In whom does iron toxicity occur?

Iron Toxicity: At-Risk Populations

Iron toxicity occurs primarily in three distinct populations: young children (especially 9-18 months) who accidentally ingest adult iron supplements, dialysis patients receiving excessive intravenous iron therapy, and individuals with genetic or acquired iron overload disorders.

Acute Iron Toxicity

Pediatric Accidental Ingestion

• Children aged 9-18 months are at highest risk for accidental iron poisoning due to ingestion of maternal iron tablets, particularly from pregnant mothers 1, 2
• Acute iron ingestions exceeding 60 mg/kg of elemental iron are potentially serious and require immediate medical attention 3
• Severe toxicity manifests with gastrointestinal symptoms, metabolic acidosis, hypoglycemia, shock, and potential multi-organ failure including hepatic and renal dysfunction 4, 3, 5
• Mortality is associated with delayed presentation, coagulopathy, and acute liver failure 2
• Preterm and low-birthweight infants are also at greater risk, though typically from deficiency rather than toxicity 1

Adolescents and Adults

• Most severe cases in older populations involve intentional ingestions by late adolescents and adults 4
• Delayed presentations (beyond 12 hours) carry significantly worse prognosis 4

Chronic Iron Overload (Iatrogenic)

Dialysis Patients

• Hemodialysis patients receiving erythropoiesis-stimulating agents (ESAs) with intravenous iron are at substantial risk for iatrogenic iron overload 6
• High-dose IV iron (>200 mg/month or cumulative doses >840 mg/6 months) significantly increases mortality and cardiovascular events 6
• Patients receiving cumulative doses of 1640-2400 mg/6 months had hazard ratios of 3.7 for mortality and 5.1 for cardiovascular events compared to those receiving minimal or no IV iron 6
• Ferritin levels consistently above 100 µg/L in dialysis patients are associated with increased risk of acute cardiocerebrovascular disease (HR: 2.22), infections (HR: 1.76), and death (HR: 2.28) 6
• Iron overload may silently increase complications without creating frank clinical signs, making it particularly insidious 6

Specific Dialysis Patient Vulnerabilities

• Patients with functional iron deficiency may be more prone to iatrogenic overload than those with true iron deficiency 6
• Diabetic dialysis patients (40% of the dialysis population) face higher risk of complications from iron overload affecting glucose regulation 6
• Young dialysis patients with repeated graft failures and long cumulative dialysis vintage (one to two decades) face prolonged exposure risk 6
• Patients with viral hepatitis B or C, non-alcoholic steatohepatitis, or other liver diseases may experience aggravation from iron accumulation 6

Pediatric Parenteral Nutrition

• Systemic iron toxicity with hepatocellular damage has been observed in pediatric patients receiving 16 mg/kg of iron sucrose 1
• Children with hemoglobinopathy receiving transfusion and chelation typically develop cardiac iron overload after 10 years of age 1

Genetic and Secondary Iron Overload Disorders

Hereditary Hemochromatosis

• Patients with genetic hemochromatosis (HFE-related, particularly C282Y homozygosity) develop progressive iron accumulation 6
• Cardiac dysrhythmias and cardiomyopathy are the most common causes of sudden death in these patients 6
• HH patients with cirrhosis face 30% mortality from hepatocellular carcinoma 6

Secondary Iron Overload Conditions

• Iron-loading anemias including thalassemia major, sideroblastic anemia, and chronic hemolytic anemias 6
• Patients with chronic liver diseases (hepatitis C and B, alcohol-induced liver disease, porphyria cutanea tarda, fatty liver disease) 6
• Ferroportin disease (SLC40A1 mutations) causes hereditary hemochromatosis type 4 with heterogeneous phenotypes 6
• Patients with TMPRSS6 mutations causing iron-refractory iron deficiency anemia (IRIDA) paradoxically risk iron overload when attempting to correct anemia with IV iron 6

Critical Clinical Considerations

Monitoring Thresholds

• In dialysis patients, serum ferritin should not exceed 500 mg/L to avoid long-term iron toxicity risk, especially in children and adolescents 6
• Historical data showed liver cell damage in dialysis patients with ferritin levels exceeding 7,500 ng/mL and transferrin saturation >88% 6
• MRI with quantitative assessment is the gold standard for cardiac and hepatic iron load monitoring 1

High-Risk Scenarios Requiring Vigilance

• Patients with collagen diseases have increased incidence of adverse effects from intravenous iron 7
• Rapid iron mobilization during chelation therapy may increase risk of cardiac complications 6
• Patients receiving high-molecular-weight iron dextran face more adverse events than with newer formulations 7

The key principle is that early treatment before development of cirrhosis and/or diabetes significantly reduces morbidity and mortality, while delayed diagnosis can lead to irreversible organ damage 1.