What are the causes of iron overload in the spleen and liver aside from hemochromatosis?

Causes of Iron Overload in Spleen and Liver Beyond Hemochromatosis

Iron overload in the spleen and liver, excluding hemochromatosis, occurs primarily from iron-loading anemias (especially thalassemia major and chronic hemolytic anemias), transfusional iron overload, chronic liver diseases (hepatitis C/B, alcoholic liver disease, NAFLD), and rare genetic disorders affecting non-HFE iron regulatory proteins. 1

Primary Categories of Non-Hemochromatosis Iron Overload

Iron-Loading Anemias (Ineffective Erythropoiesis)

These conditions cause the most severe secondary iron overload due to both increased intestinal absorption and transfusional iron:

• Thalassemia major - the most common cause requiring iron chelation therapy with deferoxamine 1
• Sideroblastic anemia - characterized by abnormal iron utilization in erythropoiesis 1
• Chronic hemolytic anemias including sickle cell disease 1, 2
• Myelodysplastic syndrome and myelofibrosis 2
• Pyruvate kinase deficiency 1, 2
• Aplastic anemia 1

Transfusional and Parenteral Iron Overload

This is always iatrogenic and represents a major cause of organ iron deposition:

• Red blood cell transfusions - each unit contains approximately 200-250 mg of iron 1
• Iron-dextran injections 1
• Long-term hemodialysis 1

Critical distinction: In iron-loading anemias and transfusional overload, iron initially accumulates in the reticuloendothelial system (spleen, bone marrow), then progressively deposits in parenchymal organs (liver, heart, pancreas) as total body iron increases 3. This contrasts with hemochromatosis where parenchymal deposition predominates from the start 1.

Chronic Liver Diseases

These conditions cause secondary iron accumulation through multiple mechanisms:

• Hepatitis C virus infection - causes dysregulated hepcidin and increased iron absorption 1
• Hepatitis B virus infection 1
• Alcoholic liver disease - alcohol increases intestinal iron absorption and causes hepatocellular injury 1
• Non-alcoholic fatty liver disease (NAFLD) - the most common cause of elevated ferritin in outpatients, though typically reflects inflammation rather than true iron overload 4, 2
• Porphyria cutanea tarda - responds to phlebotomy therapy 1
• Following portocaval shunt 1

Important caveat: In NAFLD and metabolic syndrome, elevated ferritin typically reflects hepatocellular injury and insulin resistance rather than actual iron accumulation, with transferrin saturation usually <45% 4, 5. True iron overload in these conditions is less common 1.

Rare Genetic Non-HFE Iron Overload Disorders

These mutations affect other iron regulatory proteins:

• Juvenile hemochromatosis - caused by mutations in hemojuvelin (HJV) gene or hepcidin (HAMP) gene, characterized by rapid iron accumulation in youth 1
• Transferrin receptor-2 (TfR2) mutations - produces severe early-onset iron overload 1
• Ferroportin disease (SLC40A1 mutations) - unique pattern with predominant reticuloendothelial iron loading and increased spleen iron 1
• Aceruloplasminemia - deficiency of ceruloplasmin causing iron accumulation in liver, pancreas, and brain (detectable on MRI) 1
• Congenital atransferrinemia - extremely rare disorder of iron transport 1

Miscellaneous Causes

• Neonatal iron overload - now recognized as gestational alloimmune liver disease caused by transplacental maternal IgG against fetal liver 1, 6
• African iron overload - historically attributed to dietary iron from traditional beer brewing, though genetic factors may contribute 1
• Dysmetabolic iron overload syndrome - associated with metabolic syndrome features 1, 5

Diagnostic Approach to Distinguish Causes

Key Laboratory Pattern Recognition

The transferrin saturation is the critical discriminator 4, 5:

• Transferrin saturation ≥45% with elevated ferritin → suggests true iron overload; proceed with HFE genetic testing 4, 5
• Transferrin saturation <45% with elevated ferritin → suggests inflammatory hyperferritinemia (NAFLD, chronic disease) or ferroportin disease rather than parenchymal iron overload 4, 5

Imaging Patterns on MRI

MRI R2* quantification reveals distinct distribution patterns 1:

• Hemochromatosis and aceruloplasminemia: predominant hepatic iron, minimal or no spleen iron 1
• Ferroportin disease and transfusional overload: increased spleen iron overload 1
• Aceruloplasminemia: brain iron accumulation visible on MRI in addition to liver 1

Liver Biopsy Findings

When biopsy is performed, iron distribution patterns guide diagnosis 1:

• Pure parenchymal (hepatocellular) iron: suggests hemochromatosis or end-stage cirrhosis 1
• Mesenchymal or mixed iron overload: check for associated findings like steatosis (NAFLD), chronic hepatitis (viral), or crystal inclusions 1
• Reticuloendothelial iron predominance: suggests transfusional overload or ferroportin disease 3

Treatment Implications by Cause

Phlebotomy-Responsive Conditions

These can be treated similarly to hemochromatosis 1:

• African iron overload 1
• Porphyria cutanea tarda 1
• Some cases of chronic liver disease with documented iron overload 1

Iron Chelation Required

Deferoxamine (20-40 mg/kg/day) is the treatment of choice for 1:

• Thalassemia major and other transfusion-dependent anemias 1
• Any condition where phlebotomy is contraindicated due to anemia 1

Critical pitfall: Never use ferritin alone without transferrin saturation to diagnose iron overload, as ferritin acts as an acute phase reactant and rises with inflammation independent of actual iron stores 4. This leads to unnecessary investigations and inappropriate phlebotomy in patients with inflammatory conditions like NAFLD 4, 5.