What causes elevated iron saturation in a pediatric patient?

Elevated Iron Saturation in a 12-Year-Old Girl

An iron saturation of 72% in a 12-year-old girl is abnormally elevated and suggests either hereditary hemochromatosis (most commonly HFE-related), secondary iron overload from excessive supplementation or transfusions, or chronic liver disease affecting iron metabolism.

Primary Differential Diagnosis

Hereditary Hemochromatosis

• HFE-related hemochromatosis is the most common genetic cause, with C282Y homozygosity or C282Y/H63D compound heterozygosity being the typical mutations 1
• Transferrin saturation >45% is a key screening marker for hereditary hemochromatosis, and 72% is significantly elevated 1
• While phenotypic expression typically occurs in adulthood, approximately 70% of C282Y homozygotes eventually develop iron overload, though fewer than 10% develop severe clinical manifestations 1
• Juvenile hemochromatosis (mutations in hemojuvelin or hepcidin genes) presents with rapid iron accumulation in adolescence and should be strongly considered in this age group 1

Secondary Iron Overload

• Iatrogenic causes are common and include:
  • Chronic oral iron supplementation beyond physiologic needs 2, 3
  • Parenteral iron administration (though guidelines recommend against routine IV iron in short-term settings) 1
  • Blood transfusions for underlying hematologic conditions 1
• Hematologic disorders causing secondary overload include thalassemia syndromes, myelodysplastic syndrome, sideroblastic anemias, sickle cell disease, or pyruvate kinase deficiency 4
• Oral iron ingestion does not typically cause overload except in genetically predisposed individuals or those with ineffective erythropoiesis 1

Chronic Liver Disease

• Hepatitis B, hepatitis C, alcoholic liver disease (unlikely in this age), nonalcoholic fatty liver disease, or porphyria cutanea tarda can all cause elevated iron saturation 1
• Liver dysfunction impairs hepcidin regulation, leading to increased iron absorption 1

Diagnostic Approach

Immediate Laboratory Evaluation

• Confirm the elevated transferrin saturation with repeat fasting measurement, as serum iron increases after meals and has significant diurnal variation 1
• Measure serum ferritin to assess total body iron stores; ferritin <15 mcg/L confirms iron deficiency, while >15 mcg/L with elevated saturation suggests iron overload 1
• Note that ferritin is an acute-phase reactant and can be falsely elevated with infection, inflammation, hepatitis, or malignancy 1

Genetic Testing

• HFE mutation analysis for C282Y and H63D should be pursued immediately when transferrin saturation is elevated 4
• If HFE testing is negative for C282Y homozygous or C282Y/H63D compound heterozygous mutations, consider testing for juvenile hemochromatosis genes (HJV, HAMP) given the patient's age 1
• Also consider testing for transferrin receptor-2 (TfR2) and ferroportin (SLC40A1) mutations 1

Additional Workup

• Complete blood count to evaluate for underlying anemia or hematologic disorder 4
• Liver function tests to assess for chronic liver disease 4
• Detailed medication and supplement history, specifically querying about nonprescription iron products, as chronic oral iron supplementation can cause secondary hemochromatosis 2
• MRI with quantitative iron assessment or liver biopsy (if liver disease suspected) to confirm tissue iron deposition 4

Critical Pitfalls to Avoid

• Do not dismiss elevated iron saturation in adolescents as juvenile hemochromatosis presents earlier than HFE-related disease and causes rapid iron accumulation 1
• Do not rely on ferritin alone when inflammation or infection is present, as it will be falsely elevated and mask true iron status 1
• Query about all iron sources, including over-the-counter supplements, as geriatric and pediatric patients may take nonprescription iron without medical indication 2
• Recognize that normal transferrin saturation varies by age, increasing throughout childhood and adolescence, but 72% exceeds normal ranges at any pediatric age 1

Management Considerations

• If hereditary hemochromatosis is confirmed, serial phlebotomy remains the most effective treatment for iron overload 2, 3
• If secondary to excessive supplementation, immediately discontinue all iron products 2
• Monitor for end-organ damage including liver function, glucose metabolism (diabetes risk), and cardiac function, as excess iron causes parenchymal tissue injury through free radical-mediated damage 3
• Iron status should be monitored regularly to prevent progression to iron overload complications such as hepatic cirrhosis, diabetes mellitus, and cardiac dysfunction 1, 3