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Hemochromatosis

Biology and Pathophysiology

The body absorbs 10% (1 to 2 mg) of the iron encountered in dietary sources each day, but has no efficient means of rapidly eliminating excess iron, other than loss of blood. Iron absorption is regulated in the GI tract at the initial part of the small intestine called the duodenum, which lies just beyond the stomach in the digestive tract (Murray 2003; Heli 2011; Geissler 2011).

Following absorption, iron is normally bound to specific storage or transport proteins when not in use; this limits the possibility of excess free iron catalyzing generation of damaging free radicals. Iron travels through the bloodstream bound to transferrin (an iron transport protein).

Cells that require iron (e.g., red blood cells) express a transferrin receptor on their surface, which captures circulating transferrin and pulls it into the cell, causing it to release the bound iron.

Iron, in excess of what is needed to satisfy metabolic demand, is stored bound to the iron storage protein ferritin (Geissler 2011; Fisher 2007).

Both ferritin and transferrin are used as blood markers to monitor iron load (see Diagnosis below).

Iron overload results from an elevated total body iron pool. There are primary (inherited) and secondary (acquired) causes of iron overload; many involve dysregulation of iron absorption from the gut. However, iron overload secondary to repeated blood transfusions can occur in patients with certain types of anemia (Pietrangelo 2010; Heli 2011).

Despite its many important metabolic roles, iron is a potent free-radical generator. Damaging reactive oxygen species are constantly produced during cellular energy generation. Antioxidant enzymes (e.g., superoxide dismutase and catalase) normally eliminate these pro-oxidant compounds, sparing cells from oxidative damage. Iron, however, can readily convert these reactive oxygen species into damaging hydroxyl radicals that are not cleared by antioxidant enzymes. Hydroxyl radicals can damage DNA and cellular proteins, as well as decrease the integrity of cellular membranes (Marx 1996; Emerit 2001; Heli 2011). Iron balance (homeostasis) in humans is predominantly controlled by limiting intestinal absorption, as well as efficient recycling of the body pool because virtually no iron is excreted (Heli 2011). Iron is unique among dietary nutrients in that both iron deficiency and iron excess are relatively common health concerns; in fact, iron deficiency or overload is a question of a few milligrams of iron (Heli 2011; Cogswell 2009; Fleming 2001).

Iron balance is regulated by the peptide hormone hepcidin (Pigeon 2001). Hepcidin, produced by the liver in response to high iron stores or inflammation, travels though the blood stream to the intestines where it reduces iron absorption. It is thought both genetic and acquired causes of iron overload may share a common mechanism of low hepcidin production (Siddique 2012).

Normal iron absorption (1-2 mg/day) and dysregulated iron absorption differ by only a few milligrams each day, yet this is sufficient to outpace iron loss - approximately 1 mg/day in adult men - which occurs very slowly through the sloughing of gastrointestinal and skin cells (Heli 2011; Murray 2003).

As the total body iron pool rises, its levels exceed the capacity of iron storage and transport proteins (ferritin and transferrin, respectively) to keep it safely bound (Brissot 2012). Increased levels of non-transferrin bound iron in the blood can enter cells, thus increasing free cellular iron levels. It is this free iron that is available for generating free radicals within cells, and is responsible for the cellular and tissue toxicities characteristic of iron overload (Brissot 2012).