Sulaimania Gen Hosp board training center Weekly Journal Club Iron Overload in Human Disease NEJM 2012 Prepared by: Dr. Hadi
Iron overload disorders: β-thalassemia whereas others are Common(e.g., HFE-associated hereditary hemochromatosis ) exceedingly rare. Insidious, causing progressive& sometimes irreversible end-organ injury before clinical symptoms develop. Types Others are very rare.
Iron Metabolism: Erythroid precursors (affecting iron utilization) Hepatocytes (affecting iron storage & endocrine regulation). RES (affecting iron storage / recycling) Duodenal enterocytes (affecting dietary iron absorption) 4 cells determine body Iron content /distribution
Enterocytes: Enterocytes the iron is reduced at the apical membrane& taken into the cell through the divalent metal transporter 1 (DMT1). Iron from enterocytes to plasma occurs through the basolateral transporter ferroportin regulated by hormon Hepcidin only 1 - 3 mg of absorbed iron/ day to offset losses from desquamated cells .. Stored in the form of ferritin n Hepcidin binds to the iron exporter ferroportin &induces its degradation,thus decreasing the transfer of iron from enterocytes to the circulation..
Circulating Iron: Circulating Iron: Trabsferrin-bound iron is the physiological iron available for cells Transferrin-binding capacity > plasma iron concentrations (normal transferrin saturation is 30%), In the form of transferin Cells(RBS,Macrophages, RES) regulate theiriron intake by regulating their TRC1.
RES Macrophages : RES cells: They release 25 mg of iron / day vs 3mgm circulating transferrin-bound iron. i.e > *10 After release from heme, the iron can be stored as ferritin or exported into the circulation. major hepcidin-regulated iron repository. eticuloendothelial cells RES obtain most of their iron from the phagocytosis of senescent RBCs.
Hepatocytes : Hepatocytes : By regulated production of the hormone hepcidin . Iron retention in RES decreases iron turnover as iron retention by duodenal cells reg iron absorption. important site of iron storage in the form of ferritin. Hepcidin is the “hypoferremia hormone” by down-regulating ferroportin - mediated release of iron into the cir. Hepcidin production is regulated by inflammation, iron status, erythropoietic activity, oxygen tension
HFE-associated hereditary hemochromatosis: HFE HH : 10% of white popul carries most prevalent C282Y HFE mutation. Modifying factors: gene polymorphism,enviromental The most common disorder of the hepcidin–ferroportin axis. Pen trance: 2-38% men 1- 10% women. Men present in middle age , female after menapause. Juvenile forms exist.
Management of iron over load: Management : chelation in the iron-loading anemias .. Other divalent metals also absorb through (DMT1), so will be persistently abnormal after phlebotomy. HH: iron removal by phlebotomy in the absence of anemia. ) Phlebotomy perpetuate the underlying low hepcidin state & excess iron absorption. Future trts: Newer chelating agents ,exogenous transferrin /hepcidin,hepcidin analogues, hepcidin signaling agonists.