Is a high iron level always related to hemochromatosis (hereditary iron overload disorder)?

High Iron Levels Are Not Always Related to Hemochromatosis

High iron levels are not always related to hemochromatosis, as there are multiple causes of elevated iron parameters that are unrelated to hereditary iron overload disorders. 1

Causes of Elevated Iron Levels

Hereditary Causes

• Hereditary hemochromatosis (HH) is one important cause of iron overload, with several genetic variants:
  • HFE-related (C282Y/C282Y homozygosity, C282Y/H63D compound heterozygosity) 1
  • Non-HFE related variants (mutations in hemojuvelin, transferrin receptor-2, ferroportin, or hepcidin genes) 1
• Only approximately 70% of C282Y homozygotes (the most common genetic variant) demonstrate elevated ferritin levels, indicating incomplete penetrance of the genetic mutation 1

Secondary Causes of Iron Overload

• Iron-loading anemias (thalassemia major, sideroblastic anemia, chronic hemolytic anemia) 1
• Parenteral iron overload (blood transfusions, iron-dextran injections, long-term hemodialysis) 1
• Chronic liver diseases:
  • Alcoholic liver disease
  • Nonalcoholic fatty liver disease (NAFLD)
  • Viral hepatitis (B and C)
  • Porphyria cutanea tarda 1, 2
• Dysmetabolic iron overload syndrome (associated with metabolic syndrome) 1, 2
• Inflammatory conditions (can cause elevated ferritin without true iron overload) 1

Diagnostic Considerations

Iron Parameters and Their Interpretation

• Transferrin saturation (TS) and serum ferritin are the primary screening tests for iron overload 1
• Important distinctions:
  • TS ≥45% with elevated ferritin suggests possible hemochromatosis 1
  • Elevated ferritin with normal TS often indicates secondary causes of hyperferritinemia rather than hemochromatosis 2
  • Inflammatory conditions can cause elevated ferritin without true iron overload 1

Diagnostic Algorithm

• For patients with elevated iron markers:
  • If both TS ≥45% and ferritin are elevated: Consider HFE genetic testing 1
  • If only ferritin is elevated with normal TS: Consider secondary causes of hyperferritinemia 2
  • If ferritin >1000 μg/L with elevated liver enzymes: Higher risk of cirrhosis in true hemochromatosis 1

Clinical Implications

• Most individuals with genetic susceptibility to hemochromatosis (C282Y homozygotes) never develop clinical disease 1
• Full phenotypic expression occurs in only approximately 70% of C282Y homozygotes 1
• Fewer than 10% develop end-organ manifestations like cirrhosis, diabetes, and skin pigmentation 1
• Elevated ferritin with normal transferrin saturation should prompt investigation for other causes besides hemochromatosis 2

Common Pitfalls to Avoid

• Assuming all elevated iron parameters indicate hemochromatosis 2
• Failing to distinguish between genetic susceptibility and clinical disease expression 1
• Overlooking secondary causes of hyperferritinemia, especially in patients with normal transferrin saturation 2
• Initiating aggressive phlebotomy without confirming the diagnosis, which can lead to iron deficiency 3
• Neglecting to evaluate for liver disease, which is a common cause of non-hemochromatosis hyperferritinemia 1