Editing Iron overload (section)

==Pathophysiology==
Defects in iron metabolism, specifically involving the iron regulatory protein [[hepcidin]] are thought to play an integral role in the pathogenesis of hereditary hemochromatosis.<ref name="NEJM Olynyk">{{cite journal |last1=Olynyk |first1=John K. |last2=Ramm |first2=Grant A. |title=Hemochromatosis |journal=New England Journal of Medicine |date=8 December 2022 |volume=387 |issue=23 |pages=2159–70 |doi=10.1056/NEJMra2119758|pmid=36477033 |s2cid=254432917 }}</ref>

Normally, hepcidin acts to reduce iron levels in the body by inhibiting intestinal iron absorption and inhibiting iron mobilization from stores in the [[bone marrow]] and [[liver]].<ref name="NEJM Olynyk" /> Iron is absorbed from the intestines (mostly in the [[duodenum]]) and transported across intestinal [[enterocyte]]s or mobilized out of storage in liver [[hepatocyte]]s or from [[macrophage]]s in the bone marrow by the transmembrane [[ferroportin]] transporter.<ref name="NEJM Olynyk" /> In response to elevated plasma iron levels, hepcidin inhibits the ferroportin transporter leading to decreased iron mobilization from stores and decreased intestinal iron absorption, thus functioning as a negative iron regulatory protein.<ref name="NEJM Olynyk" />

In hereditary hemochromatosis, mutations in the proteins involved in hepcidin production including [[HFE (gene)|HFE (homeostatic iron regulator)]], [[hemojuvelin]] and [[transferrin receptor 2]] lead to a loss or decrease in hepcidin production, which subsequently leads to the loss of the inhibitory signal regulating iron absorption and mobilization and thus leads to iron overload.<ref name="NEJM Olynyk" /> In very rare instances, mutations in ferroportin result in ferroportin resistance to hepcidin's negative regulatory effects, and continued intestinal iron absorption and mobilization despite inhibitory signaling from hepcidin.<ref name="NEJM Olynyk" /> 

The resulting iron overload causes iron to deposit in various sites throughout the body, especially the liver and joints, which coupled with [[oxidative stress]] leads to organ damage or joint damage and the pathological findings seen in hemochromatosis.<ref name="NEJM Olynyk" />