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Causes and Risk Factors

Primary Iron Overload

Primary iron overload results from inherited defects in genes involved in iron absorption, transport, or regulation. Hemochromatosis, the most common disease of primary iron overload, can be partitioned into 4 types. The most common is Classic (Type I) or HFE hemochromatosis. HFE hemochromatosis results from the inheritance of two mutant copies of the HFE or High Fe (iron) gene (C282Y and H63D) (Borgaonkar 2003; Sebastiani 2007). These defective genes are thought to increase iron absorption by lowering production of hepcidin, and increasing iron uptake from intestinal cells.

The other three types of hemochromatosis are much more rare: Type II is a more severe iron overload due to defective production of hepcidin; Type III is a defect in the transferrin receptor (unable to uptake iron from the blood); and Type IV results in defects in the removal of iron from certain cells (liver macrophages). Type IV may also cause the intestines to become insensitive to hepcidin, resulting in uncontrolled iron absorption (Pietrangelo 2010).

Other hereditary iron overload disorders are extremely rare. They include atransferrinemia (lack of the transferrin iron transporter), mutation in the ferritin gene, and neurodegeneration with brain iron accumulation (NBIA) (Pietrangelo 2010; Gregory 2011).

Secondary Iron Overload

Secondary iron overload can result from a variety of conditions, including repeated blood transfusion for treating certain types of anemia (Heli 2011). Additional iron is introduced with each transfusion, and since humans have no mechanism for its excretion, iron overload becomes possible. Iron overload in transfusion patients presents additional treatment challenges, as phlebotomy, the gold standard for iron overload treatment in hereditary hemochromatosis, is usually not feasible in anemic patients (Bring 2008).

Chronic liver disease. Chronic liver disease, caused by, for example, alcoholic fatty liver and the hepatitis C virus, can compromise the liver’s ability to produce the iron regulatory hormone hepcidin and the iron transport protein transferrin (Siddique 2012; Brissot 2012).

Other sources of secondary iron overload include excessive dietary intake, parenteral iron (such as intravenous iron for anemia management), and long-term hemodialysis (Pietrangelo 2010; Muñoz 2011).