidosis, and multi-organ failure, with the heart being particularly vulnerable to iron-mediated toxicity. 1

Pathophysiology of Iron Toxicity

Iron toxicity occurs in several phases:

Phase 1: Direct Gastrointestinal Injury

• Iron is directly corrosive to the gastrointestinal mucosa
• Causes hemorrhagic gastroenteritis with vomiting, abdominal pain, and bloody diarrhea
• Iron encrustations form over gastric rugae with mucosal necrosis 2

Phase 2: Systemic Toxicity

• Free iron in circulation overwhelms transferrin binding capacity
• Non-transferrin bound iron (NTBI) appears when transferrin is saturated 1
• NTBI enters cardiac myocytes through L-type calcium channels 1
• Leads to:
  • Metabolic acidosis
  • Hypoglycemia
  • Coagulopathy
  • Shock

Phase 3: Cardiovascular Collapse

• Iron overload cardiomyopathy (IOC) is a leading cause of death 1
• Mechanisms include:
  • Direct iron deposition in myocardium
  • Cardiac dysrhythmias
  • Cardiomyopathy with heart failure
  • Sudden death from cardiac complications 1

Phase 4: Multi-Organ Failure

• Liver failure: Iron is directly hepatotoxic
• Renal failure: Secondary to shock and direct toxicity
• Central nervous system effects: Coma, seizures, cerebral edema

Cellular Mechanisms of Iron Toxicity

Iron causes cell death through multiple mechanisms:

1. Oxidative stress: Free iron catalyzes formation of reactive oxygen species via Fenton reaction
2. Mitochondrial dysfunction: Iron disrupts electron transport chain
3. Lipid peroxidation: Damages cell membranes
4. Disruption of iron-regulatory hormones: Hepcidin dysregulation 1
5. Cellular apoptosis: Particularly in insulin-secreting pancreatic beta cells 1

Systemic Effects Leading to Death

Cardiovascular System

• Cardiac iron deposition is a paramount factor in mortality 1
• Elevated hepcidin-25 levels linked to fatal cardiovascular events 1
• Endothelial dysfunction and accelerated atherosclerosis 1
• Synergistic effect with FGF23, which is induced by iron and exerts cardiac toxicity 1

Immune System

• Impaired immune function increases infection risk
• Affects multiple immune cell lineages:
  • CD4+ T-cell depletion
  • Impaired phagocytic activity
  • Compromised microbial killing 1
• Iron serves as essential nutrient for bacterial growth, increasing infection severity

Metabolic Effects

• Severe metabolic acidosis
• Hyperglycemia initially, followed by hypoglycemia in severe cases 3
• Insulin resistance and pancreatic dysfunction 1

Clinical Progression in Acute Overdose

Acute iron poisoning progresses through distinct phases:

1. 0-6 hours: Gastrointestinal phase with vomiting, diarrhea, abdominal pain
2. 6-24 hours: Apparent stabilization (deceptive improvement)
3. 24-72 hours: Systemic toxicity with shock, metabolic acidosis, liver failure
4. 3-7 days: Hepatic necrosis and potential multi-organ failure

Treatment Considerations

Early aggressive treatment is critical for survival:

• Gastrointestinal decontamination
• Deferoxamine chelation therapy
• Hemodialysis in severe cases 4
• Supportive care for organ dysfunction

Pitfalls in Management

• Delayed presentation is particularly dangerous, as seen in cases where diagnosis was made days after ingestion 5
• The apparent stabilization phase can be misleading, giving false reassurance
• Serum iron levels may not correlate with severity in delayed presentations
• Vitamin C supplementation should be avoided as it can accelerate iron mobilization and increase toxicity 1

Iron overdose remains a significant cause of pharmaceutical ingestion fatality, especially in children 6. The multi-system effects and rapid progression from gastrointestinal symptoms to cardiovascular collapse highlight the importance of early recognition and intervention to prevent mortality.