What are the causes of secondary hemochromatosis in patients with conditions such as thalassemia major, sickle cell disease, or other chronic anemias?

Causes of Secondary Hemochromatosis

Secondary hemochromatosis results from iron accumulation due to increased exogenous iron administration (transfusions or dietary sources) or increased intestinal absorption in the setting of chronic liver disease and ineffective erythropoiesis, rather than from primary genetic defects in iron regulatory proteins. 1, 2

Iron-Loading Anemias (Most Severe Form)

Transfusion-dependent anemias cause the most severe secondary iron overload through two mechanisms: 1, 2

• Thalassemia major leads to iron overload from both chronic transfusions and increased intestinal iron absorption due to ineffective erythropoiesis 1, 2, 3
• Sickle cell disease causes iron accumulation primarily through repeated transfusions 1, 2
• Sideroblastic anemia increases intestinal iron absorption due to ineffective erythropoiesis 1
• Chronic hemolytic anemias contribute through both mechanisms 1, 2
• Myelodysplastic syndromes represent the most common cause in elderly patients in developed countries, requiring long-term transfusion support 3

Each unit of packed red blood cells contains 200-250 mg of elemental iron that accumulates progressively since the body has no active iron excretion mechanism. 1, 2

Chronic Liver Diseases

Multiple chronic liver conditions cause secondary iron overload through dysregulated hepcidin production and increased intestinal iron absorption: 4, 2

• Hepatitis C virus infection causes dysregulated hepcidin synthesis, leading to increased iron absorption 2
• Hepatitis B virus infection similarly disrupts iron homeostasis 1, 2
• Alcoholic liver disease increases intestinal iron absorption and causes hepatocellular injury 2
• Non-alcoholic fatty liver disease (NAFLD) is associated with mild iron overload 1, 4
• Porphyria cutanea tarda increases gastrointestinal iron absorption 1

The iron deposition pattern differs from hereditary hemochromatosis: secondary iron overload shows mild (1+ to 2+) iron deposits in both Kupffer cells and hepatocytes in a panlobular distribution, whereas hereditary hemochromatosis shows predominantly periportal hepatocyte iron deposition. 4

Iatrogenic and Dietary Causes

Excessive exogenous iron administration represents a preventable cause: 1

• Chronic intravenous iron therapy in dialysis patients creates dose-dependent iron overload risk, with recent hepatic MRI studies showing strong correlation between cumulative IV iron dose and hemosiderosis 1
• African iron overload results from high dietary iron intake from traditional beers fermented in steel drums, though genetic predisposition likely contributes 1
• Chronic blood transfusions for any indication accumulate iron over time 1

Key Diagnostic Distinction

Transferrin saturation ≥45% distinguishes true iron overload from inflammatory hyperferritinemia, which is critical since many conditions elevate ferritin without actual iron accumulation. 2 MRI R2* quantification reveals distinct distribution patterns: secondary iron overload from transfusions shows iron in both liver and spleen, whereas hereditary hemochromatosis shows predominant hepatic iron with minimal splenic involvement. 2

Clinical Pitfalls to Avoid

Do not assume all elevated ferritin represents iron overload - chronic liver disease, malignancy, infections, kidney failure, and rheumatic conditions cause hyperferritinemia without true iron overload. 5 Always check transferrin saturation to confirm actual iron accumulation before initiating iron removal therapy. 2

In dialysis patients, recent evidence challenges previous assumptions that iron overload became rare in the ESA era - hepatic MRI studies now demonstrate high frequency of iatrogenic iron overload from excessive IV iron administration. 1